Compounds with KDM5 inhibitory activity and medical uses thereof

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to a compound represented by the below-described general formula (Z), or a salt thereof, which has KDM5 inhibitory activity, and medical uses thereof. [Background technology]

[0002] Eukaryotic DNA resides in the nucleus as a chromatin structure complexed with histone proteins. Histone proteins are subject to enzymatic modifications such as methylation, acetylation, and phosphorylation, which are known to cause chromatin remodeling and transcriptional alterations. Epigenetic modifications, including histone methylation, reversibly regulate gene expression without altering the nucleotide sequence and play important roles in physiological processes.

[0003] KMD5 is a member of the JARID histone demethylase family, which demethylates the trimethylated lysine residue at position 4 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 C5HC2 zinc finger. The KDM5 family is widely distributed in blood cells and various organs in vivo, and is particularly highly expressed in cancer tissues. Epigenetic abnormalities in cancer cells are involved in cell proliferation and metastasis, and KDM5 inhibitors have been reported to be effective against cancer cells. Epigenetic abnormalities, including histone modifications, have also been reported to be involved in other pathologies, such as neuropsychiatric disorders and metabolic diseases. Therefore, compounds with KDM5 inhibitory activity may be useful for improving such epigenetic abnormalities and preventing or treating these diseases.

[0004] In the art related to the present invention, WO2014139326 reports that compounds represented by general formula (A) are useful as inhibitors of one or more histone dimethyltransferases such as KDM5. General formula (A)

[0005] [ka]

[0006] (In the formula, R 1A Ha-R A , halogen atom, -OR A , -SR A , -N(R ’A )2, -CN; R respectively A are independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R respectively ’A are independent, -R A , -C(O)R A , -CO2R A and; Ring A A teeth

[0007] [ka]

[0008] and; R 2A and R3A independently -R A , halogen atom, -OR A , -SR A , -N(R ’A )2, -CN; R 2’A -R A , -OR A , -SR A , -N(R ’A )2, -C(O)R A , -CO2R A and; X A is -N(R 4A )-, -O-, or -S-; R 4A -R A , -C(O)R A , -CO2R A or -S(O)R; R 5A -R A , -C(O)R A , -CO2R A and; R 6A -R A , halogen atom, -OR A , -SR A , -N(R ’A )2, -CN (group definitions are abbreviated). ) or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, WO2016057924 reports that compounds represented by general formula (B) are useful as inhibitors of one or more histone dimethyltransferases, such as KDM5. General formula (B)

[0010] [ka]

[0011] (In the formula: A B teeth

[0012] [ka]

[0013] is selected from the group consisting of: R 1B is an alkyl, cyclic group, etc.; R 2B is an optionally substituted cyclic group, -OR aA , -C(O)N(R aA )2, or -NR aA R bA and; R aB and R bB are each independently selected from H, optionally substituted alkyl groups, and optionally substituted cyclic groups, and the like; R 3B is H or alkyl; R 4B is H, alkyl or a cyclic group; R 5B is H, halo, alkyl, R 6B is H, alkyl, cyclic group; or R 5B and R 6B are taken together to form a cyclic group (the definition of the group is excerpted). ) or a salt thereof.

[0014] However, none of the background art discloses the compounds described below in the present invention, or salts thereof, or pharmaceutical uses thereof. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. 2014 / 139326 Brochure [Patent Document 2] International Publication No. 2016 / 057924 Brochure Summary of the Invention [Problem to be solved by the invention]

[0016] For example, compounds having inhibitory activity against KDM5 are desired for the treatment and suppression of cancer, Huntington's disease, Alzheimer's disease, and the like. [Means for solving the problem]

[0017] The present inventors have conducted extensive research to solve the above problems, and as a result have found that a compound represented by general formula (Z) or a salt thereof solves the above problems. After further investigation, they have completed the present invention.

[0018] That is, the present invention [1] General formula (Z);

[0019] [ka]

[0020] (wherein ring represents a 3-10 membered monocyclic or bicyclic heterocycle containing 1-4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom, optionally substituted with 1-3 substituents selected from C1-4 alkyl, C1-4 haloalkyl, a halogen atom, oxo or a 5- or 6-membered monocyclic carbocyclic ring; The multiple substituents may be the same or different; A is R 1 or R 1-1 -L 1 - represents; B is R 2 or R 2-1 -L 2 - represents; R 1 is a hydrogen atom, C1-4 alkyl, nitrile, halogen atom, carbamoyl, C1-4 alkylaminocarbonyl, C1-4 dialkylaminocarbonyl, 1 to 4 R 4 or 5-isopropyl-1H-pyrazole-3-carbonyl; R 4represents a 5- or 6-membered monocyclic heterocycle optionally substituted with C1-4 alkyl, C2-6 acyl, or 1 to 4 C1-4 alkyl; R 2 represents a hydrogen atom or C1-4 alkyl; R 3 is a hydrogen atom, 1 to 3 R 5 C alkyl optionally substituted with 1 to 3 R 6 C1-4 alkoxy optionally substituted with R 7 hydroxy optionally substituted with one or two R 8 an amino group optionally substituted with 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R 5 represents a C1-4 alkyl, a halogen atom, or a 5- or 6-membered monocyclic carbocyclic ring; R 6 represents a C1-4 alkyl, a halogen atom, or a 5- or 6-membered monocyclic carbocyclic ring; R 7 is 1 to 4 R 12 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 13 5- or 6-membered monocyclic heterocycle optionally substituted by, benzyl or 2-(2-tetrahydrofuryl)ethyl; R 8 represents C1-4 alkyl, or 2-(2-tetrahydrofuryl)ethyl; R 9 represents C1-4 alkyl, acetylaminomethyl, acetylaminoethyl, or a 5- or 6-membered monocyclic heterocycle; R 10represents C1-6 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-8 cycloalkyl-C1-4 alkyl, benzyl, a 5- or 6-membered monocyclic carbocycle, a 5- or 6-membered monocyclic heterocycle, acetylaminomethyl, acetylaminoethyl, cyclopropylcarbonylaminoethyl, N-methylcyclopropylcarbonylaminoethyl, tert-butylcarbonylaminoethyl, N-methyl-tert-butylcarbonylaminoethyl, tert-butoxycarbonylaminoethyl, 1-phenylethyl, or 2-hydroxy-1-phenylethyl; R 11 represents C1-4 alkyl or a 5- or 6-membered monocyclic heterocycle; R 12 represents a halogen atom or C1-4 alkyl; R 13 represents C1-4 alkyl; Multiple R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 or R 13 may be the same or different; R 1-1 is 1 to 4 R 5-1 C cycloalkyl optionally substituted with 1 to 4 R 6-1 a 5- or 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 7-1 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R 5-1 represents C1-4 alkyl, C3-8 cycloalkyl, C1-4 haloalkyl, or a halogen atom; R 6-1 is 1 to 4 R 8-1 represents C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl substituted with C1-4 alkyl, C1-4 haloalkyl, or a halogen atom optionally substituted by; R 7-1represents C1-4 alkyl, C3-8 cycloalkyl, C1-4 haloalkyl, or a halogen atom; R 8-1 represents hydroxy, a halogen atom, a nitrile, benzyloxy, or a 5- or 6-membered monocyclic carbocyclic ring; L 1 represents a bond or carbonyl (-C(=O)-); L 2 represents a bond, carbonyl (-C(=O)-), -(CH2)n-NR 9-1 C(=O)- or -C(=O)NR 10-1 - represents; R 9-1 represents a hydrogen atom or C1-4 alkyl; R 10-1 represents a hydrogen atom or C1-4 alkyl; n represents an integer of 0 to 3; R 2-1 is a hydrogen atom, 1 to 4 R 11-1 C alkyl optionally substituted with 1 to 4 R 12-1 C alkoxy optionally substituted with 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 1 to 4 R 15-1 a 5- or 6-membered monocyclic heterocycle optionally substituted with -S(O) m -(C1-4 alkyl); R 11-1 represents hydroxy, a halogen atom, or C3-8 cycloalkyl; R 12-1 represents hydroxy, a halogen atom, or C3-8 cycloalkyl; R 13-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 14-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 15-1is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C3-8 cycloalkyl, a halogen atom, 1 to 4 R 16-1 phenyl, phenoxy, pyridin-2-yl, 1-methylpyrazol-4-yl, or oxo, optionally substituted by R 16-1 represents C1-4 alkyl or C1-4 alkoxy; m represents an integer of 0 to 2; R 5-1 , R 6-1 , R 7-1 , R 8-1 , R 11-1 , R 12-1 , R 13-1 , R 14-1 , R 15-1 , or R 16-1 When substituted with more than one of the following, they may be the same or different; and r represents an integer of 0 to 1.) or a salt thereof;

[0021] [2] The general formula (Z) is the general formula (I);

[0022] [ka]

[0023] (wherein general formula (I) represents the following formula:

[0024] [ka]

[0025] R 51 represents a hydrogen atom or C1-4 alkyl; R 52 represents C1-4 alkyl; R 53 represents a hydrogen atom or C1-4 alkyl; The other symbols are the same as those in the above [1].) the compound according to the above [1], or a salt thereof;

[0026] [3] The general formula (Z) or (I) is general formula (I-1), (I-5) or (I-7);

[0027] [ka]

[0028] (wherein all symbols have the same meanings as defined in [1] or [2] above), or a salt thereof;

[0029] [4] The compound represented by the general formula (I-1-1);

[0030] [ka]

[0031] (In the formula, R 1Y is 1 to 4 R 4 represents an optionally substituted 5- or 6-membered monocyclic heterocycle; R 2Y represents C1-4 alkyl; The other symbols have the same meanings as those described in the above [1] to [3], or a salt thereof;

[0032] [5] The compound (1) 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-phenylazetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (2) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one; (3) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (4) 3-isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (5) 7-(1H-imidazol-5-yl)-3-isopropyl-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.25 equivalents of formate salt; (6) 3-isopropyl-7-(1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (7) N-(2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide; (8) 3-isopropyl-2-methyl-7-(1-(5-methylpyridin-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; or (9) The compound according to any one of the above [1] to [4], which is N-(2-(4-(7-(1H-imidazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide, or a salt thereof;

[0033] [6] The compound represented by the general formula (I-5-1);

[0034] [ka]

[0035] (wherein all symbols have the same meanings as defined in the above [1] or [4]), or a salt thereof;

[0036] [7] The compound (1) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide; or (2) The compound according to any one of the above [1] to [3] and [6], which is 3-isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide, or a salt thereof;

[0037] [8] The compound represented by the general formula (I-7-1);

[0038] [ka]

[0039] (In the formula, R 3Y is 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by The other symbols have the same meanings as those described in the above [1] or [2].) The compound according to any one of [1] to [3] above, or a salt thereof;

[0040] [9] The compound (1) The compound according to any one of the above [1] to [3] and [8], which is 7-isopropyl-8-oxo-6-phenyl-5,8-dihydroimidazo[1,2-b]pyridazine-3-carbonitrile, or a salt thereof;

[0041]

[10] The general formula (Z) is the general formula (II);

[0042] [ka]

[0043] (Wherein, general formula (II) represents the following formula:

[0044] [ka]

[0045] R 3-1 represents a hydrogen atom, a C1-4 alkyl, a C1-4 haloalkyl, or a halogen atom; R 4-1 represents a hydrogen atom, a C1-4 alkyl, or a 5- or 6-membered monocyclic carbocyclic ring; R 17-1 represents a hydrogen atom or C1-4 alkyl; JPEG0007786517000014.jpg1683 shows the α-configuration; JPEG0007786517000015.jpg1785 shows the β-configuration; JPEG0007786517000016.jpg1594 represents the α-configuration, the β-configuration, or a mixture of the α- and β-configurations; The other symbols have the same meanings as those described in the above [1].) the compound according to the above [1], or a salt thereof;

[0046]

[11] The general formula (Z) or (II) is the general formula (II-1), (II-5), (II-8) or (II-12);

[0047] [ka]

[0048] (wherein all symbols have the same meanings as defined in [1] or

[10] above), or a salt thereof;

[0049]

[12] The compound represented by the general formula (II-1-1):

[0050] [ka]

[0051] (In the formula, R 1-1Y represents the following compound:

[0052] [ka]

[0053] In the group, the arrow represents the bond to the carbonyl carbon atom; R 2-1Y is 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 represents a 4- to 15-membered bicyclic carbocyclic ring optionally substituted by The other symbols have the same meanings as those in the above [1]. The compound according to the above [1],

[10] or

[11] , which is a compound represented by the formula:

[0054]

[13] The compound (1) The compound according to the above [1] or

[10] to

[12] , which is N-(1-(5-isopropyl-1H-pyrazole-3-carbonyl)azetidin-3-yl)cyclopropanecarboxamide, or a salt thereof;

[0055]

[14] The compound represented by the general formula (II-5-1):

[0056] [ka]

[0057] (In the formula, R 2-1S is 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 1 to 4 R 15-1 represents an optionally substituted 5- or 6-membered monocyclic heterocycle; The other symbols have the same meanings as those in the above

[10] or

[12] . The compound according to the above [1],

[10] or

[11] , which is a compound represented by the formula:

[0058]

[15] The compound (1) (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (2) (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone; (3) (5-isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (4) (5-isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; or (5) The compound according to [1],

[10] ,

[11] or

[14] , which is [2-(4-fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone, or a salt thereof;

[0059]

[16] The compound represented by the general formula (II-8-1):

[0060] [ka]

[0061] (wherein all symbols have the same meanings as defined in [1] above), the compound according to [1],

[10] or

[11] above, or a salt thereof;

[0062]

[17] The compound (1) The compound according to [1],

[10] ,

[11] or

[16] , which is 1-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-6-oxa-2,7-diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-propan-1-one, or a salt thereof;

[0063]

[18] The compound represented by the general formula (II-12-1):

[0064] [ka]

[0065] (In the formula, R 1-1S is 1 to 4 R 6-1 a 5-membered monocyclic aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom, optionally substituted with R 2-1T is 1 to 4 R 15-1 represents an optionally substituted 5- or 6-membered monocyclic heterocycle; The other symbols have the same meanings as those described in the above

[10] .) The compound according to the above [1],

[10] or

[11] , or a salt thereof;

[0066]

[19] The compound (1) The compound according to [1],

[10] ,

[11] or

[18] , which is (5-isopropyl-1H-pyrazol-3-yl)((1R,5S,6r)-6-(5-methyl-4-phenylisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone, or a salt thereof;

[0067]

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

[0068]

[21] The pharmaceutical composition according to

[20] , which is a KDM5 inhibitor;

[0069]

[22] The pharmaceutical composition according to

[20] or

[21] above, which is an agent for preventing and / or treating a KDM5-related disease;

[0070] [23-1] KDM5-related diseases include hyperproliferative diseases, cancer, stroke, diabetes, liver dysfunction, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, and inflammatory bowel disease. the pharmaceutical composition according to

[22] , which is for treating asthma, allergic diseases, inflammation, neurological diseases, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions associated with T cell activation, CNS disorders, myeloproliferative disorders, Parkinson's disease, Lewy body diseases, frontotemporal lobar degeneration, mild cognitive impairment, cognitive dysfunction, cerebrovascular disorders, schizophrenia, depression, anxiety disorders, bipolar disorders, autism spectrum disorders, attention deficit hyperactivity disorder, learning disabilities, movement disorders, obsessive-compulsive disorders, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disorders, intellectual disabilities, post-traumatic stress disorder, or hepatitis;

[0071] [23-2] The pharmaceutical composition according to

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

[0072]

[24] A prophylactic and / or therapeutic agent for a KDM5-related disease, comprising the compound represented by general formula (Z) according to [1] above or a salt thereof as an active ingredient, 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;

[0073]

[25] A method for preventing and / or treating a KDM5-associated disease, comprising administering to a mammal an effective amount of the compound represented by general formula (Z) according to [1] above or a salt thereof;

[0074]

[26] A compound represented by the general formula (Z) according to [1] above, or a salt thereof, for the prevention and / or treatment of a KDM5-related disease;

[0075]

[27] Use of a compound represented by general formula (Z) according to [1] above or a salt thereof for the manufacture of an agent for the prophylaxis and / or treatment of a KDM5-associated disease; and

[0076]

[28] General formulas (I-1-1), (I-5-1), (I-7-1), (II-1-1), (II-5-1), (II-8-1) and (II-12-1);

[0077] [ka]

[0078] (In the formula, R 1 is a hydrogen atom, C1-4 alkyl, nitrile, halogen atom, carbamoyl, C1-4 alkylaminocarbonyl, C1-4 dialkylaminocarbonyl, 1 to 4 R 4 or 5-isopropyl-1H-pyrazole-3-carbonyl; R 4 represents a 5- or 6-membered monocyclic heterocycle optionally substituted by C1-4 alkyl, C2-6 acyl, or 1 to 4 C1-4 alkyl; R 2 represents a hydrogen atom or C1-4 alkyl; R 3 is a hydrogen atom, 1 to 3 R 5 C alkyl optionally substituted with 1 to 3 R 6 C1-4 alkoxy optionally substituted by R 7 hydroxy optionally substituted with one or two R 8an amino group optionally substituted with 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 represents an optionally substituted 4- to 15-membered bicyclic heterocycle; R 5 represents a C1-4 alkyl, a halogen atom, or a 5- or 6-membered monocyclic carbocyclic ring; R 6 represents a C1-4 alkyl, a halogen atom, or a 5- or 6-membered monocyclic carbocyclic ring; R 7 is 1 to 4 R 12 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 13 5- or 6-membered monocyclic heterocycle optionally substituted by , benzyl, or 2-(2-tetrahydrofuryl)ethyl; R 8 represents C1-4 alkyl, or 2-(2-tetrahydrofuryl)ethyl; R 9 represents C1-4 alkyl, acetylaminomethyl, acetylaminoethyl, or a 5- or 6-membered monocyclic heterocycle; R 10 represents C1-6 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-8 cycloalkyl-C1-4 alkyl, benzyl, a 5- or 6-membered monocyclic carbocycle, a 5- or 6-membered monocyclic heterocycle, acetylaminomethyl, acetylaminoethyl, cyclopropylcarbonylaminoethyl, N-methyl-cyclopropylcarbonylaminoethyl, tert-butylcarbonylaminoethyl, N-methyl-tert-butylcarbonylaminoethyl, tert-butoxycarbonylaminoethyl, 1-phenylethyl, or 2-hydroxy-1-phenylethyl; R 11 represents C1-4 alkyl, or a 5- or 6-membered monocyclic heterocycle; R 12 represents a halogen atom or C1-4 alkyl; R 13 represents C1-4 alkyl; Multiple R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , or R 13 may be the same or different; R 1-1 is 1 to 4 R 5-1 C cycloalkyl optionally substituted with 1 to 4 R 6-1 a 5- or 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 7-1 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R 5-1 represents C1-4 alkyl, C3-8 cycloalkyl, C1-4 haloalkyl, or a halogen atom; R 6-1 is 1 to 4 R 8-1 represents C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl substituted with C1-4 alkyl, C1-4 haloalkyl, or a halogen atom optionally substituted by; R 7-1 represents C1-4 alkyl, C3-8 cycloalkyl, C1-4 haloalkyl, or a halogen atom; R 8-1 represents hydroxy, a halogen atom, a nitrile, benzyloxy, or a 5- or 6-membered monocyclic carbocyclic ring; L 2 represents a bond, carbonyl (-C(=O)-), -(CH2) n -NR 9-1 C(=O)- or -C(=O)NR 10-1 - represents; R 9-1 represents a hydrogen atom or C1-4 alkyl; R 10-1 represents a hydrogen atom or C1-4 alkyl; n represents an integer of 0 to 3; R 2-1 is a hydrogen atom, 1 to 4 R 11-1 C alkyl optionally substituted with 1 to 4 R 12-1C alkoxy optionally substituted with 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 1 to 4 R 15-1 a 5- or 6-membered monocyclic heterocycle optionally substituted with -S(O) m -(C1-4 alkyl); R 11-1 represents hydroxy, a halogen atom, or C3-8 cycloalkyl; R 12-1 represents hydroxy, a halogen atom, or C3-8 cycloalkyl; R 13-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 14-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 15-1 is C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C3-8 cycloalkyl, a halogen atom, 1 to 4 R 16-1 phenyl, phenoxy, pyridin-2-yl, 1-methylpyrazol-4-yl, or oxo, optionally substituted by R 16-1 represents C1-4 alkyl or C1-4 alkoxy; m represents an integer of 0 to 2; Multiple R 5-1 , R 6-1 , R 7-1 , R 8-1 , R 11-1 , R 12-1 , R 13-1 , R 14-1 , R 15-1 , or R 16-1 may be the same or different; R 53 represents a halogen atom or C1-4 alkyl; R 1Y is 1 to 4 R 4 represents an optionally substituted 5- or 6-membered monocyclic heterocycle; R 2Y represents C1-4 alkyl; R 3Y is 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R 3-1 represents a hydrogen atom, a C1-4 alkyl, a C1-4 haloalkyl or a halogen atom; R 4-1 represents a hydrogen atom, a C1-4 alkyl, or a 5- or 6-membered monocyclic carbocyclic ring; R 17-1 represents a hydrogen atom or C1-4 alkyl; JPEG0007786517000024.jpg1371 represents the α-configuration; JPEG0007786517000025.jpg1275 represents the β-configuration; JPEG0007786517000026.jpg1376 represents the α-configuration, β-configuration, or a mixture of the α- and β-configurations; R 1-1Y teeth

[0079] [ka]

[0080] represents; In the group, the arrow indicates the bond to the carbonyl carbon atom; R 2-1Y is 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 represents a 4- to 15-membered bicyclic carbocyclic ring optionally substituted by R 2-1S is 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 1 to 4 R 15-1represents an optionally substituted 5- or 6-membered monocyclic heterocycle; In the formula, R 1-1S is 1 to 4 R 6-1 a 5-membered monocyclic aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen molecule and / or 1 sulfur atom, optionally substituted with R 2-1T is 1 to 4 R 15-1 A compound represented by the general formula: wherein R is an integer of 1 to 6 and R is an integer of 1 to 6, and R is an integer of 1 to 6, or a salt thereof. [Effects of the Invention]

[0081] The compound or salt represented by general formula (Z) disclosed herein (hereinafter collectively referred to as the present compound) has KDM5 inhibitory activity. Therefore, the present compound is effective in treating hyperproliferative diseases, cancer, stroke, diabetes, liver dysfunction, cardiovascular diseases, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, arteriosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic diseases, inflammation, neurological diseases, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, and T-cell activation. The compound can be used as a therapeutic and / or preventative agent for diseases such as pathological immune conditions accompanied by aging, central nervous system diseases, myeloproliferative disorders, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, cognitive dysfunction, 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, or hepatitis. DETAILED DESCRIPTION OF THE INVENTION

[0082] In the present invention, the term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0083] In the present invention, "C1-4 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0084] In the present invention, "C1-6 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, neohexyl, sec-hexyl and tert-hexyl groups.

[0085] In the present invention, "C1-4 alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and isobutoxy groups.

[0086] In the present invention, "C1-4 alkoxy-C1-4 alkyl" includes methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl and butoxybutyl groups.

[0087] In the present invention, "C1-4 haloalkyl" includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl), perfluoro(tert-butyl), and perfluoro(isobutyl) groups.

[0088] In the present invention, "C cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 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 and bicyclo[2.2.2]octyl groups.

[0089] In the present invention, "C3-8 cycloalkyl-C1-4 alkyl" includes, for example, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl and cyclohexylbutyl groups.

[0090] In the present invention, examples of "C3-8 cycloalkyl optionally substituted at C1-4" include 1-methylcyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 1-ethylcyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2,2-dimethylcyclopentyl, 3,3-dimethylcyclopentyl, 1-ethylcyclopentyl, 1-propylcyclopentyl, 1-butylcyclopentyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,2-dimethylcyclopentyl, Cyclohexyl, 3,3-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-butylcyclohexyl, 1-methylcycloheptyl, 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl, 2,2-dimethylcycloheptyl, 3,3-dimethylcycloheptyl, 4,4-dimethylcycloheptyl, 1-ethylcycloheptyl, 1-propylcycloheptyl, 1-butylcycloheptyl, 1-methylcyclooctyl, 2-methylcyclooctyl, 3-methylcyclooctyl, 4-methylcyclooctyl, 5-methylcyclooctyl, 2,2-dimethylcyclooctyl, 3,3-dimethylcyclooctyl, 5,4-dimethylcyclooctyl, 4,5-dimethylcyclooctyl, 1-ethylcyclooctyl, 1-propylcyclooctyl, and 1-butylcyclooctyl groups.

[0091] In the present invention, "C1-4 alkylaminocarbonyl" includes, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, and isobutylaminocarbonyl groups.

[0092] In the present invention, "C1-4 dialkylaminocarbonyl" includes, for example, dimethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, dipropylaminocarbonyl, diisopropylaminocarbonyl, dibutylaminocarbonyl, di-sec-butylaminocarbonyl, di-tert-butylaminocarbonyl and diisobutylaminocarbonyl groups.

[0093] In the present invention, "-S(O) m -(C alkyl)" includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, isobutylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, isobutylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and isobutylsulfonyl groups.

[0094] In the present invention, "C2-6 acyl" includes, for example, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, neopentanoyl, hexanoyl, isohexanoyl, and neohexanoyl.

[0095] In the present invention, the "3- to 8-membered monocyclic carbocyclic ring" includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, and a benzene ring.

[0096] In the present invention, "5- or 6-membered monocyclic carbocyclic ring" includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene and benzene rings.

[0097] In the present invention, the "4- to 15-membered bicyclic carbocyclic ring" includes, for example, bicyclo[1.1.0]butane, bicyclo[1.1.1]pentane, spiro[2.2]pentane, bicyclo[3.1.0]hexane, spiro[2.3]hexane, bicyclo[3.2.0]heptane, indene, dihydroindene, naphthalene, dihydronaphthalene, and tetrahydronaphthalene rings.

[0098] In the present invention, the "4- to 6-membered monocyclic heterocycle" includes, for example, "a 4- to 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and / or 1 sulfur atom".

[0099] In the present invention, examples of the "4- to 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and / or 1 sulfur atom" include azetidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiazin, thiazin Diazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyrazine Examples of the rings include tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiaazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, and dioxole rings.

[0100] In the present invention, the term "5- or 6-membered monocyclic heterocycle" includes, for example, "5- or 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms, and / or 1 sulfur atom."

[0101] In the present invention, examples of the "5- or 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and / or 1 sulfur atom" include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropy ... Dihydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane and dioxole rings.

[0102] In the present invention, the "4- to 15-membered bicyclic heterocycle" includes, for example, a "4- to 15-membered bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms, and / or 1 sulfur atom". In the present invention, the "4- to 15-membered bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms, and / or 1 sulfur atom" includes, for example, indole, benzimidazole, benztriazole, indazole, benzofuran, benzothiophene, benzoxazole, benzoxazine, indoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene, dihydrobenzoxazole, and dihydrobenzoxazine rings.

[0103] In the present invention, the "five-membered monocyclic aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom, and / or 1 sulfur atom" includes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole rings.

[0104] In the present invention, examples of the "3- to 10-membered monocyclic or bicyclic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom" include 3,4-dihydroimidazo[2,1-f][1,2,4]triazine, 3,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine, 4,7-dihydropyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, 3,4-dihydropyrido[3,2-d]pyrimidine, 3,4-dihydropyrido[3,4-d]pyrimidine, 5,8 ... These include roimidazo[1,2-b]pyridazine, azetidine, piperidine, piperazine, pyridine, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 6-oxa-2,7-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, octahydro-1H-pyrrolo[3,2-b]pyridine, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole, and 3-azabicyclo[3.1.0]hexane rings.

[0105] In the present invention, unless otherwise specified, the symbols JPEG0007786517000028.jpg1362 indicates that the molecule is bonded to this side of the paper (i.e., the β-configuration), JPEG0007786517000029.jpg1563 indicates bonding to the other side of the paper (i.e., α-configuration), JPEG0007786517000030.jpg1674 represents an α-configuration, a β-configuration, or a mixture of these in any ratio.

[0106] In the present invention, A is preferably R 1 Examples include:

[0107] In the present invention, A is preferably R 1-1 -L 1 - can also be mentioned.

[0108] In the present invention, B is preferably R 2Examples include:

[0109] In the present invention, B is preferably R 2-1 -L 2 - can also be mentioned.

[0110] In the present invention, R 1 is preferably, for example, a hydrogen atom, nitrile, carbamoyl, or 1 to 4 R 4 and more preferably a hydrogen atom, carbamoyl, or a 5- or 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 4 is a 5- or 6-membered monocyclic heterocycle optionally substituted with

[0111] In the present invention, R 2 A preferred example of the alkyl group is C1-4 alkyl.

[0112] In the present invention, R 3 is preferably, for example, 1 to 3 R 5 C alkyl optionally substituted with 1 to 3 R 6 C1-4 alkoxy optionally substituted with R 7 hydroxy optionally substituted with one or two R 8 an amino group optionally substituted with 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 and more preferably, a 4- to 15-membered bicyclic heterocycle optionally substituted with 1 to 4 R 9 a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 10 a 4- to 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 11 and a 4- to 15-membered bicyclic heterocycle optionally substituted with

[0113] In the present invention, R 1-1 is preferably, for example, 1 to 4 R 6-1and more preferably, for example,

[0114] [ka]

[0115] and; In the group, the arrow indicates the bond to the carbonyl carbon atom; Or 1 to 4 R 6-1 and a 5-membered monocyclic aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom, which may be substituted with

[0116] In the present invention, L 1 A preferred example of the group is a bond.

[0117] In the present invention, L 1 Preferred examples of the alkyl group include carbonyl (-C(=O)-).

[0118] In the present invention, L 2 A preferred example of the group is a bond.

[0119] In the present invention, L 2 Preferred examples of the alkyl group include carbonyl (-C(=O)-).

[0120] In the present invention, L 2 Preferably, -(CH2) n -NR 9-1 C(=O)- is also included.

[0121] In the present invention, n is preferably an integer of 0 to 1, for example, and more preferably 0, for example.

[0122] In the present invention, R 2-1 is preferably, for example, 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 1 to 4 R 15-1 and more preferably, for example, a 5- or 6-membered monocyclic heterocycle optionally substituted with 1 to 4 R 13-1 a 3- to 8-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R 14-1 R is a 4- to 15-membered bicyclic carbocyclic ring optionally substituted with 2-1 is preferably, for example, 1 to 4 R 15-1 and optionally substituted 5- or 6-membered monocyclic heterocycles.

[0123] In the present invention, preferred examples of general formula (Z) include general formula (I):

[0124] [ka]

[0125] (wherein all symbols have the same meanings as above),

[0126] Or general formula (II):

[0127] [ka]

[0128] (wherein all symbols have the same meanings as above).

[0129] In the present invention, preferred examples of general formula (Z) include general formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7):

[0130] [ka]

[0131] (wherein all symbols have the same meanings as above).

[0132] In the present invention, preferred examples of general formula (Z) include general formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11) or (II-12):

[0133] [ka]

[0134] (wherein all symbols have the same meanings as above).

[0135] In the present invention, preferred examples of general formula (Z) include general formula (IA):

[0136] [ka]

[0137] (Ring A in the formula is

[0138] [ka]

[0139] wherein Y1 and Y2 each represent a carbon atom or a nitrogen atom, the dotted line represents a double bond or a single bond, and the other symbols have the same meanings as defined above.

[0140] In the present invention, preferred examples of general formula (Z) or general formula (IA) include general formula (I-1), (I-5) or (I-7):

[0141] [ka]

[0142] (wherein all symbols have the same meanings as above).

[0143] In the present invention, preferred examples of general formula (Z) include general formula (II-A):

[0144] [ka]

[0145] (In the formula, ring 2 represents a saturated heterocycle containing one or two nitrogen atoms selected from piperazine, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 6-oxa-2,7-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, (3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridine, azetidine, piperidine, and (1R,5S,6r)-3-azabicyclo[3.1.0]hexane, which may be substituted; Y3 represents a carbon atom or a nitrogen atom; and the other symbols have the same meanings as defined above.)

[0146] In the present invention, preferred examples of general formula (Z) or general formula (II-A) include general formula (II-1), (II-5), (II-8) or (II-12):

[0147] [ka]

[0148] (wherein all symbols have the same meanings as above).

[0149] In the present invention, preferred examples of general formula (Z) include general formula (I-1-1), (I-5-1), (I-7-1), (II-1-1), (II-5-1), (II-8-1) or (II-12-1):

[0150] [ka]

[0151] (wherein all symbols have the same meanings as above).

[0152] In the present invention, preferred examples of general formula (Z) include general formula (I-1-1):

[0153] [ka]

[0154] (wherein all symbols have the same meanings as above).

[0155] In the present invention, preferred examples of general formula (Z) include general formula (I-5-1):

[0156] [ka]

[0157] (wherein all symbols have the same meanings as above).

[0158] In the present invention, preferred examples of general formula (Z) include general formula (I-7-1):

[0159] [ka]

[0160] (wherein all symbols have the same meanings as above).

[0161] In the present invention, preferred examples of general formula (Z) include general formula (II-1-1):

[0162] [ka]

[0163] (wherein all symbols have the same meanings as above).

[0164] In the present invention, preferred examples of general formula (Z) include general formula (II-5-1):

[0165] [ka]

[0166] (wherein all symbols have the same meanings as above).

[0167] In the present invention, preferred examples of general formula (Z) include general formula (II-8-1):

[0168] [ka]

[0169] (wherein all symbols have the same meanings as above).

[0170] In the present invention, preferred examples of general formula (Z) include general formula (II-12-1):

[0171] [ka]

[0172] (wherein all symbols have the same meanings as above).

[0173] In the present invention, or as an example of general formula (Z), (I), (I-1) or (I-1-1), preferably, for example, (1) 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-phenylazetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (2) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one; (3) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (4) 3-isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (5) 7-(1H-imidazol-5-yl)-3-isopropyl-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.25 equivalents of formate salt; (6) 3-isopropyl-7-(1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one; (7) N-(2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide; (8) 3-isopropyl-2-methyl-7-(1-(5-methylpyridin-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one or (9) N-(2-(4-(7-(1H-imidazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide or a salt thereof.

[0174] In the present invention, or as a compound of general formula (Z), (I), (I-5) or (I-5-1), preferably, for example, (1) 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide; or (2) 3-isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide; or a salt thereof.

[0175] In the present invention, or as a compound of general formula (Z), (I), (I-7) or (I-7-1), preferably, for example, (1) 7-isopropyl-8-oxo-6-phenyl-5,8-dihydroimidazo[1,2-b]pyrimidine-3-carbonitrile; or a salt thereof.

[0176] In the present invention, or as a compound of general formula (Z), (II), (II-1) or (II-1-1), preferably, for example, (1) N-(1-(5-isopropyl-1H-pyrazole-3-carbonyl)azetidin-3-yl)cyclopropanecarboxamide; or a salt thereof.

[0177] In the present invention, or as a compound of general formula (Z), (II), (II-5) or (II-5-1), preferably, for example, (1) (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (2) (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone; (3) (5-isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (4) (5-isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone, or (5) [2-(4-Fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl)]-(5-isopropyl-1H-pyrazol-3-yl)methanone or a salt thereof.

[0178] In the present invention, or as a compound of general formula (Z), (II), (II-8) or (II-8-1), for example, (1) 1-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-6-oxa-2,7-diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-propan-1-one; or a salt thereof.

[0179] In the present invention, or as a compound of general formula (Z), (II), (II-12) or (II-12-1), preferably, for example, (1) (5-isopropyl-1H-pyrazol-3-yl)((1R,5S,6r)-6-(5-methyl-4-phenylisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone; or a salt thereof.

[0180] [Isomers] In the present invention, all isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and the like include both straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, and trans isomers) in double bonds, rings, and fused rings; isomers due to the presence of asymmetric carbons (R and S isomers, α and β isomers, enantiomers, and diastereomers); optically active isomers with optical rotation (D, L, d, and l isomers); polar isomers (highly polar and less polar) obtained by chromatographic separation; equilibrium compounds; rotational isomers; mixtures of these in any proportion; and racemic mixtures are all encompassed in the present invention. Furthermore, all isomers due to tautomerism are also encompassed in the present invention.

[0181] [Salts and solvates] Salts of the compounds represented by general formula (Z) disclosed in the present invention include all pharmaceutically acceptable salts. Pharmaceutically acceptable salts are preferably low-toxicity, water-soluble salts. Suitable salts include, for example, 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., aspartate, glutamate, etc.], etc.).

[0182] Furthermore, the salt also includes quaternary ammonium salts. Quaternary ammonium salts are compounds in which the nitrogen atom of the compound represented by general formula (Z) is R 0 represents a quaternized group, where R 0 The group represents, for example, a C1-8 alkyl group optionally substituted by a phenyl group.

[0183] The compound represented by formula (Z) can be converted into the above salt, N-oxide or solvate by known methods.

[0184] The N-oxide of the compound represented by general formula (Z) refers to a compound in which the nitrogen atom of the compound represented by general formula (Z) is oxidized. Such an N-oxide may also form a salt such as the above-mentioned acid addition salt.

[0185] The compound represented by general formula (Z), its salt, or its N-oxide may form a solvate with, for example, water or an alcoholic solvent (e.g., ethanol, etc.) Preferably, the solvate is low-toxic and water-soluble.

[0186] The compound represented by general formula (Z) 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 (Z) and its salts can be converted into a solvate by a known method.

[0187] The compound represented by general formula (Z) and its salts can form co-crystals with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO 2006 / 007448.

[0188] In the present invention, all references to the compound of the present invention include the compound represented by general formula (Z), a salt thereof, a solvate (e.g., hydrate) thereof, an N-oxide thereof, or a co-crystal thereof, or a solvate (e.g., hydrate) of a salt of the compound represented by general formula (Z), an N-oxide thereof, or a co-crystal thereof.

[0189] That is, in the present invention, the compound represented by general formula (Z) or a salt thereof includes a solvate (for example, a hydrate) of the compound represented by general formula (Z), its N-oxide, or a co-crystal thereof, or a solvate (for example, a hydrate) of a salt of the compound represented by general formula (Z), its N-oxide, or a co-crystal thereof.

[0190] [Prodrug] The prodrug of the compound represented by general formula (Z) refers to a compound that is converted into the compound represented by general formula (Z) in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of the prodrug of the compound represented by general formula (Z) include, when the compound represented by general formula (Z) has an amino group, compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group of the compound represented by general formula (Z) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); and, when the compound represented by general formula (Z) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group of the compound represented by general formula (Z) has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated). Furthermore, the prodrug of the compound represented by general formula (Z) may be one that is converted into the compound represented by general formula (Z) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198 (published in 1990), Hirokawa Shoten. These prodrugs of the compound represented by general formula (Z) can be produced by methods known per se. Furthermore, like the compound represented by general formula (Z), the prodrug of the compound represented by general formula (Z) may form a salt such as the above-mentioned acid addition salt, or may form a solvate with water or an alcoholic solvent (e.g., ethanol).

[0191] [Labeled compound] In the present invention, the compound represented by general formula (Z) or a salt thereof also includes so-called labeled compounds in which some or all of the atoms constituting the compound are substituted with their isotopes. These labeled compounds can be produced by methods known per se. Isotopes used for labeling include, but are not limited to, for example: 2 H, 3 H,13 C. 14 C. 15 N, 16 N, 17 O. 18 O. 35 S, 36 Cl, 77 Br, 125 I and the like can be suitably used.

[0192] [Manufacturing method] [Method of producing the compound of the present invention] Compounds represented by general formula (I) or (II) or salts thereof can be prepared by known methods, such as those shown in Schemes I to XII, methods analogous thereto, methods shown in the Examples, methods analogous thereto, or methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), modified and combined as appropriate, but not limited to, the methods described herein. In each of the following preparation methods, starting compounds may be used in the form of salts. Examples of such salts include those described above as salts of compounds represented by general formula (I) or (II).

[0193] Cross Coupling Cross-coupling is a well-known reaction. For example, the following method can be used: (1) Suzuki-Miyaura coupling (2) Still coupling and (3) Negishi coupling These techniques are described below. (1) Suzuki-Miyaura coupling is a well-known method for creating carbon-carbon bonds using organoboron compounds and aryl halides. For example, Suzuki-Miyaura coupling is performed in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture thereof) with a base (e.g., sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, fluoride, etc.). cesium, barium hydroxide, tetrabutylammonium fluoride, etc.) or their aqueous solutions or mixtures thereof with a catalyst (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos)2PdCl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(tri-tert-butylphosphine)palladium (Pd(tBu)3), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OA) c)2), palladium black, palladium on carbon, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl2(dppf)), diallylpalladium dichloride (PdCl2(allyl)2), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh3)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), etc.) in the presence of ligands (e.g., triphenylphosphine (PPh3), tributylphosphine (PBu3), tricyclohexylphosphine This can be done by reacting at room temperature to 150°C in the presence or absence of (PCy3), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 1,2-bis(diphenylphosphino)ethane (DPPE), (PCy2-dicyclohexylphosphino-2'-6'-diisopropoxybiphenyl (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), etc.

[0194] (2) Stille coupling is a well-known method for creating carbon-carbon bonds using organotin compounds and aryl halides. For example, Stille coupling is performed in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture thereof) with an additive (e.g., tetrabutylammonium fluoride, tetrabutylammonium chloride, cesium fluoride, lithium fluoride, lithium chloride, potassium fluoride, copper chloride, copper bromide, copper iodide, copper oxide, etc.). etc.) or their mixtures with catalysts (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos)2PdCl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(tri-tert-butylphosphine)palladium (Pd(tBu)3), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, palladium on carbon, 1,1'-biphenylphosphine, ...2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)2), tetrakis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), tetrakis(triphenylphosphine)pallad In the presence of ligands such as triphenylphosphine (PPh3), tributylphosphine (PBu3), tricyclohexylphosphine (PCy3), 1,1'-bis(diphenylphosphine ... The reaction can be carried out at room temperature to 150°C in the presence or absence of 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), tri(2-furyl)phosphine (trp), or the like.

[0195] (3) Negishi coupling is a well-known method for creating carbon-carbon bonds using organozinc compounds and aryl halides. For example, in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture thereof), the coupling can be performed using catalysts such as bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos)2PdCl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(tri-tert-butylphosphine)palladium (Pd(tBu)3), bis(triphenylphosphine)palladium dichloride (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl2(dppf)), di ... In the presence of ligands (e.g., triphenylphosphine (PPh3), tributylphosphine (PBu3), etc.), iodophenyl bis(triphenylphosphine)palladium (PhPdI(PPh3)2), iodophenyl bis(triphenylphosphine)palladium (PhPdI(PPh3)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), nickel chloride (NiCl2), nickel(II) bis(acetylacetonate) (Ni(acac)2), etc.), The reaction can be carried out at room temperature to 150°C in the presence or absence of a phosphine-containing amine, such as 2-dicyclohexylphosphino-2'-6'-diisopropoxybiphenyl (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), tri(2-furyl)phosphine (trp), or terpyridine.

[0196] Amidation Amidation is a known reaction, for example, as follows: (1) Reaction via acyl halide (2) Reaction via mixed acid anhydride (3) Reaction using a condensing agent (4) Reaction via ester These techniques are described below. (1) Reactions via acyl halides 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 in a non-solvent at about -20°C to reflux. The resulting acyl halide derivative can be reacted with an amine in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at 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 a basic aqueous solution (e.g., sodium bicarbonate, sodium hydroxide) at about -78°C to 40°C.

[0197] (2) Reactions via mixed acid anhydrides can be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g., pivaloyl chloride), a sulfonyl chloride (e.g., p-toluenesulfonyl chloride, methanesulfonyl chloride, etc.), or a chloroformate (e.g., ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, etc.) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in a non-solvent in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine) at about 0 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, tetrahydrofuran) at about 0 to 40°C.

[0198] (3) The reaction using a condensing agent can be carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (e.g., chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran) or in a non-solvent, in the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline, or dimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence or absence of 1-hydroxybenzothiazole (HOBt), at about 0°C to 40°C.

[0199] (4) The reaction via an ester can be carried out by combining an ester with a large amount of amine in an organic solvent (e.g., benzene, toluene, xylene, etc.) or in a non-solvent at 60°C to 150°C.

[0200] Esters can be readily prepared by treating the corresponding carboxylic acid with a diazoalkane and heating in alcohol with an acid catalyst, an acyl halide and an alcohol, or a mixture of an acid anhydride and an alcohol.

[0201] The reactions described in (1), (2), (3) and (4) can be carried out in an inert atmosphere (e.g., argon, nitrogen) free of water to obtain favorable results.

[0202] Oxidative halogenation reactions The oxidative halogenation reaction is a known reaction, for example, the following method. (1) Oxidative chlorination (2) Oxidative bromination (3) Oxidative iodination These techniques are described below. (1) Oxidative chlorination can be carried out by reacting a chlorinating agent (e.g., N-chlorosuccinimide, N-chlorophthalimide, trichloroisocyanuric acid, etc.) with a solvent (e.g., DMF, DMA, THF, DME, CH3CN, or a mixture thereof) in an inert atmosphere at 0°C to 100°C. (2) Oxidative bromination can be carried out by reacting a brominating reagent (e.g., N-bromosuccinimide, N-bromophthalimide, pyridinium bromide perbromide, bromine, etc.) and a solvent (e.g., DMF, DMA, THF, DME, CH3CN, or a mixture thereof) in an inert atmosphere at 0°C to 80°C. (3) Oxidative iodination can be carried out by reacting an iodinating reagent (e.g., N-iodosuccinimide, N-iodosaccharin, iodine, etc.) and a solvent (e.g., dimethylformamide, dimethylacetamide, tetrahydrofuran, dimethoxyethane, acetonitrile, or a mixture thereof) in an inert atmosphere at −20° C. to 40° C.

[0203] Dehydration halogenation reaction The dehydration halogenation reaction is a known reaction, for example, the following method. (1) Dehydration chlorination (2) Dehydration bromination These techniques are described below. (1) Dehydration chlorination can be carried out using POCl3 in a solvent (e.g., benzene, toluene, xylene, etc.) or in a non-solvent in an inert atmosphere (e.g., nitrogen or argon) at room temperature to 150°C. (2) Dehydrobromination can be carried out using POBr3 in a solvent (e.g., benzene, toluene, xylene, etc.) or in a non-solvent in an inert atmosphere (e.g., nitrogen or argon) at room temperature to 150°C.

[0204] SnAr substitution reaction The SnAr substitution reaction is a well-known reaction, for example, as follows: (1) SnAr substitution reaction using alcohol (2) SnAr substitution reaction using amines These techniques are described below. (1) The SnAr substitution reaction using an alcohol can be carried out by reacting an allyl halide with an alcohol in a solvent (e.g., dioxane, tetrahydrofuran, dimethoxyethane, dimethylformamide, etc., or a mixture thereof) with a base (e.g., sodium hydride, potassium carbonate, potassium tert-butoxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, etc.) at 0°C to 40°C. (2) The SnAr substitution reaction using an amine can be carried out by reacting an allyl halide with an amine in a solvent (e.g., isopropanol, dioxane, tetrahydrofuran, dimethoxyethane, dimethylformamide, etc.) or a mixture thereof with a base (e.g., trimethylamine, diisopropylethylamine, potassium carbonate, tripotassium phosphate, potassium tert-butoxide, etc.) at 80°C to 150°C.

[0205] Imidazotriazinone Cyclization Reaction The imidazotriazinone cyclization reaction is a known reaction, for example, the following method. (1) Reaction via iminochloride (2) Reaction via orthoester (1) The reaction via iminochloride can be carried out by reacting 1-amino-2-imidazolecarboxylic acid with iminochloride using a base (potassium carbonate, sodium methoxide, trimethylamine, etc.) and the catalyst 4-dimethylpyridine (DMAP) in a solvent (e.g., acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethene, etc., or a mixture thereof) at 50°C to 120°C. (2) The reaction via an orthoester can be carried out by reacting 1-amino-2-imidazolecarboxamide with an orthoester in a solvent (e.g., benzene, toluene, xylene, or a mixture thereof) or without a solvent at 80°C to 150°C.

[0206] Deprotection reaction of the amino moiety protecting group The deprotection reaction of the protecting group of the amino moiety can be carried out under suitable conditions for each protecting group. For example, the deprotection reaction of a tert-butoxycarbonyl (Boc) group can be carried out using an acidic reagent (e.g., a dioxane solution of hydrogen chloride, trifluoroacetic acid, or methanesulfonic acid) in a solvent (e.g., dioxane, dichloromethane) at 0°C to 40°C. For example, the deprotection reaction of the benzyloxycarbonyl (Z) group can be carried out by hydrogenation in the presence of a catalyst (e.g., palladium carbon, palladium hydroxide, etc.) in a solvent (e.g., methanol, ethanol, etc.) or a mixed solvent thereof at room temperature to 80°C under a hydrogen atmosphere. The deprotection of amino-protecting groups is known and is described in detail in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

[0207] Deprotection of carboxylic acid protecting groups The deprotection reaction of the carboxylic acid protecting group can be carried out under conditions suitable for each protecting group. For example, the deprotection reaction of a methyl group can be carried out under basic solution conditions (eg, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, etc.) in a solvent (eg, methanol, ethanol, etc.) at room temperature to 80°C. For example, the deprotection reaction of a tert-butyl group can be carried out using an acid (e.g., trifluoroacetic acid, methanesulfonic acid, hydrogen chloride in acetic acid, etc.) in a solvent (e.g., dichloromethane, dioxane, etc.) at room temperature to 40°C. For example, the deprotection reaction of a benzyl group can be carried out by hydrogenation in the presence of a catalyst (e.g., palladium carbon, palladium hydroxide, etc.) in a solvent (e.g., methanol, ethanol, etc.) or a mixed solvent thereof at room temperature to 80°C under a hydrogen atmosphere. The deprotection reaction of a carboxylic acid protecting group is known and is described in detail in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

[0208] Urea-forming reaction The urea-forming reaction can be carried out, for example, by the following method. (1) Reaction via isocyanate (2) Reaction via carbonylation reagent (1) The reaction via an isocyanate can be carried out by reacting an amine with an isocyanate in a solvent (e.g., dichloromethane, acetonitrile, dioxane, etc.) or a mixed solvent thereof at 0°C to room temperature. (2) The reaction via a carbonylation reagent is a two-step reaction that can be carried out using two amines and a carbonylation reagent (e.g., CDI, phosgene, triphosgene, etc.). The first step can be carried out by combining one amine and a carbonylation reagent in a solvent (e.g., DCM, CH3CN, dioxane, etc., or a mixture thereof) under an inert atmosphere at 0°C to room temperature. The second step can be carried out by adding another amine under an inert atmosphere at room temperature to 100°C.

[0209] Protecting groups in Schemes I-XII P in Reactions I-XII 1 represents a protecting group for a carboxylic acid. P 1 includes methyl, ethyl, propyl, tert-butyl, phenyl, benzyl, allyl, and the like. P in Reactions I-XII 2 represents a protecting group for an amino group. P 2include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (MPM), benzyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl (SEM), and the like.

[0210] Metals and halogens in reactions I-XII In reactions I, II, and IV, M is B(OH)2; [ka] represents SnBu3, ZnCl, ZnBr or ZnI. X in Reactions I-IV 1 and X 2 represents Cl, Br or I. In reaction formula IV, X 3 represents Cl, Br, I, O-mesyl, O-tosyl or O-nosyl. Reaction formulas I to V show methods for synthesizing the compounds represented by general formula (I).

[0211] Reaction Scheme I

[0212] [ka]

[0213] R in the compound represented by general formula (I-1) 3 But, OR 7 , NHR 8 or N(R 8 )2, the compound represented by general formula (I-1) can be prepared by the method described in Reaction Scheme I.

[0214] The compound represented by general formula (I-1) can be produced by subjecting a compound represented by general formula (XI) and a compound represented by general formula (XII) to the above-mentioned cross-coupling reaction.

[0215] The compound represented by general formula (XI) can be produced by subjecting the compound represented by general formula (IX) and the compound represented by general formula (X) to the above-mentioned cross-coupling reaction.

[0216] The compound represented by the general formula (IX) can be produced by subjecting the compound represented by the general formula (VIII) to the above-mentioned dehydration halogenation reaction.

[0217] The compound represented by the general formula (VIII) can be produced by subjecting the compound represented by the general formula (VII) to the above-mentioned oxidative halogenation reaction.

[0218] The compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to an imidazotriazinedione cyclization reaction. The imidazotriazinedione cyclization reaction can be carried out at 100°C to 150°C using an alkyl or aryl chloroformate (e.g., ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, etc.) and a solvent (e.g., acetonitrile, DMF, toluene, etc.) or a mixed solvent thereof.

[0219] The compound represented by general formula (VI) can be produced by subjecting the compound represented by general formula (IV) and the compound represented by general formula (V) to the above-mentioned amidation reaction.

[0220] The compound represented by the general formula (IV) can be produced by subjecting the compound represented by the general formula (III) to a hydrazination reaction. Hydrazine can be produced by reacting a base (e.g., BuLi, LDA, LiHMDS, etc.) and O-(diphenylphosphinyl)hydroxylamine in a solvent (e.g., DMF, THF, etc.) or a mixture thereof at 0°C to 25°C under an inert atmosphere.

[0221] Reaction Scheme II

[0222] [ka]

[0223] Alternatively, the compound represented by general formula (I-1) in reaction scheme I can also be prepared by another method shown in reaction scheme II.

[0224] The compound represented by general formula (I-1) can be produced by subjecting a compound represented by general formula (XV) and a compound represented by general formula (X) to the above-mentioned cross-coupling reaction.

[0225] The compound represented by the general formula (XV) can be produced by subjecting the compound represented by the general formula (XIV) to the above-mentioned oxidative halogenation reaction.

[0226] The compound represented by general formula (XIV) can be produced by subjecting the compound represented by general formula (IV) and the compound represented by general formula (XIII) to the above-mentioned imidazotriazinone cyclization reaction.

[0227] Alternatively, the compound represented by general formula (XIV) can be produced by subjecting a compound represented by general formula (XVI) and a compound represented by general formula (XII) to the above-mentioned cross-coupling reaction.

[0228] The compound represented by the general formula (XVI) can be produced by subjecting the compound represented by the general formula (VII) to the above-mentioned dehydration halogenation reaction.

[0229] In addition, the compound represented by general formula (XIV) can be produced by subjecting the compound represented by general formula (VI) and the compound represented by general formula (XVII) to the above-mentioned imidazotriazinone cyclization reaction.

[0230] Reaction Scheme III

[0231] [ka]

[0232] In reaction formula I, R in the compound represented by general formula (I-1) 3 But, OR 7 , NHR 8 or N(R 8 ) 2, the compound represented by general formula (I-1) can be reacted with the compound represented by general formula (I-1) A ), (I-1 B ) or (I-1 C ) can be described as a compound represented by the formula:

[0233] General formula (I-1 A ), (I-1 B ) or (I-1 C The compounds represented by general formula (XI) and the compounds represented by general formulas (XVIII), (XIX) and (XX) can be produced by subjecting the compounds represented by general formula (XI) and (XVIII), (XIX) and (XX) to the above-mentioned SnAr substitution reaction, respectively.

[0234] Reaction Scheme IV

[0235] [ka]

[0236] In reaction formula IV, the compound represented by general formula (I-3) can be produced by subjecting a compound represented by general formula (XXVI) and a compound represented by general formula (X) to a cross-coupling reaction.

[0237] The compound represented by the general formula (XXVI) can be produced by subjecting a compound represented by the general formula (XXV) and a compound represented by the general formula (XXVII) to an alkylation reaction.

[0238] The alkylation reaction can be carried out using an alkylating reagent (e.g., alkyl halide, alkyl mesylate, alkyl tosylate, etc.) and a base (e.g., sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, potassium carbonate, tripotassium phosphate, etc.) in a solvent (e.g., tetrahydrofuran, dimethoxyethane, dioxane, etc.) or a mixed solvent thereof under an inert atmosphere at 0°C to 60°C.

[0239] The compound represented by general formula (XXV) can be produced by subjecting a compound represented by general formula (XXIII) and a compound represented by general formula (XXIV) to a pyrazolopyrimidinone cyclization reaction.

[0240] The pyrazolopyrimidinone cyclization reaction can be carried out by reacting a beta-ketoester and a 3-aminopyrazole derivative with titanium tetrachloride in a solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, dioxane, benzene, toluene, xylene, etc.) or a mixture thereof at 60°C to 120°C under an inert atmosphere.

[0241] The compound represented by general formula (XXIII) can be produced by subjecting a compound represented by general formula (XXI) and a compound represented by general formula (XXII) to a Claisen condensation reaction.

[0242] The Claisen condensation reaction can be carried out by reacting a nucleophilic carbonyl compound (e.g., a ketone, ester, or aldehyde having a hydrogen atom at the α-position) with an ester or acid chloride in a base (e.g., LDA, LiHMDS, sodium hydride, potassium tert-butoxide, trimethylamine, etc.) and a solvent (e.g., dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethoxyethane, etc.) under an inert atmosphere at temperatures between -78°C and room temperature.

[0243] Reaction Equation V

[0244] [ka]

[0245] In reaction formula V, the compound represented by general formula (I-5) can be produced by a pyridinopyridazinone cyclization reaction between the compound represented by general formula (XXVIII) and the compound represented by general formula (XIII).

[0246] The pyridinopyridazinone cyclization reaction can be carried out by reacting an ester of a 3-aminonicotinic acid derivative with an iminochloride using a base (e.g., potassium carbonate, tripotassium phosphate, etc.) in a solvent (e.g., acetonitrile, tetrahydrofuran, dimethylformamide, etc.) or a mixture of these solvents at 50°C to 100°C.

[0247] Representative methods for synthesizing compounds represented by general formula (XXVIII) are described in Chemical and Pharmaceutical Bulletin, vol. 31, #10, pp. 3490-3464, U.S. Patent No. 5,591,742 (1997), or U.S. Application Publication No. 2019 / 194174.

[0248] Reaction formulas VI to XII show the synthesis of compounds represented by general formula (II).

[0249] [ka]

[0250] represents a saturated heterocycle containing two nitrogen atoms (e.g., piperazine, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 6-oxa-2,7-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, (3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridine, etc.).

[0251] [ka]

[0252] represents a saturated heterocycle containing one nitrogen atom and optionally substituted with an amino group (eg, azetidin-3-amine, piperidin-4-amine, etc.).

[0253] [ka]

[0254] represents a saturated heterocycle containing one nitrogen atom and optionally substituted with a carboxyl group (e.g., azetidine-3-carboxylic acid, piperidine-4-carboxylic acid, (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, etc.).

[0255] Reaction Equation VI

[0256] [ka]

[0257] L 1 , L 2 is —C(═O)—, the compounds represented by the general structural formulae (II-3), (II-5), (II-6), (II-9) and (II-10) can be prepared by the reaction of (II A ) can be written as

[0258] General formula (II A The compound represented by formula (XXXII) can be produced by subjecting a compound represented by formula (XXXIII) to the above-mentioned amidation reaction.

[0259] The compound represented by the general formula (XXXII) can be produced by subjecting the compound represented by the general formula (XXXI) to the deprotection reaction of the protecting group of the amino moiety described above.

[0260] The compound represented by general formula (XXXI) can be produced by subjecting the compound represented by general formula (XXIX) and the compound represented by general formula (XXX) to the above-mentioned amidation reaction.

[0261] Reaction Scheme VII

[0262] [ka]

[0263] Alternatively, the general formula (II A The compound represented by formula (XXX) can be produced by subjecting a compound represented by formula (XXXV) to the above-mentioned amidation reaction.

[0264] The compound represented by general formula (XXXV) can be produced by subjecting the compound represented by general formula (XXXIV) to the deprotection reaction of the protecting group of the amino moiety described above.

[0265] The compound represented by general formula (XXXIV) can be produced by subjecting the compound represented by general formula (XXXIII) and the compound represented by general formula (XXIX-1) to the above-mentioned amidation reaction.

[0266] Reaction Equation VIII

[0267] [ka]

[0268] L 1 is -C(=O)- and L 2 is —N(H)C(═O)—, the compounds represented by general formulas (II-1) and (II-2) can be reacted with the following compound in reaction formula VIII: B ) can be written as

[0269] General formula (II BThe compound represented by formula (XXXVIII) can be produced by subjecting a compound represented by formula (XXXIII) to the above-mentioned amidation reaction.

[0270] The compound represented by the general formula (XXXVIII) can be produced by subjecting the compound represented by the general formula (XXXVII) to the deprotection reaction of the protecting group of the amino moiety described above.

[0271] The compound represented by general formula (XXXVII) can be produced by subjecting a compound represented by general formula (XXX) and a compound represented by general formula (XXXVI) to the above-mentioned amidation reaction.

[0272] Reaction Equation IX

[0273] [ka]

[0274] Alternatively, the general formula (II B ) can be produced by subjecting a compound represented by general formula (XXX) and a compound represented by general formula (XLI) to the above-mentioned amidation reaction.

[0275] The compound represented by general formula (XLI) can be produced by subjecting the compound represented by general formula (XL) to the deprotection reaction of the protecting group of the amino moiety described above.

[0276] The compound represented by general formula (XL) can be produced by subjecting the compound represented by general formula (XXXIII) and the compound represented by general formula (XXXIX) to the above-mentioned amidation reaction.

[0277] Reaction Equation X

[0278] [ka]

[0279] L 1 is -C(=O)- and L 2 -C(=O)N(R 10-1 )-, the compounds represented by the general formulae (II-1), (II-2) and (II-12) can be reacted with the compounds represented by the general formulae (II-1), (II-2) and (II-12) in reaction formula X, respectively, as follows: C ) can be written as

[0280] General formula (II C The compound represented by formula (XXXIII) can be produced by subjecting a compound represented by formula (XLV) to the above-mentioned amidation reaction.

[0281] The compound represented by general formula (XLV) can be produced by subjecting the compound represented by general formula (XLIV) to the deprotection reaction of the protecting group of the amino moiety described above.

[0282] The compound represented by general formula (XLIV) can be produced by subjecting the compound represented by general formula (XLIII) and the compound represented by general formula (XLII) to the above-mentioned amidation reaction.

[0283] Reaction Equation XI

[0284] [ka]

[0285] Alternatively, the general formula (II C ) can be produced by subjecting a compound represented by general formula (XLVIII) and a compound represented by general formula (XLVIII) to the above-mentioned amidation reaction.

[0286] The compound represented by the general formula (XLVIII) can be produced by subjecting the compound represented by the general formula (XLVII) to the deprotection reaction of the above-mentioned carboxylic acid protecting group.

[0287] The compound represented by general formula (XLVII) can be produced by subjecting the compound represented by general formula (XXXIII) and the compound represented by general formula (XLVI) to the above-mentioned amidation reaction.

[0288] Reaction Equation XII

[0289] [ka]

[0290] L 1 is -C(=O)- and L 2 is C(═O)N(H)—, the compounds represented by the general formulae (II-3), (II-5), (II-6), (II-8), (II-9) and (II-10) can be reacted with the following compounds in reaction formula XII: D ) or (II E ) can be written as

[0291] General formula (II D The compound represented by general formula (XXXV) and the compound represented by general formula (XLIX) can be produced by subjecting them to the above-mentioned urea-forming reaction.

[0292] The compound represented by general formula (IIE) can be produced by subjecting a compound represented by general formula (XXXV) and a compound represented by general formula (XLIII) to the above-mentioned urea-forming reaction.

[0293] In reaction schemes I to XII, the compounds represented by general formulae (III), (V), (X), (XII), (XIII), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIV), (XXVII), (XXVIII), (XXIX), (XXIX-1), (XXX), (XXXIII), (XXXVI), (XXXIX), (XLII), (XLIII), (XLVI) and (XLIX) are commercially available or can be easily prepared by known methods such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons, 1999).

[0294] In the reactions exemplified herein, heating means such as a water bath, oil bath, sand bath, microwave, etc. may be used.

[0295] In the reactions exemplified herein, solid-phase supported reagents, such as those supported on polymers (such as polystyrene, polyacrylamide, polypropylene, and polyethylene glycol), can be used where appropriate.

[0296] The products obtained by the reactions exemplified herein can be purified by conventional purification methods, such as atmospheric or reduced pressure distillation, chromatography (high performance liquid chromatography, thin layer chromatography, or column chromatography) using silica gel, ion exchange resins, scavenger resins, or magnesium silicate, washing, or recrystallization. Purification can be carried out after each reaction step or after a series of reactions.

[0297] [toxicity] The compounds of the present invention have low toxicity and can therefore be safely used as pharmaceuticals.

[0298] [Application to pharmaceuticals] Since the compounds of the present invention have KDM5 inhibitory activity, they can be used as drugs for preventing and / or treating KDM5-associated diseases in mammals, particularly humans.

[0299] Such diseases include, for example, hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic diseases, inflammation, neurological diseases, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions associated with cell death, thrombin-induced Examples of conditions that may be present include: chronic platelet aggregation, liver disease, pathological immune conditions associated with T cell activation, CNS diseases, myeloproliferative disorders, Parkinson's disease, Lewy body diseases, frontotemporal lobar degeneration, mild cognitive impairment, cognitive disorders, cerebrovascular diseases, schizophrenia, depression, anxiety disorders, bipolar disorder, autism spectrum disorders, 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.

[0300] In particular, the compound 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, cognitive impairment, 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 is particularly suitable for the prevention and / or treatment of cancer and Alzheimer's disease.

[0301] In addition to having potent KDM5 inhibitory activity, this compound has excellent permeability in wild-type MDCK cell lines.

[0302] When the present compound is used as a pharmaceutical, the present compound can be used alone or in combination with an additional active ingredient for the purposes described below, for example, (1) to supplement and / or enhance the effects of the present compound for the prevention, treatment, and / or amelioration of symptoms, (2) to improve kinetics and absorption, to reduce the dosage of the present compound, and / or (3) to reduce side effects.

[0303] 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 5HT 1A 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.

[0304] Further examples of such other therapeutic agents include calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins), and lipid-lowering agents, 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 (epidermal growth factor receptor) inhibitors, FP RL-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 treat neuroinflammation by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and / or antibodies, drugs that promote or enhance amyloid excretion and / or clearance, histone deacetylase (HDAC) inhibitors, EP2 antagonists, 11-beta HSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimetics and / or ligands and / or activators and / or inhibitors, butyrylcholinesterase inhibitors, kynuric acid antagonists and / or kynurenine aminotransferase (KAT) inhibitors, orphanin FQ / nociceptin (NOP) / opioid-like receptor 1 (ORL1) inhibitors, excitatory amino acid transporter (EAAT) ligands (activators or inhibitors), and plasminogen activator inhibitor-1 (PAI-1) inhibitors, niacin and / or GPR109 agonists or PAMs in combination with cholesterol-lowering agents and / or HMGCoA reductase inhibitors (statins), dimebolins or similar agents, antihistamines, metal binding / chelating agents, antibiotics, growth hormone secretagogues, cholesterol-lowering agents, vitamin E, cholesterol absorption inhibitors, cholesterol efflux promoters and / or activators, and insulin secretagogues.

[0305] The present compound may be combined 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.

[0306] The combination of the compound of the present invention and these other drugs may be administered in the form of a combination drug in which both components are combined in a single preparation, or may be administered as separate preparations via the same or different administration routes. When separate preparations are administered, they do not necessarily have to be administered simultaneously, and a time lag may be set between the administrations as needed. When a time lag is set between the administrations, there are no particular limitations on the order of administration, and the order may be adjusted appropriately so as to obtain the desired pharmacological effect.

[0307] The dosage of these other drugs used in combination with the compound of the present invention can be increased or decreased as appropriate based on the clinically used dosage of the drug or similar drug. The compounding ratio of the compound of the present invention to the other drug can be adjusted as appropriate, taking into consideration the age and weight of the subject, the administration method and time, the target disease, symptoms, etc. Generally, the other drug can be combined in a range of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention. Multiple other drugs may be used. In addition to the drugs listed above, the other drugs may also be drugs with the same mechanism of action. Such drugs include not only those discovered to date but also those to be discovered in the future.

[0308] The dosage of the compound of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually administered orally in a range of 0.1 mg to 300 mg per dose per adult once to several times a day, or parenterally in a range of 0.1 mg to 150 mg per dose per adult once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.

[0309] Of course, as mentioned above, the dosage varies depending on various conditions, so that in some cases a smaller dosage than the above-mentioned dosage is sufficient, and in other cases it is necessary to administer a dosage exceeding the range.

[0310] To use the compound of the present invention as a single agent or as a combination agent in combination with other drugs for the prevention and / or treatment of the above-mentioned diseases, the active ingredient is typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in pharmaceutical formulations. A pharmaceutically acceptable carrier is preferably one that exhibits no pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those described in "Dictionary of Pharmaceutical Additives," published by Yakuji Nipposha in 2000 (edited by the Japan Pharmaceutical Additives Association) can be appropriately selected depending on the purpose.

[0311] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, mouthwashes, etc.), injectable preparations (e.g., injectables, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external application, liquid preparations for external application, sprays, ointments, creams, gels, patches, etc.).

[0312] [Oral administration formulation] Oral formulations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral formulations include rapidly disintegrating formulations, in which the release of the active ingredient from the formulation is not specifically controlled, and modified-release formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is specifically controlled by a specific formulation design and manufacturing method. Enteric-coated formulations are designed to release the active ingredient primarily in the small intestine rather than in the stomach, for purposes such as preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach. These formulations are typically prepared 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 controlled for purposes such as reducing the frequency of administration or reducing side effects. These formulations are typically prepared by using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as a sugar, sugar alcohol, or polymer compound for the purpose of facilitating administration or preventing decomposition of the active ingredient.

[0313] (1) Tablets Tablets are solid preparations having a certain shape that are administered orally, and include those generally called tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and dry-coated tablets, as well as oral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. When plain tablets are manufactured, the following method (a), (b), or (c) is usually used: (a) Add excipients, binders, disintegrants, and other additives to the active ingredient and mix until homogeneous, then granulate using water or a solution containing a binder in an appropriate manner, add lubricants, mix, and compress; (b) The active ingredient is mixed with additives such as excipients, binders, disintegrants, etc. to form a homogeneous mixture, which is then directly compressed and molded, or the active ingredient and lubricants are added to granules prepared in advance with additives, mixed together to form a homogeneous mixture, and then compressed and molded; (c) The active ingredient is mixed with additives such as excipients and binders to make it homogeneous, and the mixture is moistened with a solvent and poured into a mold to form the mixture, after which it is dried in an appropriate manner; are used. Film-coated tablets can usually be produced by coating a plain tablet with a thin coating of an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating a plain tablet with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be produced by stacking powder particles of different compositions in layers using an appropriate method and compressing them. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using known appropriate methods. Orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of excipients, and can be produced in accordance with the above-mentioned tablet production methods. Furthermore, an intraorally rapidly disintegrating tablet is a tablet that can be taken by quickly dissolving or disintegrating in the mouth; a chewable tablet is a tablet that is taken by chewing; an effervescent tablet is a tablet that dissolves or disperses while rapidly effervescent in water; a dispersible tablet is a tablet that is taken by dispersing in water; and a dissolving tablet is a tablet that is taken by dissolving in water. Effervescent tablets can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

[0314] (2) Capsules Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be produced by blending the active ingredient with additives such as excipients to form a homogeneous mixture, or by forming it into granules or molded products using an appropriate method, and then filling the mixture directly into a capsule or by lightly molding it. Soft capsules can be produced by encapsulating the active ingredient with additives and molding it into a specific shape using an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, etc. Capsules can also be made into enteric-coated capsules or sustained-release capsules using appropriate known techniques, and coloring agents, preservatives, etc. can also be added to the capsule base.

[0315] (3) Granules Granules are preparations that have been granulated into granules, and include not only those generally called granules but also effervescent granules. When manufacturing granules, the following methods (a), (b), or (c) are usually used: (a) The powdered active ingredient is mixed with an excipient, binder, disintegrant, or other additive to form a homogeneous mixture, and then granulated by a suitable method; (b) Add excipients and other additives to the pre-granulated active ingredient and mix until homogeneous; (c) Add excipients and other additives to the active ingredient that has been prepared in advance into granules, mix them, and form them into granules by an appropriate method; Granules can be coated as needed, and can also be made into enteric coated granules or sustained-release granules using known appropriate methods. Effervescent granules can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that dissolve or disperse in water while rapidly effervescent. Granules can also be made into fine granules by adjusting the particle size.

[0316] (4) Powder Powders are powdered preparations, and can usually be produced by adding excipients or other additives to the active ingredient, mixing them together, and making them homogeneous.

[0317] (5) Oral liquid Oral liquids are liquid or fluid, viscous gel-like preparations, and include not only those commonly referred to as oral liquids but also elixirs, suspensions, emulsions, lemonades, etc. Oral liquids are typically prepared by adding additives and purified water to the active ingredient, mixing to form a homogeneous solution, or emulsifying or suspending the mixture, and then filtering as necessary. Elixirs are clear, liquid oral liquids containing sweet and aromatic ethanol, typically prepared by dissolving a solid active ingredient or its extract in ethanol, purified water, flavoring agents, and sucrose, other sugars, or sweeteners, and then filtering or otherwise preparing a clear liquid. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended, typically prepared by adding suspending agents or other additives and purified water or oil to the solid active ingredient, suspending the mixture in an appropriate manner, and homogenizing the entire mixture. An emulsion is an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it in an appropriate manner, and making the whole homogeneous. Meanwhile, a lemonade is a clear, liquid oral preparation with a sweet and sour taste.

[0318] (6) Syrup Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup preparations. Syrups are typically prepared by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying the mixture, boiling the mixture as needed, and then filtering it while hot. Syrup preparations are granular or powder preparations that become syrups upon addition of water, and are sometimes referred to as dry syrups. Syrup preparations typically use sugars or sweeteners as additives and can be prepared in accordance with the manufacturing methods for the granules or powders described above.

[0319] (7) Oral jelly Oral jellies are non-flowable, molded gel-like preparations, and can usually be produced by mixing the active ingredient with additives and a polymer gel base, gelling it using an appropriate method, and molding it into a specific shape.

[0320] [Oral preparations] (1) Oral tablets Oral tablets are solid preparations of a specific shape that are applied to the oral cavity, and include troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc. Oral tablets can usually be manufactured in accordance with the manufacturing methods for tablets described above. Note that a troche is an oral tablet that gradually dissolves or disintegrates in the oral cavity and is applied locally to the oral cavity, pharynx, etc.; a sublingual tablet is an oral tablet that rapidly dissolves the active ingredient under the tongue and is absorbed through the oral mucosa; a buccal tablet is an oral tablet that gradually dissolves the active ingredient between the molar and cheek and is absorbed through the oral mucosa; an adhesive tablet is an oral tablet that is used by adhering to the oral mucosa; and a gum is an oral tablet that releases the active ingredient by chewing.

[0321] (2) Oral spray Oral sprays are preparations in which the active ingredient is sprayed as a mist, powder, foam, paste, or the like. They can usually be produced by dissolving or suspending the active ingredient and additives in a solvent or the like, filtering if necessary, and then filling a container with liquefied gas or compressed gas, or by preparing a solution or suspension using the active ingredient and additives, filling the container with the solution, and then attaching a spray pump.

[0322] (3) Oral semi-solid preparation Oral semisolid preparations are preparations applied to the oral mucosa and include creams, gels, ointments, etc. Oral semisolid preparations can typically be prepared by emulsifying the active ingredient and additives in purified water and an oily component such as petrolatum, or by blending the active ingredient and additives in a polymer gel or oil base to form a homogeneous mixture. Creams refer to semisolid preparations emulsified as oil-in-water or water-in-oil, and lipophilic preparations emulsified as water-in-oil are sometimes called oily creams. Creams are typically prepared by forming an oil phase using petrolatum, higher alcohol, etc., either directly or with the addition of an emulsifier or other additive, and separately forming an aqueous phase using purified water, either directly or with the addition of an emulsifier or other additive, adding the active ingredient to either phase, heating each, and emulsifying the oil and aqueous phases together until homogeneous. Gels refer to gel-like preparations and include aqueous gels, oily gels, etc. Aqueous gels can be produced by dissolving or suspending the active ingredient in purified water with a polymer compound, other additives, and the like, followed by heating and cooling or by adding a gelling agent to cause crosslinking. Oily gels can be produced by adding a liquid oily base, such as glycols or higher alcohols, and other additives to the active ingredient and mixing them together. Ointments refer to semi-solid preparations in which the active ingredient is dissolved or dispersed in a base, and include oleaginous ointments, water-soluble ointments, and the like. Oleaginous ointments are typically produced by heating and melting an oleaginous base, such as fats and oils, waxes, or hydrocarbons such as paraffin, adding the active ingredient, mixing to dissolve or disperse the active ingredient, and then mixing and kneading until the mixture is homogeneous. Water-soluble ointments can typically be produced by heating and melting a water-soluble base, such as macrogol, adding the active ingredient, and mixing and kneading until the mixture is homogeneous.

[0323] (4) Mouthwash Mouthwashes are liquid preparations to be applied locally to the oral cavity, pharynx, etc., and also include solid preparations that are dissolved before use. Mouthwashes can usually be produced by adding a solvent and additives to the active ingredient, mixing them to dissolve homogeneously, and filtering as necessary. Solid preparations that are dissolved before use can usually be produced in accordance with the production methods for the above-mentioned tablets or granules.

[0324] [Injectable preparation] (1) Injectable Injections are solutions, suspensions, emulsions, or solid sterile preparations that are administered subcutaneously, intramuscularly, or directly into body tissues or organs such as blood vessels, and are dissolved or suspended just before use. In addition to what is generally called an injection, these include freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusions, implanted injections, and sustained-release injections. When manufacturing injections, the following method (a) or (b) is usually used: (a) The active ingredient, either as is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as it is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filtered aseptically, or the homogeneous solution is prepared aseptically and filled into a container for injection and sealed; Freeze-dried injectables are typically prepared by dissolving the active ingredient directly or with additives such as excipients in water for injection, sterile filtering, and filling into an injectable container followed by freeze-drying, or by freeze-drying in a dedicated container and then filling directly into a container. Powdered injectables are typically prepared by sterile filtering, followed by crystallization of the powder, or by adding sterilized additives to the powder, and then filling into an injectable container. Prefilled syringes are typically prepared by filling the syringe with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Cartridges are injectables that are inserted into dedicated syringes and used with a drug solution. Cartridges filled with drug solutions are typically prepared by filling the cartridge with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Infusion solutions are injectables typically 100 mL or more that are administered intravenously. An implantable injection refers to a solid or gel-like injection that is administered subcutaneously, intramuscularly, etc. using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. An implantable injection can usually be produced by using a biodegradable polymer compound and forming it into pellets, microspheres, or a gel. A sustained-release injection refers to an injection that is administered intramuscularly, etc., with the aim of releasing the active ingredient over a long period of time, and can usually be produced by dissolving or suspending the active ingredient in vegetable oil, etc., or by forming it into a suspension of microspheres using a biodegradable polymer compound.

[0325] [Dialysis preparations] (1) Dialysis agents Dialysis agents are liquid or solid preparations that dissolve before use and are used for peritoneal dialysis or hemodialysis, and include peritoneal dialysis agents and hemodialysis agents. Peritoneal dialysis agents refer to sterile dialysis agents used for peritoneal dialysis, and can typically be produced by adding additives to the active ingredient and dissolving them in a solvent to a fixed volume, or by filling a container with the active ingredient and additives added, sealing the container, and optionally sterilizing it. Solid preparations that dissolve before use can typically be produced in a manner similar to the production methods for tablets or granules, etc. described above. Hemodialysis agents refer to dialysis agents used in hemodialysis, and can typically be produced by adding additives to the active ingredient and dissolving them in a solvent to a fixed volume, or by filling a container with the active ingredient and additives added. Solid preparations that dissolve before use can typically be produced in a manner similar to the production methods for tablets or granules, etc. described above.

[0326] [Inhalation preparations] (1) Inhalants Inhalants are formulations in which the active ingredient is inhaled as an aerosol and administered to the bronchi or lungs, and include powder inhalants, inhalation solutions, and inhalation aerosols. Powder inhalants are formulations inhaled as a solid particle aerosol, prepared to provide a consistent inhaled dose. They are typically prepared by forming the active ingredient into fine particles and blending them with additives such as lactose, if necessary, to form a homogeneous solution. Inhalation solutions are liquid inhalants administered using a nebulizer or other device. They are typically prepared by adding a solvent and appropriate isotonicity agents, pH adjusters, etc. to the active ingredient, blending them to form a homogeneous solution or suspension, and filtering, if necessary. Inhalation aerosols are metered-dose inhalants that spray a consistent amount of the active ingredient together with a propellant filled into a container. Inhalation aerosols are typically prepared by adding a solvent and appropriate dispersants, stabilizers, etc. to the active ingredient to form a solution or suspension, filling a pressure-resistant container with the liquid propellant, and attaching a metering valve.

[0327] [Ophthalmic preparations] (1) Eye drops Eye drops are sterile liquid or solid preparations that are applied to ocular tissues such as the conjunctival sac and are dissolved or suspended immediately before use. Eye drops are usually produced by adding additives to the active ingredient and dissolving or suspending it in a solvent or the like to a fixed volume, or by filling a container with the active ingredient and additives.

[0328] (2) Eye ointment Eye ointments are semi-solid sterile preparations to be applied to ocular tissues such as the conjunctival sac, and can usually be produced by mixing a base such as petrolatum with a solution or fine powder of the active ingredient to make it homogeneous, and then filling it into a container.

[0329] [Otalologic preparations] (1) Ear drops Ear drops are liquid, semi-solid, or solid preparations that are administered to the outer or middle ear and are dissolved or suspended immediately before use. Ear drops are typically produced by adding additives to the active ingredient and dissolving or suspending it in a solvent or the like to a fixed volume, or by filling a container with the active ingredient and additives.

[0330] [Nasal preparations] (1) Nasal drops Nasal drops are preparations administered to the nasal cavity or nasal mucosa, and include nasal powders, nasal liquids, etc. Nasal powders refer to finely powdered nasal drops administered to the nasal cavity and can usually be produced by grinding the active ingredient into appropriately fine particles and mixing with additives as needed to make it homogeneous. Nasal liquids refer to liquid nasal drops administered to the nasal cavity, or solid nasal drops that are dissolved or suspended before use. They can usually be produced by adding a solvent and additives to the active ingredient, dissolving or suspending it, and filtering it as needed. Additives that can be used for nasal liquids include isotonic agents and pH adjusters.

[0331] [Rectal preparation] (1) Suppositories Suppositories are semi-solid preparations of a specific shape that are applied rectally and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Suppositories are typically manufactured by mixing the active ingredient with additives such as dispersants and emulsifiers to form a homogeneous mixture, dissolving or dispersing the mixture in a liquefied base by heating, filling a specified amount into a container, and solidifying / molding the mixture. Suppository bases are typically oily or hydrophilic.

[0332] (2) Semisolid rectal preparation Semisolid rectal preparations are preparations to be applied around or inside the anus, and include rectal creams, rectal gels, rectal ointments, etc. Rectal semisolid preparations can typically be prepared by emulsifying the active ingredient and additives in purified water and an oily component such as petrolatum, or by blending the active ingredient and additives into a homogeneous mixture using a polymer gel or oil as a base. Rectal creams are typically prepared by forming an oil phase using petrolatum, a higher alcohol, etc., either directly or with the addition of an emulsifier or other additive, and separately forming an aqueous phase using purified water, either directly or with the addition of an emulsifier or other additive. The active ingredient is added to either of these phases, heating each, and emulsifying the combined oil and aqueous phases by stirring until homogeneous. Rectal gels refer to gel-like preparations and include aqueous gels, oily gels, etc. Aqueous gels can be prepared by dissolving or suspending the active ingredient in purified water with a polymer compound, other additives, and purified water, followed by heating and cooling or the addition of a gelling agent to crosslink the resulting mixture. Oily gels can be produced by adding and mixing an active ingredient with a liquid oily base such as glycols or higher alcohols and other additives. Rectal ointments refer to semi-solid preparations in which the active ingredient is dissolved or dispersed in a base, and include oleaginous ointments, water-soluble ointments, etc. Oleaginous ointments can typically be produced by heating and melting an oleaginous base such as oils, waxes, or hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing it, and mixing and kneading until the entire mixture is homogeneous. Water-soluble ointments can typically be produced by heating and melting a water-soluble base such as macrogol, adding the active ingredient, and mixing and kneading until the entire mixture is homogeneous.

[0333] (3) Enema Enemas are liquid or viscous gel preparations to be applied through the anus, and are usually produced by dissolving or suspending the active ingredient in purified water or an appropriate aqueous solvent to a certain volume and filling it into a container. Additives that can be used for enemas include dispersants, stabilizers, pH adjusters, etc.

[0334] [Vaginal preparations] (1) Vaginal tablets Vaginal tablets are solid preparations of a specific shape that are applied to the vagina and release the active ingredient by gradually dissolving or dispersing in water, and can usually be manufactured in accordance with the manufacturing method for the above-mentioned tablets.

[0335] (2) Vaginal suppositories Vaginal suppositories are semi-solid preparations of a specific shape that are applied to the vagina and release their active ingredient by melting at body temperature or gradually dissolving or dispersing in water, and can usually be manufactured in accordance with the manufacturing methods for the above-mentioned rectal suppositories, etc.

[0336] [Skin preparations] (1) Solid preparations for external use External solid preparations are solid preparations that are applied or sprinkled on the skin, including the scalp, or on nails, and include external powders, etc. External powders refer to powdered external solid preparations, and can usually be produced by adding additives such as excipients to the active ingredient, mixing them to make a homogeneous mixture, and then powdering them.

[0337] (2) Topical liquid Topical solutions are liquid preparations applied to the skin, including the scalp, or nails, and include liniments, lotions, etc. Topical solutions are typically prepared by adding a solvent, additives, etc. to the active ingredient, dissolving, emulsifying, or suspending the mixture, and filtering as needed. Liniments are liquid or muddy topical solutions that are rubbed into the skin. Lotions are topical solutions in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid, and are typically prepared by homogenizing the active ingredient, additives, and purified water to form a solution, suspension, or emulsion.

[0338] (3) Spray Sprays are preparations in which the active ingredient is sprayed onto the skin in the form of a mist, powder, foam, paste, or the like, and include topical aerosols, pump sprays, and the like. Sprays are typically produced by preparing a solution or suspension of the active ingredient, filtering it as needed, and then filling it into a container. Topical aerosols are sprays in which the active ingredient is sprayed together with liquefied or compressed gas filled into a container. Topical aerosols are typically produced by preparing a solution or suspension of the active ingredient, filling it into a pressure-resistant container together with a liquid propellant, and attaching a continuous spray valve. Additives such as dispersants and stabilizers can also be added to topical aerosols as needed. Pump sprays are sprays in which the active ingredient in the container is sprayed using a pump. Pump sprays are typically produced by dissolving or suspending the active ingredient and additives, and then attaching a pump to the filled container.

[0339] (4) Ointments Ointments are semi-solid preparations to be applied to the skin in which an active ingredient is dissolved or dispersed in a base, and include oleaginous ointments, water-soluble ointments, etc. Oleaginous ointments can usually be produced by heating and melting an oleaginous base such as fats and oils, waxes, or hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing it, and mixing and kneading until the entire mixture is homogeneous. Water-soluble ointments can usually be produced by heating and melting a water-soluble base such as macrogol, adding the active ingredient, and mixing and kneading until the entire mixture is homogeneous.

[0340] (5) Creams Creams are semi-solid preparations that are applied to the skin and are emulsified into oil-in-water or water-in-oil types, and lipophilic preparations that are emulsified into water-in-oil types are sometimes called oily creams. Creams are usually produced by forming an oil phase using petrolatum, a higher alcohol, etc., either as is or with the addition of an emulsifier or other additive, and separately forming an aqueous phase using purified water, either as is or with the addition of an emulsifier or other additive, adding an active ingredient to either of these phases, heating each, and emulsifying the oil and aqueous phases together by stirring until the whole is homogeneous.

[0341] (6) Gel Gels are gel-like preparations to be applied to the skin, and include aqueous gels, oily gels, etc. Aqueous gels can be produced by dissolving or suspending the active ingredient in purified water with a polymer compound, other additives, and then heating and cooling the mixture or by adding a gelling agent to cause crosslinking. Oily gels can be produced by mixing the active ingredient with a liquid oil base such as glycols or higher alcohols and other additives.

[0342] (7) Patches Patches are preparations that are applied to the skin and include tapes, poultices, etc. Patches are typically prepared by mixing the active ingredient with a polymeric compound or a mixture thereof as a base, forming a homogeneous mixture, and then spreading the mixture onto a support or liner (release material). A release-modifying membrane can also be used to create a transdermal formulation. Patches can also contain additives such as adhesives and absorption enhancers, as needed. Tapes are patches that use a base that contains almost no water and include plasters, plasters, etc. Tapes typically use a water-insoluble natural or synthetic polymeric compound such as resin, plastic, or rubber as a base. The active ingredient, either as is or with additives, is homogenized, spread onto fabric or plastic film, or encapsulated in the resulting mixture. Alternatively, patches can be prepared by encapsulating a mixture of the active ingredient and base or other additives in a release material consisting of a release-modifying membrane, a support, and a liner (release material), and then encapsulating the mixture. A cataplasm is a patch that uses a water-containing base, and can usually be produced by mixing the active ingredient with a liquid substance such as purified water or glycerin and homogenizing the whole, or by mixing and kneading a natural or synthetic polymer compound such as a water-soluble polymer or a water-absorbent polymer with purified water, adding the active ingredient, homogenizing the whole, and spreading it on a cloth or the like to form it.

[0343] 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.

[0344] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification may be incorporated herein by reference in their entirety. [Example]

[0345] 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."

[0346] Analysis method 1H NMR spectra were obtained on a Varian Unity Inova 400 spectrometer equipped with a 5 mm inverse-detected triple-resonance probe operating at 400 MHz, or a Bruker Avance DRX 400 spectrometer equipped with a 5 mm inverse-detected triple-resonance TXI probe operating at 400 MHz, or a Bruker Avance DPX 300 spectrometer equipped with a standard 5 mm dual-frequency probe operating at 300 MHz, or a Bruker Avance 400 MHz spectrometer equipped with a 5 mm QNP probe for H, C, F, and P, a two-channel instrument running a single Z gradient, and TopSpin 2.1, or a Bruker Advance III 400 MHz spectrometer equipped with a 5 mm BBFO Plus probe, a two-channel instrument running a single Z gradient, and TopSpin 3.1. Shift values ​​are given in ppm relative to tetramethylsilane (δ = 0 ppm).

[0347] The liquid chromatography mass spectrometry (LCMS) methods used were as follows: Method 1 ACQUITY UPLC (binary pump / PDA detector) + ZQ Mass Spectrometer, ACQUITY UPLC BEH C maintained at 40°C 18 Equipped with a 1.7 μm, 100 × 2.1 mm column. Mobile phase (A): water + 0.1% formic acid; Mobile phase (B): acetonitrile B214 + 0.1% formic acid

[0348] [Table 1]

[0349] Method 2 ACQUITY H-Class (Quaternary Pump / PDA Detector) + QDa Mass Spectrometer, ACQUITY UPLC CSH C maintained at 40°C 18 Equipped with a 1.7 μm, 50 × 2.1 mm column. Mobile phase (A): water + 0.1% formic acid; Mobile phase (B): acetonitrile + 0.1% formic acid

[0350] [Table 2]

[0351] Method 3 ACQUITY i-Class (Quaternary Pump / PDA Detector) + Quattro Micro Mass Spectrometer, ACQUITY UPLC BEH C maintained at 40°C 18 Equipped with a 1.7 μm, 100 × 2.1 mm column. Mobile phase (A): water + 0.1% formic acid; Mobile phase (B): acetonitrile + 0.1% formic acid

[0352] [Table 3]

[0353] Method 4 ACQUITY H-Class (Quaternary Pump / PDA Detector) + QDa Mass Spectrometer, ACQUITY BEH C at 40°C 18 Equipped with 1.7 μm, 50 × 2.1 mm. Mobile phase (A): 7.66 mM ammonia aqueous solution; Mobile phase (B): 7.66 mM ammonia-acetonitrile solution

[0354] [Table 4]

[0355] Method 5 ACQUITY Classic+996 PDA detector+Waters ZMD Mass Spectrometer, ACQUITY UPLC CSH C at 40℃ 18 Equipped with a 1.7 μm, 50 × 2.1 mm column. Mobile phase (A): water + 0.1% formic acid; Mobile phase (B): acetonitrile + 0.1% formic acid

[0356] [Table 5]

[0357] Method 6 ACQUITY Classic+996 PDA detector+Waters ZMD Mass Spectrometer, ACQUITY UPLC BEH C at 40℃ 18 Equipped with a 1.7 μm, 50 × 2.1 mm column. Mobile phase (A): 0.1% aqueous ammonia (v / v); Mobile phase (B): 0.1% ammonia-acetonitrile (v / v).

[0358] [Table 6]

[0359] Method 7 ACQUITY UPLC (binary pump / PDA detector) + Waters SQD2; LC / MS: single quadrapole UPLC-MS, ACQUITY UPLC HSS C maintained at 40°C 18 Equipped with a 1.8 μm, 100 × 2.1 mm column. Mobile phase (A): water + 0.1% formic acid; Mobile phase (B): acetonitrile + 0.1% formic acid

[0360] [Table 7]

[0361] Method 8 ACQUITY UPLC (binary pump / PDA detector) + Waters SQD2; LC / MS: single quadrapole UPLC-MS equipped with an ACQUITY UPLC BEH Shield RP18 1.7 μm, 100 × 2.1 mm column maintained at 40 °C. Mobile phase (A): water + 10 mM ammonium bicarbonate; Mobile phase (B): acetonitrile.

[0362] [Table 8]

[0363] Method 9 ACQUITY UPLC (binary pump / PDA detector) + ZQ Mass Spectrometer, ACQUITY UPLC BEH C maintained at 40°C 18 Equipped with a 1.7 μm, 100 × 2.1 mm column. Mobile phase (A): 0.1% aqueous ammonia (v / v); Mobile phase (B): 0.1% ammonia-acetonitrile (v / v).

[0364] [Table 9]

[0365] Method 10 HP1100 (Quaternary Pump / PDA Detector) + ZQ Mass Spectrometer, Waters Xbridge BEH C at 40°C 18 Equipped with a 3.5 μm, 50 × 4.6 mm column. Mobile phase (A): 7.66 mM ammonia aqueous solution; Mobile phase (B): 7.66 mM ammonia-acetonitrile solution

[0366] [Table 10]

[0367] Method 11 Simadzu LC20-MS2010, Agilent Pursit 5 at 50°C 18 Equipped with a 20 x 2.0 mm column. Mobile phase (A): 1.5 mL of TFA - 4 L of water; Mobile phase (B): 0.75 mL of TFA-acetonitrile solution

[0368] [Table 11]

[0369] Reverse-phase preparative HPLC purification was performed using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or a Gilson preparative HPLC system (322 pump, 155 UV / VIS detector, GX-281 liquid handler). The columns used for compound purification were Waters Sunfire OBD, Phenomenex Luna Phenyl Hexyl, or Waters Xbridge Phenyl 10 μm 19 x 150 mm columns unless otherwise noted. An appropriate gradient was selected from the acetonitrile and MeOH solvent system under either acidic or basic conditions. The standard gradient was from 5% to 20% MeCN over 1 min, followed by a 2.5 min hold, 80% MeCN over 12.5 min, a 7.5 min hold, and then a 3 min re-equilibration to the initial conditions. The flow rate was 20 ml / min. Prior to the purification step, compounds were analytically screened. Each sample was run under acidic and basic conditions (2 μl injection, 5 / 95 gradient, 5 min). The pH and gradient used were then determined based on where the target elutes and separation is achieved. The modifiers used under acidic and basic conditions were formic acid (0.1% v / v) and ammonium bicarbonate (10 mM), respectively, or TFA (0.1% v / v) if method development was required. Purification was controlled using Waters Fractionlynx software by monitoring elution wavelengths from 210 nm to 400 nm, revealing the presence of the target molecular ion, as observed under targeted ESI conditions and threshold recovery values ​​at 260 nm. Collected fractions were analyzed by LCMS (Waters ACQUITY systems with Waters SQD). Fractions containing the target eluates were dried overnight in a Genevac lyophilizer. Due to the complex mixtures of compounds, some may undergo a second purification step to achieve the required purity. More focused gradient or isocratic conditions may be used for more challenging separations.

[0370] Separation of enantiomers by supercritical fluid chromatography (SFC) was performed using either a Waters Thar Prep 100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module) or a Waters Thar Investigator semi-preparative system (Waters Fluid Delivery Module, 2998 UV / VIS detector, Waters Fraction Collection Module). When using the Waters 2767 liquid handler, it functioned as both the autosampler and fraction collector.

[0371] Unless otherwise stated, compounds were purified from YMC Amylose-C, YMC Cellulose-C, YMC Cellulose-SC, Phenomenex LUX Cellulose-3, or Phenomenex LUX Cellulose-4 (10 × 250 mm, 5 μm) using the appropriate column.

[0372] Under unmodified or basic conditions, the appropriate isocratic method was selected from methanol, ethanol, or isopropanol solvent systems. The standard method was modifier / CO2, 100 ml / min (or as appropriate), 120 Bar back pressure, and 40 °C column temperature, with the specific modifier composition as specified during method development.

[0373] All compounds were analytically screened before purification. Each sample was run through ethanol, methanol, and isopropanol under both pure and basic conditions (5.0 μL, 5 / 55 gradient over 5 min). If necessary, a secondary screen covering a wide range of solvents, including acetonitrile, ethyl acetate, and THF, could also be performed. The pH and isocratic conditions used were then determined based on where the target compounds eluted and where separation was achieved.

[0374] The modifier used under basic conditions was diethylamine (0.1% V / V). Alternative modifiers such as formic acid (0.1% V / V) and acetic acid (0.1% V / V) can be used as acidic modifiers. Purification was controlled using Waters Fractionlynx or Waters Chromscope software by monitoring from 210 to 400 nm to determine the presence of threshold recovery values ​​at the appropriate wavelengths. Collected fractions were analyzed by SFC (Waters / Thar SFC system with a Waters SQD or Waters UPCC with a Waters QDa). Fractions containing the target material were concentrated by vacuum centrifugation.

[0375] All samples were pre-purified in a non-chiral system to confirm purity before SFC chiral purification.

[0376] Some compounds may undergo a second purification step to achieve the required %ee or %de purity.

[0377] Reverse phase chromatography was performed using either 0.1% formic acid or 0.1% NH4OH as a modifier and eluting with a gradient of MeCN / HO. 18 It was carried out in a cartridge.

[0378] 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.

[0379] Suzuki-Miyaura Basic Step 1 A mixture of aryl chloride or bromide (1.0 eq), boronic acid or ester (1.3 eq), potassium carbonate (2.0 eq), XPhos (0.1 eq), and XPhosPdG2 (0.1 eq) in dioxane / water (10:1, 100 mM) was degassed and stirred at 80 °C for 16 h. Further boronic acid, Xphos, and XPhosPdG2 were added as needed to complete the reaction. Water and DCM were added, and the layers were separated. The aqueous layer was extracted with DCM (x2), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in DCM and purified with ISOLUTE (登録商標) It was pre-adsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with 2N NH3 / MeOH in DCM.

[0380] Suzuki-Miyaura Basic Step 2 A mixture of aryl chloride or bromide (1.0 eq), boronic acid or ester (1.3 eq), cesium carbonate (2.5 eq), and Pd(PPh3)4 (0.1 eq) in dioxane / water (10:1, 100 mM) was degassed and stirred at 80 °C for 16 h. Further boronic acid and Pd(PPh3)4 were added as needed to drive the reaction to completion. Water and DCM were added, and the layers were separated. The aqueous layer was extracted with DCM (x2), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in DCM and purified with ISOLUTE. (登録商標) It was pre-adsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with a gradient of 2N NH3 / MeOH in DCM.

[0381] THP Deprotection Procedure 1 A 100 mM suspension of the THP-protected compound in methanol was treated with 5 eq of 1N HCl (aq), and the reaction mixture was stirred at room temperature until the reaction was complete as determined by LC-MS (3-24 h). The reaction was diluted with water and lyophilized. The resulting white solid was purified by reverse-phase chromatography to give the title compound.

[0382] Trityl Deprotection Procedure 1 A 200 mM suspension of the trityl-protected compound in methanol was treated with 5 eq of 1N HCl (aq), and the reaction mixture was stirred at room temperature for 21 h. The solid was collected by filtration, washed with MeOH, and pumped dry. Further purification by reverse-phase chromatography gave the title compound.

[0383] Trityl Deprotection Step 2 A solution of the trityl-protected compound in TFA / DCM (1:1, final concentration 100 mM) was stirred at room temperature. After completion of the reaction by LCMS, the reaction mixture was diluted with toluene and the volatiles were evaporated under reduced pressure. The residue was azeotroped with toluene (x2) and purified by reverse phase chromatography to give the title compound.

[0384] SnAr and Deprotection General Procedure 1 A mixture of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (1.0 eq) and amine hydrochloride (1.2 eq) in IPA (190 mM concentration) was treated with triethylamine (1.5 eq) and heated at 120 °C for 1 h under microwave irradiation. 1N HCl(aq) (6.5 eq) was added to the reaction mixture and stirred at room temperature for 16 h. The solid was collected by filtration, washed with IPA and water, dried at the pump, dissolved in MeCN / HO / formic acid, and purified by reverse-phase chromatography (C18 cartridge) eluting with 10–98% MeCN / HO + 0.1% formic acid.

[0385] SnAr and Deprotection General Procedure 2 A mixture of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (1.0 eq) and amine hydrochloride (1.2 eq) in IPA (190 mM) was treated with triethylamine (1.5 eq) and heated at 120 °C under microwave irradiation for 1 h. TFA (6.5 eq) and water were added dropwise to the reaction mixture, which was then stirred at room temperature for 16 h. The solid was collected by filtration, washed with IPA and water, dried at the pump, dissolved in DMSO / formic acid, and purified by reverse-phase chromatography (C18 cartridge) eluting with 10–98% MeCN / HO + 0.1% formic acid.

[0386] SnAr Basic Procedure 3 A mixture of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (1.0 eq) and an amine or amine hydrochloride (1.0 eq) in dioxane (0.2 mM) was treated with triethylamine (5 eq) and heated to 100 °C. Further amine or amine hydrochloride was added if necessary to drive the reaction to completion. The reaction was cooled to room temperature, and the white precipitate was collected by filtration. Volatiles were concentrated under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography, eluting with a gradient of MeOH in DCM.

[0387] Bromination Basic Procedure 1 To a solution of the aryl (1.0 eq) in anhydrous DMF (0.1 M) was added N-bromosuccinimide (1.0 eq) in one portion. The resulting solution was stirred at room temperature for 2 h. Additional N-bromosuccinimide was added as needed to achieve reaction completion (as determined by LC-MS analysis). The reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3 (x2) and water, added to HCl, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in DCM and, if necessary, purified by silica gel chromatography eluting with a gradient of EtOAc in DCM.

[0388] Basic procedure for nitrile hydrolysis A suspension of the nitrile (1 eq) and Perkin's catalyst (5 mol%) in EtOH / HO (9:1, 0.34 M) was heated at 80 °C until complete by LC-MS. The reaction mixture was diluted with DCM and purified with ISOLUTE (登録商標) It was pre-adsorbed onto a HM-N column (Biotage) and purified by silica gel chromatography eluting with a gradient of MeOH in DCM.

[0389] Example Example 1 2-(furan-2-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one formate (0.6 eq) Ethyl 1-amino-1H-imidazole-2-carboxylate A solution of ethyl imidazole-2-carboxylate (65.0 g, 0.463 mol) in DMF (2 L) was cooled in an ice / water bath, followed by the dropwise addition of lithium bis(trimethylsilyl)amide (1 M in THF, 510 mL, 0.510 mol) while maintaining the temperature at 10–15 °C. To the resulting solution, O-(diphenylphosphinyl)hydroxylamine (119 g, 0.510 mol) was added in small portions. The resulting mixture was mechanically stirred for 16 h. The reaction was quenched with water and evaporated under reduced pressure. The residue was triturated with EtOAc (×4), filtered, and the solid was washed with EtOAc. The combined filtrate was evaporated to give a brown solid, which was dissolved in DCM and passed through a pad of silica gel, eluting with DCM followed by 5% MeOH in DCM. These fractions were collected and concentrated under reduced pressure to give a pale yellow semi-solid. The solid was triturated with Et2O and filtered to give the title compound (61.2 g, 84%) as a white solid. 1 H NMR(400MHz, CDCl3)δ, ppm, 7.19(1H,d,J=1.0Hz), 7.07(1H,d,J=1.0Hz), 5.81(2H,s), 4.43(2H,q,J=7.1Hz), 1.43(3H,t,J=7.1Hz).

[0390] 1-Amino-N-isopropyl-1H-imidazole-2-carboxamide Ethyl 1-amino-1H-imidazole-2-carboxylate (20 g, 0.13 mol) was dissolved in isopropylamine (120 mL, 13 mol) and heated under reflux for 48 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give a yellow oil, which crystallized upon standing (21.7 g, quant.). 1 H NMR(400MHz, CDCl3)δ, ppm, 7.09(1H,d,J=1.1Hz), 6.92(1H,d,J=1.1Hz), 6.12(2H,s), 4.24-4.15(1H,m), 1.26(6H,d,J=6.6Hz).

[0391] 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione hydrochloride Phenyl chloroformate (17.8 mL, 0.14 mol) was added to a solution of 1-amino-N-isopropyl-1H-imidazole-2-carboxamide (22.0 g, 0.13 mol) in acetonitrile (500 mL) and heated to reflux for 54 h. The product precipitated as a white solid, which was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure (~40 mL), and the residue was transferred to two 25 mL microwave reactor vials, each of which was heated at 180 °C for 45 min in a microwave reactor. The resulting brown suspension was diluted with MeCN (100 mL) and refluxed for 16 h. The resulting white suspension was filtered and washed with acetonitrile to give the title compound as a white solid. A total of 25.8 g (quantitative yield) was isolated from the two filtrates. 1 H NMR (400MHz, DMSO) δ, ppm, 7.78(1H,d,J=1.4Hz), 7.73(1H,d,J=1.4Hz), 5.12-4.99(1H,m), 1.43(6H,d,J=7.1Hz).

[0392] 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione, triethylamine salt 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione hydrochloride (16.7 g, 72.6 mmol) was suspended in MeOH (380 mL). Triethylamine (20.2 mL, 140 mmol) was added, and the reaction mixture was stirred at room temperature until complete dissolution (30-45 min). The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM (x4). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the title compound (21.4 g, quant.) as an orange paste. 1 H NMR (400MHz, CDCl3)δ, ppm 7.28(1H,d,J=0.9Hz), 7.21(1H,d,J=0.9Hz), 5.37-5.26(1H,m), 3.16(6H,q,J=7.3Hz), 1.52(6H,d,J=7.4Hz), 1.34(9H,t,J=7.3Hz).

[0393] 7-Iodo-3-isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione, triethylamine salt To a solution of 3-isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione, triethylamine salt (21.4 g, 72.6 mmol) in MeOH (380 mL) was added N-iodosuccinimide (16.3 g, 72.6 mmol) in one portion. The resulting orange solution was stirred at room temperature for 3 h. Additional N-iodosuccinimide (1.80 g, 7.98 mmol) was added in one portion, and after stirring at room temperature for 1 h, the reaction was judged complete by LC-MS analysis. The reaction was concentrated under reduced pressure and partitioned between DCM and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3 (x3) and water, dried (MgSO4), and concentrated under reduced pressure to give a light brown oil that crystallized on standing (20.9 g, 68%). 1 H NMR(400MHz, CDCl3)δ, ppm 13.50(1H,s), 7.33(1H,s), 5.34-5.24(1H,m), 3.26(6H,q,J=7.2Hz), 1.50(6H,d,J=7.0Hz), 1.37(9H,t,J=7.3Hz).

[0394] 2-chloro-7-iodo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one A suspension of 7-iodo-3-isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione, triethylamine salt (9.45 g, 22.4 mmol) in phosphorus oxychloride (20.9 mL) was stirred at 80 °C for 43 h. The reaction mixture was diluted with toluene, concentrated under reduced pressure, and azeotroped with toluene (x2). The residue was partitioned between DCM and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with water and saturated brine, dried (MgSO4), and concentrated under reduced pressure to give a brown solid. The crude product was purified by silica gel chromatography, eluting with 0–40% EtOAc in cyclohexane, to give the title compound (5.3 g, 70%) as an off-white solid. LCMS method 2: room temperature 1.30 min, [MH + ]339,341.

[0395] 4-(tributylstannyl)-1-trityl-1H-imidazole Under an argon atmosphere, ethylmagnesium bromide (3M in diethyl ether, 4.58 mL, 13.8 mmol) was added dropwise to a solution of 4-iodo-1-trityl-1H-imidazole (5.00 g, 11.5 mmol) in DCM (100 mL). The reaction was stirred for 1 hour, and then tributyltin chloride (3.73 mL, 13.8 mmol) was added. The resulting white suspension was stirred overnight. The reaction was concentrated under reduced pressure. The concentrate was purified by ISOLUTE (登録商標) The eluate was dry-packed onto a 200 g SiO2 cartridge using a HM-N column (Biotage) and eluted with 0–20% EtOAc in cyclohexane. Concentration of the target-containing fractions gave a clear oil that solidified under high vacuum to give a white solid (4.038 g, 59% yield). 1 H NMR(400MHz,CDCl3)δ, ppm 7.63(1H,s), 7.32 -7.30(9H,m), 7.15-7.12(6H,m), 6.76(1H,d,J=1.1Hz), 1.54-1.46(6H,m), 1.39-1.23(12H,m), 1.03-0.98(6H,m), 0.84(9H,t,J=7.3Hz).

[0396] 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A solution of 2-chloro-7-iodo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (2.80 g, 8.27 mmol), 4-(tributylstannyl)-1-trityl-1H-imidazole (5.98 g, 9.93 mmol), and CuI (79 mg, 0.41 mmol) in 1,4-dioxane (28 mL) was bubbled with argon for 15 min, and Pd(PPh3)4 (960 mg, 0.827 mmol) was added. The resulting suspension was heated at 100 °C for 18 h. The reaction mixture was concentrated under reduced pressure and loaded onto a 220 g SiO2 cartridge with DCM and eluted with 0–100% EtOAc in cyclohexane. Concentration of the product containing fractions afforded the title compound (3.73 g, 72%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ, ppm7.94(1H,s), 7.66(1H,d,J=1.4Hz), 7.51(1H,d,J=1. 4Hz), 7.39-7.36(9H,m), 7.21-7.18(6H,m), 5.21(1H,s), 1.63(6H,d,J=7.0Hz).

[0397] 2-(furan-2-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 2-furylboronic acid using Suzuki-Miyaura general procedure 1 to afford 44 mg (55%) of the title compound as a white foam. LCMS method 4: room temperature 1.76 min, [MH + ]553.

[0398] 2-(furan-2-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.6 eq formate Synthesized from 2-(furan-2-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one using trityl deprotection procedure 1 and purified by reverse-phase preparative HPLC to give 4.5 mg (19%) of the title compound as a white solid after lyophilization. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.39(1H,s), 8.23(0.6H,s), 8.06(1H,dd,J=0.8,1.8Hz), 7.82(1H,d,J=1.1Hz), 7.75(1H,s), 7.70(1H,d,J=1. 0Hz), 7.22(1H,dd,J=0.8,3.4Hz), 6.79(1H,dd,J=1.8, 3.4Hz), 4.25(1H,hept,J=6.8Hz), 1.57(6H,d,J=6.8Hz). LCMS method 1: room temperature 2.53 min, [MH + ]311.1.

[0399] Example 2 7-(1H-imidazol-5-yl)-3-isopropyl-2-phenylimidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.6 eq formate 3-Isopropyl-2-phenyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and phenylboronic acid according to Suzuki-Miyaura general procedure 1 to afford 25 mg (31%) of the title compound as a pale yellow glass. LCMS method 4: room temperature 1.81 min, [MH + ]563.

[0400] 7-(1H-imidazol-5-yl)-3-isopropyl-2-phenylimidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.6 eq formate Synthesized from 3-isopropyl-2-phenyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give 4.1 mg (32%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.30(1H,s), 8.35(0.6H,s), 7.78(1H,d,J=1.1Hz), 7.75-7.71(3H,m), 7.64-7.5 9(3H,m), 7.53(1H,d,J=0.9Hz), 4.07(1H,hept,J=6.8Hz), 1.50(6H,d,J=6.8Hz). LCMS method 1: room temperature 2.80 min, [MH + ]321.1.

[0401] Example 3 7-(1H-imidazol-5-yl)-3-isopropyl-2-(5-methylfuran-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(5-methylfuran-2-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 5-methyl-2-furanboronic acid according to Suzuki-Miyaura general procedure 1 to afford 66 mg (61%) of the title compound as an off-white foam. LCMS method 4: room temperature 1.82 min, [MH + ]567.

[0402] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(5-methylfuran-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one This compound was synthesized from 3-isopropyl-2-(5-methylfuran-2-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one according to the trityl deprotection procedure 1, except that TFA (11 eq) was also added to the reaction mixture. It was purified by reversed-phase chromatography (C) eluting with 10–98% MeCN / HO + 0.1% formic acid. 18 Cartridge) to give 17 mg (45%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 8.60(1H,s), 7.94(1H,s), 7.91(1H,d,J=1.1Hz), 7.16(1H,d,J=3.3Hz), 6.42(1H, dd,J=1.0,3.3Hz), 4.36(1H,hept,J=6.7Hz), 2.42(3H,s), 1.58(6H,d,J=6.7Hz). LCMS method 1: room temperature 2.83 min, [MH + ]325.1.

[0403] Example 4 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-methylazetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one This was synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 3-methylazetidine hydrochloride according to general SnAr and deprotection procedure 2, except starting with 100 mg of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, the reaction mixture was heated at 120 °C for 30 min under microwave irradiation, followed by addition of amine (0.5 eq) and triethylamine (0.8 eq) and further heating at 120 °C for 30 min under microwave irradiation. 6 h after the addition of TFA, DCM (0.5 mL) was added, and the mixture was stirred at room temperature for an additional 40 h. The title compound was isolated as a white solid, 45 mg (75%). 1H NMR(400MHz,d6-DMSO)δ, ppm 12.56(1H,s), 7.87(1H,s), 7.74(1H,s), 7.62(1H,s), 4.44-4.34(1H,hept,J=6.7Hz), 4.25(2H,t, J=7.9Hz), 3.79(2H,t,J=7.0Hz), 2.82-2.73(1H,m), 1.53(6H,d,J=6.7Hz), 1.24(3H,d,J=6.7Hz). LCMS method 1: 2.65 min at room temperature, [MH + ]314.1.

[0404] Example 5 7-(1H-imidazol-5-yl)-3-isopropyl-2-(2-(tetrahydrofuran-2-yl)ethoxy)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(2-(tetrahydrofuran-2-yl)ethoxy)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A solution of 2-(tetrahydrofuran-2-yl)ethan-1-ol (111 mg, 0.96 mmol) in anhydrous DMF (2.0 mL) was treated with sodium hydride (60% oil dispersion, 38 mg, 0.96 mmol) under a nitrogen atmosphere and stirred at room temperature. After 10 min, a 0.9 mL portion of this mixture was added to a 2.0 mL solution of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.38 mmol) in anhydrous DMF under argon. The reaction mixture was stirred at room temperature for 30 min, followed by the addition of another 0.5 mL portion of the alkoxide solution. After stirring for an additional 30 min, the mixture was diluted with EtOAc and saturated aqueous ammonium chloride. The layers were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried (MgSO4), and concentrated under reduced pressure to give a yellow viscous substance. This viscous substance was dissolved in DCM and purified by ISOLUTE (登録商標)Pre-adsorption onto an HM-N column (Biotage) and purification by silica gel chromatography (40 g cartridge) eluting with 0-4% (2N NH3 / MeOH) in DCM gave the title compound (116 mg, 50%) as a white foam. LCMS method 5: room temperature 2.02 min, [MH + ]601.

[0405] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(2-(tetrahydrofuran-2-yl)ethoxy)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(2-(tetrahydrofuran-2-yl)ethoxy)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one using trityl deprotection procedure 2 to give the title compound (43 mg, 63%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.39(1H,s), 7.82(1H,d,J=0.9Hz), 7.77(1H,s), 7.66(1H,s), 5.24(1H,hept,J=6.9Hz), 4.62-4.53(2H,m), 4.02-3.94(1H ,m), 3.84-3.77(1H,m), 3.67-3.61(1H,m), 2.12-1.96(3H,m), 1.93-1.78(2H,m), 1.58-1.49(1H,m), 1.45(6H,d,J=6.9Hz). LCMS method 1: room temperature 2.77 min, [MH + ]359.1. The enantiomers of Example 5 were separated by chiral SFC using a YMC Amylose-C column eluting with 20% EtOH (+0.1% diethylamine):80% CO, 15 mL / min, 120 bar, 40°C, DAD 230 nm to give Examples 6 and 7.

[0406] Example 6 Enantiomer A: white solid 17 mg Analytical equipment: Analytical SFC; Column: YMC Amylose-C (4.6 x 250 mm, 5 micron); Mobile phase: 20% EtOH (+0.1% diethylamine) / 80% CO2; Flow rate: 5.0 mL / min; Pressure: 120 bar, Temperature: 40 °C; Detector: DAD 230 nm; Retention time: 2.1 min.

[0407] Example 7 Enantiomer B: white solid 16 mg Analytical equipment: Analytical SFC; Column: YMC Amylose-C (4.6 x 250 mm, 5 micron); Mobile phase: 20% EtOH (+0.1% diethylamine) / 80% CO2; Flow rate: 5.0 mL / min; Pressure: 120 bar; Temperature: 40 °C; Detector: DAD 230 nm; Retention time: 3.2 min.

[0408] Example 8 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-phenylazetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Starting from 100 mg of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 3-phenylazetidine hydrochloride, this was synthesized according to the SnAr method and deprotection general procedure 2, except that 2.5 eq of triethylamine was used and the reaction mixture was heated at 120 °C for 30 min under microwave irradiation. A second addition of TFA (5.0 eq) was added 24 h after the first addition, and the mixture was stirred at room temperature for 7.5 h and then at 50 °C for 16 h. The title compound (27 mg, 38%) was isolated as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.27(1H,s), 7.79(1H,s), 7.74(1H,s), 7.62(1H,s), 7.46(2H,d,J=7.6Hz), 7.38(2H,t,J=7.5Hz), 7.28(1H,t,J=7.3Hz) , 4.54(2H,t,J=8.2Hz), 4.48(1H,hept,J=6.5Hz), 4.26(2H,t,J=7.5Hz), 4.00(1H,quin,J=7.8Hz), 1.56(6H,d,J=6.7Hz). LCMS method 1: 3.30 min at room temperature, [MH + ]376.1.

[0409] Example 9 7-(1H-imidazol-5-yl)-3-isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Starting with 200 mg of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and N-methyl-2-tetrahydrofuran-2-yl-ethanamine hydrochloride, this was synthesized according to general SnAr and deprotection procedure 2, except that the reaction mixture was heated at 120 °C for 90 min under microwave irradiation followed by heating at 80 °C for 72 h under conventional heating. The amine hydrochloride (0.8 eq) and triethylamine (1.5 eq) were then added and heated at 120 °C for 60 min under microwave irradiation. The reaction mixture was treated with 8.2 eq of TFA. The title compound (57 mg, 40%) was isolated as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ, ppm 8.02 (1H, s), 7.77 (1H, d, J = 1.0 Hz), 7.68 (1H, s), 4.70 (1H, hept, J = 6.8 Hz), 3.82-3.71 (2H, m), 3.61-3.55 (1H, m), 3.21-3.12 (1H, m), 2.84 (3H, m), 1.99-1.90 (1H, m), 1.88-1.71 (4H, m), 1.57 (6H, d, J = 6.8 Hz), 1.48-1.38 (1H, m), plus one proton hidden by the water peak. LCMS method 1: room temperature 2.81 min, [MH + ]372.2. The enantiomers of Example 9 were separated by chiral SFC using a YMC Cellulose-C column eluting with 40% MeCN (+0.1% diethylamine):60% CO, 15 mL / min, 120 bar, 40°C, DAD 230 nm to give Examples 10 and 11.

[0410] Example 10 Enantiomer A: Light yellowish brown solid 8mg Analytical equipment: Analytical SFC; Column: YMC Cellulose-C (4.6 x 250 mm, 5 micron); Mobile phase: 40% MeCN (+0.1% diethylamine) / 60% CO2; Flow rate: 5.0 mL / min; Pressure: 120 bar; Temperature: 40 °C; Detector: DAD 230 nm; Retention time: 4.1 min.

[0411] Example 11 Enantiomer B: Light yellowish brown solid 8mg Analytical equipment: Analytical SFC; Column: YMC Cellulose-C (4.6 x 250 mm, 5 micron); Mobile phase: 40% MeCN (+0.1% diethylamine) / 60% CO2; Flow rate: 5.0 mL / min; Pressure: 120 bar; Temperature: 40 °C; Detector: DAD 230 nm; Retention time: 4.8 min.

[0412] Example 12 7-(1H-imidazol-5-yl)-3-isopropyl-2-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(1-methyl-1H-imidazol-4-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.19 mmol), N-methyl-4-(tributylstannyl)imidazole (85 mg, 76 μL, 0.23 mmol), and copper(I) iodide (1.8 mg, 0.010 mmol) in dry dioxane (2.0 mL) was degassed and then treated with tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and stirred at 100° C. for 16 hours. Further N-methyl-4-(tributylstannyl)imidazole (30 μL, 0.090 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) were added, and the mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted with DCM (x2). The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated brine, dried (MgSO), and concentrated under reduced pressure to give a yellow oil. The oil was purified by silica gel chromatography (40 g cartridge) eluting with 0–4% (2N NH / MeOH) in DCM to give the title compound (35 mg, 32%) as a milky-white viscous material. LCMS method 5: room temperature 1.63 min, [MH + ]567.

[0413] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(1-methyl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(1-methyl-1H-imidazol-4-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 2 to give the title compound (9 mg, 47%) as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.35(1H,s), 7.92(1H,d,J=1.1Hz), 7.88(1H,d,J=1.2Hz), 7.81(1H,d,J=0.9Hz), 7. 76(1H,s), 7.72(1H,s), 4.98(1H,hept,J=6.7Hz), 3.79(3H,s), 1.56(6H,d,J=6.8Hz). LCMS method 1: room temperature 1.99 min, [MH + ]325.1.

[0414] Example 13 (S)-7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-phenylpyrrolidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and (3S)-3-phenylpyrrolidine hydrochloride using SnAr and deprotection general procedure 1 to afford the title compound (34 mg, 45%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.31(1H,s), 7.79(1H,s), 7.69(1H,s), 7.62(1H,s), 7.42-7.34(4H,m), 7.27(1H,tt,J=1.9,6.8Hz), 4.63(1H,hept,J=6.6H z), 3.85-3.73(2H,m), 3.62-3.46(3H,m), 2.40-2.32(1H,m), 2.15-2.05(1H,m), 1.66(3H,d,J=6.7Hz), 1.50(3H,d,J=6.6Hz). LCMS method 3: room temperature 3.38 min, [MH + ]390.3.

[0415] Example 14 (R)-7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-phenylpyrrolidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and (3R)-3-phenylpyrrolidine hydrochloride according to general SnAr and deprotection procedure 2, except the reaction mixture was heated under microwave irradiation at 100° C. for 1 h. The title compound (28 mg, 25%) was isolated as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.70(1H,s), 7.90(1H,s), 7.71(1H,d,J=0.8Hz), 7.64(1H,s), 7.42-7.34(4H,m), 7.27(1H,tt,J=1.9,6.9Hz), 4.63(1H,hept,J= 6.7Hz), 3.85-3.73(2H,m), 3.62-3.46(3H,m), 2.40-2.32(1H,m), 2.15-2.05(1H,m), 1.66(3H,d,J=6.7Hz), 1.50(3H,d,J=6.6Hz). LCMS method 1: 3.40 min at room temperature, [MH + ]390.1.

[0416] Example 15 (R)-7-(1H-imidazol-5-yl)-3-isopropyl-2-((2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one This compound was synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 2-[(2R)-tetrahydrofuran-2-yl]ethanamine hydrochloride using the SnAr method and general deprotection procedure 1, except that the reaction mixture was heated under microwave irradiation for 30 minutes. Upon completion of the reaction, a small amount of solid was separated by filtration, and the filtrate was diluted with 2N NH3 / MeOH in DCM and saturated aqueous NaHCO3, and the layers were separated. The aqueous layer was extracted with DCM (x2), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in MeOH / DCM and purified with ISOLUTE. (登録商標)Pre-adsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with a gradient of 0-10% 2N NH3 / MeOH in DCM to give the title compound (21 mg, 30%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.32(1H,s), 7.80-7.77(2H,m), 7.55(1H,s), 6.80(1H,t,J=5.0Hz), 4.76-4.68(1H,m), 3.92-3.85(1H,m), 3.85-3.79(1H ,m), 3.69-3.62(1H,m), 3.52-3.34(2H,m), 2.05-1.96(1H,m), 1.91-1.78(4H,m), 1.52(6H,d,J=6.8Hz), 1.49-1.43(1H,m). LCMS method 3: room temperature 2.57 min, [MH + ]358.4.

[0417] Example 16 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-(methoxymethyl)azetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one formate 0.6 eq This compound was synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 3-methoxymethylazetidine hydrochloride by the SnAr method and general deprotection procedure 1, except that the reaction mixture was heated under microwave irradiation for 30 min. At the end of the reaction, the mixture was lyophilized and the residue was dissolved in 2N NH3 / MeOH in DCM and purified with ISOLUTE (登録商標) The product was pre-adsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with a gradient of 0-10% 2N NH3 / MeOH in DCM. The product was then purified by reversed-phase chromatography (C) eluting with 10-98% MeCN / HO + 0.1% formic acid. 18 The product was purified by column chromatography (pure water cartridge) to give the title compound (34 mg, 52%) as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.31(1H,s), 8.18(0.6H,s), 7.80(1H,d,J=0.9Hz), 7.72(1H,s), 7.61(1H,s), 4.37(1H,hept,J=6.7Hz), 4.22(2H,t, J=8.1Hz), 3.93(2H,dd, J=6.2, 7.8Hz), 3.55(2H,d,J=6.7Hz), 3.29(3H,s), 2.97-2.86(1H,m), 1.53(6H,d,J=6.7Hz). LCMS method 1: room temperature 2.58 min, [MH + ]344.2.

[0418] Example 17 7-(1H-imidazol-5-yl)-3-isopropyl-2-(3-(2,2,2-trifluoroethyl)azetidin-1-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one This compound was synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 3-(2,2,2-trifluoroethyl)azetidine hydrochloride by the general SnAr and deprotection procedure 1, except that 1.1 eq of the amine hydrochloride was used and the reaction mixture was heated under microwave irradiation for 30 min. At the end of the reaction, the solid was collected by filtration, dissolved in 2N NH3 / MeOH in DCM, and purified with ISOLUTE (登録商標) Pre-adsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with a gradient of 0-10% 2N NH3 / MeOH in DCM to give the title compound (21 mg, 22%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.33(1H,s), 7.80(1H,d,J=0.8Hz), 7.72(1H,s), 7.61(1H,s), 4.40(1H,hept,J=6.7Hz), 4.29(2H,t, J=8.0Hz), 4.02(2H,t,J=7.3Hz), 2.99(1H,hept,J=7.4Hz), 2.78-2.65(2H,m), 1.53(6H,d,J=6.7Hz). LCMS method 1: room temperature 3.03 min, [MH + ]382.2.

[0419] Example 18 2-(indolin-5-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-Chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (460 mg, 2.37 mmol) was suspended in phosphorus oxychloride (5.0 mL) and stirred at 120 °C for 48 h. POCl (5 mL) was added, and the mixture was stirred at 120 °C until the reaction was complete as confirmed by LCMS. Water was then added, and NaHCO was added slowly in small portions at 40 °C to adjust the pH to 6. DCM was added, and the layers were separated. The aqueous solution was extracted with DCM (x2) using a phase separation cartridge, and the combined organic layers were concentrated under reduced pressure to give the title compound (285 mg, 57%) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ, ppm 7.54-7.52(2H,m), 5.24-5.24(1H,m), 1.67(6H,d,J=6.9Hz).

[0420] tert-Butyl 5-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate Synthesized from 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate using the Suzuki-Miyaura general procedure 1. Purification by silica gel chromatography eluting with 0–75% EtOAc in cyclohexane afforded the title compound (116 mg, 31%) as a colorless gum. LCMS method 4: 1.55 min at room temperature, [MH + ]396.

[0421] tert-Butyl 5-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate A solution of tert-butyl 5-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate (114 mg, 0.29 mmol) in anhydrous DMF (2.0 mL) was treated with NBS (38 mg, 0.22 mmol), and the reaction mixture was stirred at room temperature for 16 h. Further NBS (15 mg, 0.085 mmol) was added, and the reaction mixture was stirred for 2 h. EtOAc and water were added, and the layers were separated. The aqueous layer was extracted with EtOAc (x2), and the combined organic layers were washed with water, saturated aqueous NaHCO3, and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in MeOH / DCM and purified with ISOLUTE. (登録商標) Pre-adsorption onto an HM-N column (Biotage) and purification by silica gel chromatography eluting with 0-100% EtOAc in cyclohexane afforded the title compound (97 mg, 71%) as a golden gum. LCMS method 4: 1.68 min at room temperature, [MH+]474,476.

[0422] tert-Butyl 5-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate Synthesized from tert-butyl 5-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole using the Suzuki-Miyaura general procedure 1, except that the dioxane:water ratio was 9:1. Purification by silica gel chromatography, eluting with 0–100% EtOAc in cyclohexane, afforded the title compound (68 mg, 62%) as a colorless glass. LCMS method 4: room temperature 1.68 min, [MH + ]546.

[0423] 2-(indolin-5-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A solution of tert-butyl 5-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)indoline-1-carboxylate (66 mg, 0.12 mmol) in methanol (1.2 mL) was treated with 1 N HCl(aq) (1.2 mL) and stirred at room temperature for 18 hours. Concentrated HCl (1.2 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. Water was added, and the mixture was lyophilized. Purification by reverse-phase preparative HPLC afforded the title compound (18 mg, 41%) as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ, ppm 8.16 (2H, s), 7.78 (1H, s), 7.35 (1H, d, J = 1.4 Hz), 7.26 (1H, dd, J = 1.7, 8.0 Hz), 6.68 (1H, d, J = 8.1 Hz), 4.29 (1H, hept, J = 6.8 Hz), 3.56 (2H, t, J = 8.6 Hz), 3.04 (2H, t, J = 8.6 Hz), 1.50 (6H, d, J = 6.8 Hz). In addition, two exchangeable protons were not observed. LCMS method 7: room temperature 3.07 min, [MH+ ]362.2.

[0424] Example 19 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one A solution of ethyl 1-amino-1H-imidazole-2-carboxylate (1.83 g, 11.8 mmol) in anhydrous MeCN (35 mL) was treated with 1-(cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carbimidoyl chloride (3.19 g, 14.2 mmol) and stirred at 50 °C under argon. After 2 h, an additional 1.33 g (5.9 mmol) of 1-(cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carbimidoyl chloride was added, and the reaction mixture was stirred at 50 °C for 1 h. DMAP (0.029 mg, 0.24 mmol) and potassium carbonate (1.63 g, 11.8 mmol) were added, and the reaction mixture was stirred at reflux for 16 h, at which time a very thick precipitate formed. MeCN (10 mL) was added to aid stirring, and stirring at reflux was continued for 6 h. An additional 10 mL of MeCN was added, and the reaction mixture was stirred for 1.5 hours, after which an additional 10 mL of MeCN was added and stirring at reflux continued for 24 hours. Additional DMAP (0.029 mmol, 0.24 mmol) was added, and the reaction mixture was stirred at reflux for 16 hours, after which additional potassium carbonate (1.63 g, 11.8 mmol) and MeCN (10 mL) were added, and stirring at reflux continued for 7 hours, whereupon LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give a dark brown solid. The solid was dissolved in MeOH / DCM and purified with ISOLUTE (登録商標) Pre-adsorption onto an HM-N column (Biotage) and purification by silica gel chromatography eluting with 0-5% IPA in DCM gave the title compound (1.49 g, 42%) as a golden viscous oil. 1H NMR(400MHz,d6-DMSO)δ, ppm 8.24(1H,s), 7.94(1H,d,J=1.0Hz), 7.80(1H,d,J=0.6Hz), 7.51(1H,d,J=1.1Hz), 4.51(1H,hept,J=6.8Hz ), 4.07(2H,d,J=7.2Hz), 1.54(6H,d,J=6.8Hz), 1.35-1.25(1H,m), 0.59-0.53(2H,m), 0.43-0.38(2H,m). LCMS method 1: room temperature 3.44 min, [MH + ]299.3.

[0425] 7-Bromo-2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Under argon, a solution of 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (1.49 g, 5.0 mmol) in anhydrous DMF (35 mL) was treated with NBS (0.89 g, 5.0 mmol) and stirred at room temperature for 18 hours. Further NBS (87 mg, 0.49 mmol) was added to the reaction mixture and stirred for 1 hour. EtOAc and water were added, and the layers were separated. The aqueous layer was extracted with EtOAc (x2), and the combined organic layers were washed with water, saturated aqueous NaHCO3, and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in MeOH / DCM and purified with ISOLUTE (登録商標) Pre-absorbed onto an HM-N column (Biotage) and purified by silica gel chromatography (80 g cartridge) eluting with 0-75% EtOAc in cyclohexane. The reaction product was treated with ether and evaporated again (x2) to give the title compound (1.38 g, 73%) as a white solid. 1H NMR (400MHz, CDCl3)δ, ppm 7.95(1H,s), 7.77(1H,d,J=0.6Hz), 7.51(1H,s), 4.73-4.66(1H,m), 4.08(2H,d,J=7. 3Hz), 1.67(6H,d,J=6.8Hz), 1.41-1.34(1H,m), 0.78-0.73(2H,m), 0.49-0.45(2H,m). LCMS method 7: room temperature 4.16 min, [MH + ]377.0, 379.2.

[0426] 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Ethyl magnesium bromide (3.0 M in ether, 0.11 mL, 0.35 mmol) was added dropwise to a solution of 4-iodo-1-trityl-1H-imidazole (127 mg, 0.29 mmol) in anhydrous THF under argon and stirred at room temperature for 30 minutes. Zinc chloride (2.0 M in 2-methyl-1H-tetrahydrofuran, 0.29 mL, 0.58 mmol) was added dropwise to form a creamy suspension, which was stirred at room temperature for 2 hours. 7-Bromo-2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.27 mmol) was added, and the reaction mixture was degassed. Tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) was then added and the mixture was stirred at reflux for 3 hours. An additional 15 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred at reflux for 16 h before being cooled to room temperature. EtOAc and saturated aqueous ammonium chloride were added, and a small amount of insoluble solid was dissolved with a small amount of MeOH / DCM. The layers were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, and saturated brine, dried (MgSO4), and concentrated under reduced pressure to give a golden oil. The viscous material was dissolved in DCM and purified by silica gel chromatography (25 g cartridge) eluting with 0–100% EtOAc in cyclohexane to give the title compound (69 mg, 43%) as a cream-colored viscous material. LCMS method 5: room temperature 1.84 min, [MH + ]607.

[0427] 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (as bishydrochloride salt) A solution of 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (69 mg, 0.11 mmol) in MeOH (1.0 mL) was treated with 1 N HCl(aq) (0.34 mL, 0.34 mmol), and the reaction mixture was stirred at room temperature for 16 h. The solid was collected by filtration, washed with MeOH, then with ether, and dried to give the title compound (17 mg, 41%) as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ, ppm: 9.17 (1H, s), 8.40 (1H, s), 8.08 (1H, s), 8.06 (1H, d, J = 1.2 Hz), 7.96 (1H, d, J = 0.6 Hz), 4.63 (1H, hept, J = 6.7 Hz), 4.10 (2H, d, J = 7.2 Hz), 1.59 (6H, d, J = 6.7 Hz), 1.38-1.28 (1H, m), 0.61-0.55 (2H, m), 0.46-0.41 (2H, m), plus three non-exchangeable protons. LCMS method 3: room temperature 2.60 min, [MH + ]365.1.

[0428] Example 20 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 7-bromo-2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.40 mmol), 1H-pyrazole-4-boronic acid (67 mg, 0.60 mmol), sodium carbonate (126 mg, 1.2 mmol) in DMF (1.2 mL), and water (0.3 mL) was degassed, then treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.040 mmol) and stirred at 100 °C for 3 h. Additional [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.040 mmol) was added, and the reaction mixture was stirred at 100 °C for an additional 2 h. Additional 1H-pyrazole-4-boronic acid (67 mg, 0.60 mmol) and sodium carbonate (126 mg, 1.2 mmol) were added and the reaction mixture was stirred for 18 hours at 100° C. EtOAc and water were added and the mixture was filtered through a celite pad. (登録商標) The mixture was filtered through filtration and the layers were separated. The aqueous layer was extracted with EtOAc (x2) and the combined organic layers were washed with water, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in MeOH / DCM and purified with ISOLUTE (登録商標) Pre-adsorption onto an HM-N column (Biotage) and purification by silica gel chromatography (25 g cartridge) eluting with 0-5% MeOH / DCM gave a pink solid (25 mg). The solid residue from the initial filtration was washed repeatedly with 10% MeOH / DCM. After washing the solution with water, the aqueous layer was extracted with DCM (x2). The combined DCM extracts were washed with saturated aqueous NaHCO3 and saturated brine, dried (MgSO4), and concentrated under reduced pressure to a solid (112 mg). The two solids were combined, dissolved in MeOH / DCM, and purified with ISOLUTE (登録商標)Preabsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography (25 g cartridge) eluting with 0-5% MeOH / DCM to give a pink solid (89 mg). The solid was triturated with MeOH / DCM, filtered, and washed with MeOH / DCM and then with ether to give the title compound. A second crop was obtained from the mother liquor by the same trituration procedure. The two solids were combined, stirred in ether, and filtered to give the title compound (46 mg, 32%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.17(1H,s), 8.37(1H,s), 8.34(1H,s), 8.11(1H,s), 7.90(1H,s), 7.76(1H,s), 4.59(1H,hept,J=6.6Hz ), 4.10(2H,d,J=7.2Hz), 1.58(6H,d,J=6.7Hz), 1.38-1.28(1H,m), 0.60-0.55(2H,m), 0.46-0.42(2H,m). LCMS method 3: room temperature 3.27 min, [MH + ]365.1.

[0429] Example 21 3-Isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-chloro-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one iPrMgCl (1.3 M in THF, 7.25 mL, 9.42 mmol) was added dropwise to a cooled (0 °C) solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.38 g, 8.57 mmol) in THF (20 mL). The resulting white suspension was stirred for 10 min, and then ZnCl (1.9 M in 2-MeTHF, 5.86 mL, 11.1 mmol) was added dropwise. The resulting yellow solution was stirred for 30 min, after which Pd(PPh) (683 mg, 0.591 mmol) and 2-chloro-7-iodo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (2.00 g, 5.91 mmol) were added rapidly, and the resulting solution was heated to reflux. After 15 min, the reaction was cooled and diluted with DCM. The organic layer was washed with 10% aqueous citric acid and saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting yellow oil was washed with DCM and loaded onto a 120 g SiO2 cartridge and eluted with 10–70% EtOAc in DCM. The product-containing fractions were concentrated to give the title compound (1.13 g, 53%) as an off-white solid. 1 H NMR (400MHz, CDCl3)δ, ppm 8.24(1H,d,J=0.4Hz), 8.03(1H,d,J=0.6Hz), 7.63(1H,s), 5.47(1H,dd,J=3.1,9.1Hz), 5.26(1H,s ), 4.13-4.07(1H,m), 3.78-3.71(1H,m), 2.24-2.05(3H,m), 1.77-1.70(2H,m), 1.70-1.62(7H,m).

[0430] 3-Isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-methylimidazole-5-boronic acid using Suzuki-Miyaura general procedure 1 to afford 146 mg (77%) of the title compound as a white fluffy solid. 1 H NMR (400MHz, CDCl3)δ, ppm 8.16(1H,s), 8.03(1H,s), 7.82(1H,d,J=1.2Hz), 7.66(1H,s), 7.48(1H,d,J= 8.5Hz), 7.38-7.33(1H,m), 7.22(1H,d,J=3.1Hz), 6.63(1H,d,J=3.1Hz), 5.3 6(1H, dd, J=2.2, 9.5Hz), 4.39-4.27(1H,m), 4.06-3.99(1H,m), 3.90(3H,s), 3.70-3.63(1H,m), 2.16-2.01(1H,m), 2.06-1.97(2H,m), 1.78-1.55(9H,m).

[0431] 3-Isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via THP deprotection procedure 1 to give 18 mg (15%) of the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO) δ, ppm 8.13 (2H, s), 7.91 (1H, d, J = 1.2 Hz), 7.78 (1H, s), 7.65 (1H, d, J = 8.5 Hz), 7.51 (1H, d, J = 3.3 Hz), 7.45 (1H, dd, J = 1.7, 8.5 Hz), 6.59 (1H, d, J = 2.6 Hz), 4.24-4.13 (1H, m), 3.88 (3H, s), 1.49 (6H, d, J = 6.8 Hz), plus one exchangeable proton not observed. LCMS method 1: 3.80 min at room temperature, [MH + ]374.1.

[0432] Example 22 7-(1H-imidazol-5-yl)-3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.25 equivalents formate salt 3-Isopropyl-2-(1-methyl-1H-pyrazol-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using Suzuki-Miyaura general procedure 1 to afford 50 mg (46%) of the title compound as a white foam. LCMS method 4: room temperature 1.64 min, [MH + ]567.

[0433] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to afford 20.8 mg (71%) of the title compound as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.33(1H,s), 8.24(0.3H,s), 7.96(1H,d,J=2.2Hz), 7.81(1H,s), 7.74(1H,s), 7.66( 1H,s), 6.80(1H,d,J=2.2Hz), 4.72-4.64(1H,m), 3.98(3H,s), 1.54(6H,d,J=6.8Hz). LCMS method 1: 2.25 min at room temperature, [MH + ]325.3.

[0434] Example 23 7-(1H-imidazol-5-yl)-3-isopropyl-2-(6-(piperidin-1-yl)pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(6-(piperidin-1-yl)pyridin-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 2-(1-piperidyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using Suzuki-Miyaura general procedure 1 to afford 46 mg (37%) of the title compound as a white foam. LCMS method 4: room temperature 1.54 min, [MH + ]647.

[0435] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(6-(piperidin-1-yl)pyridin-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(6-(piperidin-1-yl)pyridin-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to afford 5.5 mg (19%) of the title compound as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.32(1H,s), 8.40(1H,d,J=2.3Hz), 7.81-7.77(2H,m), 7.72(1H,s), 7.61(1H,s), 6.97(1H,d, J=8.8Hz), 4.33-4.23(1H,m), 3.65(4H,t,J=5.3Hz), 1.68-1.55(6H,m), 1.53(6H,d,J=6.5Hz). LCMS method 7: room temperature 3.06 min, [MH + ]405.0.

[0436] Example 24 2-(3,5-dimethylphenyl)-3-isopropyl-7-(1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one

[0437] 2-(3,5-dimethylphenyl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 3,5-dimethylbenzeneboronic acid using Suzuki-Miyaura general procedure 1 to afford 28 mg (46%) of the title compound as a glassy solid in a 2:1 ratio. LCMS method 4: room temperature 1.70 min, [MH + ]591 and room temperature 1.74 minutes, [MH + ]607.

[0438] 2-(3,5-dimethylphenyl)-3-isopropyl-7-(1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(3,5-dimethylphenyl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to afford 6.3 mg (9% over 2 steps) of the title compound as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.26(1H,s), 7.78(1H,s), 7.73(1H,s), 7.54(1H,s), 7.31(2H,s), 7.25(1H,s), 4.12-4.02(1H,m), 2.38(6H,s), 1.49(6H,d,J=6.8Hz). LCMS method 1: 3.35 min at room temperature, [MH + ]349.3.

[0439] Example 25 2-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-(cyclohexylmethyl)-1H-imidazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a cooled (0 °C) solution of 1-(cyclohexylmethyl)-4-iodo-1H-imidazole (167 mg, 0.576 mmol) in THF (2.5 mL) was added iPrMgCl (1.3 M in THF, 0.532 mL, 0.691 mmol) dropwise. After stirring the reaction for 30 min, ZnCl (1.9 M in 2-MeTHF, 0.455 mL, 0.864 mmol) was added dropwise. After stirring the resulting yellow solution for 30 min, 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.192 mmol), XPhosPdG2 (15 mg, 10 mol%), and XPhos (9.0 mg, 10 mol%) were quickly added and the reaction was heated to reflux. After 1 h, the reaction was cooled and diluted with EtOAc. The organic layer was washed with 10% aqueous citric acid and saturated brine, dried (Na2SO4), and concentrated under reduced pressure. This crude mixture was loaded onto a 24 g SiO2 cartridge with DCM and eluted with 0–10% MeOH in DCM. The product-containing fractions were concentrated to give the title compound (40 mg, 32%) as a glassy solid. LCMS method 4: room temperature 1.85 min, [MH + ]649.

[0440] 2-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)-7-(1H-imidazol-5-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(1-(cyclohexylmethyl)-1H-imidazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give 5 mg (20%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.37(1H,s), 7.95(1H,d,J=1.2Hz), 7.90(1H,d,J=1.3Hz), 7.81(1H,s), 7.76(1H,s), 7.72(1H,s), 5.07-4.97(1H,m), 3.95(2H,d,J=7.2Hz), 1.85-1.56(12H,m), 1.26-1.12(3H,m), 1.04-0.92(2H,m). LCMS method 1: room temperature 3.32 min, [MH + ]407.3.

[0441] Example 26 7-(1H-imidazol-5-yl)-3-isopropyl-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.25 equivalents formate salt 3-Isopropyl-2-(thiophen-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane using Suzuki-Miyaura general procedure 1 to afford 106 mg of the title compound as a yellow oil. LCMS showed 57% purity and this compound was used without further purification. LCMS method 4: room temperature 1.92 min, [MH + ]569.

[0442] 7-(1H-imidazol-5-yl)-3-isopropyl-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.25 equivalents formate salt Synthesized from 3-isopropyl-2-(thiophen-3-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to afford 15 mg (24% over two steps) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.37(1H,s), 8.28(0.2H,s), 7.92(1H,d,J=4.9Hz), 7.81(1H,s), 7.74(1H,s), 7.64 -7.60(2H,m), 7.29(1H,dd,J=3.8, 4.8Hz), 4.52-4.41(1H,m), 1.57(6H,d,J=6.7Hz). LCMS method 1: room temperature 2.68 min, [MH + ]327.1.

[0443] Example 27 3-Isopropyl-7-(1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (130 mg, 76%) from 2-chloro-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane using Suzuki-Miyaura general procedure 1 gave 130 mg (76%) of the title compound as an off-white solid. LCMS method 4: room temperature 1.44 min, [MH + ]411.

[0444] 3-Isopropyl-7-(1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(thiophen-2-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via THP deprotection procedure 1 to give 22 mg (13%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.17(1H,s), 8.30(1H,s), 8.10(1H,s), 7.92(1H,dd,J=1.2,5.1Hz), 7.79(1H,s), 7.61(1H ,dd,J=1.2,3.6Hz), 7.29(1H,dd,J=3.6,5.1Hz), 4.52-4.42(1H,m), 1.57(6H,d,J=6.8Hz). LCMS method 1: room temperature 3.44 min, [MH + ]327.0.

[0445] Example 28 7-(1H-imidazol-4-yl)-3-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole according to Suzuki-Miyaura general procedure 1 to afford 54 mg (24%) of the title compound as an off-white solid. LCMS method 4: room temperature 1.59 min, [MH + ]567.

[0446] 7-(1H-imidazol-4-yl)-3-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give 2.6 mg (8%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.38(1H,s), 8.29(1H,s), 7.87(1H,s), 7.80(1H,d,J=0.8Hz), 7.71(1H,s), 7.70(1H,d,J=0.8Hz), 4.62-4.51(1H,m), 3.97(3H,s), 1.56(6H,d,J=6.8Hz). LCMS method 1: room temperature 2.11 min, [MH + ]325.

[0447] Example 29 7-(1H-imidazol-4-yl)-3-isopropyl-2-(1-methyl-1H-indol-5-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.3 eq formate 3-Isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole via Suzuki-Miyaura general procedure 1 to afford 26 mg (14%) of the title compound as an off-white solid. LCMS method 2: room temperature 1.67 min, [MH + ]616.

[0448] 7-(1H-imidazol-4-yl)-3-isopropyl-2-(1-methyl-1H-indol-5-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one, 0.3 eq formate Synthesized from 3-isopropyl-2-(1-methyl-1H-indol-5-yl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give 3.6 mg (23%) of the title compound as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.26(1H,s), 8.41(0.3H,s), 7.91(1H,d,J=1.2Hz), 7.77(1H,s), 7.74(1H,s), 7.65(1H,d,J=8.5Hz), 7.55(1H,s), 7.51(1H, d,J=3.1Hz), 7.45(1H,dd,J=1.6,8.4Hz), 6.59(1H,dd,J=0.7,3.1Hz), 4.24-4.13(1H,m), 3.88(3H,s), 1.49(6H,d,J=6.8Hz). LCMS method 1: room temperature 3.12 min, [MH + ]374.1.

[0449] Example 30 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide Ethyl 2-amino-2-cyanoacetate A saturated solution of NaHCO3 (440 mL, 1.2 M, 0.528 mol) was carefully added to a suspension of ethyl(hydroxyimino)cyanoacetate (75 g, 0.528 mol) in water (300 mL). After 15 min, sodium dithionite (255 g, 1.46 mol) was added portionwise over 30 min. The reaction temperature was raised to 40 °C and cooled in an ice bath. After 1 h, the ice bath was removed and the reaction temperature was allowed to return to room temperature. After 3 h, the reaction was saturated with NaCl and extracted with CHCl3 (4 × 500 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound (26.60 g, 40%) as a black oil. 1H NMR (300 MHz, CDCl) δ, ppm, 4.47 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 1.35 (3H, t, J = 7.1 Hz), plus two exchangeable protons not observed.

[0450] Ethyl 2-cyano-2-formamidoacetate A mixture of formic acid (16.3 mL, 433 mmol) and acetic anhydride (39.8 mL, 421 mmol) was heated to 55 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was allowed to cool, then added to THF (350 mL) and cooled to below 10 °C. A solution of ethyl 2-amino-2-cyanoacetate (30.0 g, 234 mmol) in THF (350 mL) was added via the addition funnel over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure (azeotropically dried with toluene (3 × 100 mL)). The residue was dissolved in DCM (20 mL) and loaded onto a 330 g SiO2 cartridge. The product was eluted with 0–40% EtOAc in cyclohexane. The product was concentrated to give the title compound (13.26 g, 36%) as an off-white solid. 1 H NMR(400MHz, CDCl3)δ, ppm 8.32(1H,s), 6.48(1H,s), 5.56(1H,d,J=7.6Hz), 4.39(2H,q,J=7.2Hz), 1.39(3H,t,J=7.1Hz).

[0451] Ethyl 3-amino-4-cyanopicolinate A solution of ethyl 2-cyano-2-formamidoacetate (13.00 g, 83.26 mmol), acrylonitrile (32.9 mL, 499.55 mmol), and TFA (6.4 mL, 83 mmol) in 1,2-dichloroethane (83 mL) was heated at reflux for 72 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting black residue was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was collected, and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and purified by ISOLUTE. (登録商標)The resulting mixture was loaded onto a HM-N column (Biotage). This was then loaded onto an 80 g SiO2 cartridge and eluted with 20-50% EtOAc in cyclohexane. The product was concentrated to give the title compound (8.78 g, 55%) as a white solid. 1 H NMR(400MHz, CDCl3)δ, ppm 8.12(1H,d,J=4.6Hz), 7.45(1H,d,J=4.6Hz), 6.56-6.44(2H,m), 4.49(2H,q,J=7.1Hz), 1.46(3H,t,J=7.1Hz).

[0452] 1-(Cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid Potassium carbonate (15.0 g, 107 mmol) and (bromomethyl)cyclopropane (14.0 mL, 143 mmol) were added to a solution of ethyl 4-pyrazolecarboxylate (10.0 g, 71.3 mmol). The resulting mixture was heated at reflux for 5 h. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting yellow oil was dissolved in THF (160 mL) and water (40 mL), treated with LiOH·HO (12.0 g, 285 mmol), and heated at reflux for 72 h. The reaction was cooled to room temperature, diluted with 1 M HCl (300 mL), and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated brine (300 mL), dried (MgSO), and concentrated under reduced pressure to give a white solid. The obtained solid was triturated with diethyl ether / cyclohexane (1:1, 200 mL) to give the title compound (7.32 g, 62%) as a white solid. 1 H NMR (400 MHz, CDCl) δ, ppm 8.09 (1H, s), 7.99 (1H, s), 4.03 (2H, d, J = 7.2 Hz), 1.38-1.26 (1H, m), 0.74-0.68 (2H, m), 0.41 (2H, q, J = 5.2 Hz). In addition, one exchangeable proton was not observed.

[0453] 1-(Cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carboxamide Oxalyl chloride (1.6 mL, 18.05 mmol) and DMF (9.3 μL, 0.120 mmol) were added to a stirred suspension of 1-(cyclopropylmethyl)-1H-pyrazole-4-carboxylic acid (2.00 g, 12.04 mmol) in DCM under a nitrogen atmosphere. After 4 h, the resulting clear solution was concentrated under reduced pressure (azeotropically dried with toluene (3 × 10 mL)) to give a colorless oil. This oil was dissolved in DCM (30 mL) and treated with a solution of isopropylamine (2.10 mL, 24.1 mmol) in DCM (20 mL). The resulting solution was stirred overnight. The reaction was diluted with DCM (40 mL), washed with saturated aqueous NH₄Cl (40 mL), dried (Na₂SO₄), and concentrated under reduced pressure to give the title compound (2.27 g, 91%) as a white solid. 1 H NMR (400MHz, CDCl3)δ, ppm 7.97(1H,s), 7.69(1H,s), 5.53(1H,d,J=5.7Hz), 4.30-4.21(1H,m), 3.98(2 H,d,J=7.2Hz), 1.25-1.23(7H,m), 0.71-0.65(2H,m), 0.39(2H,q,J=5.2Hz).

[0454] 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carbonitrile A solution of 1-(cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carboxamide (1.71 g, 8.25 mmol) in thionyl chloride (2 mL) was stirred at 80° C. under an argon atmosphere for 2 hours. The reaction was diluted with toluene (10 mL) and concentrated under reduced pressure (using azeotropic drying with toluene (2×10 mL)) to give 1-(cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carbimidoyl chloride. The resulting yellow oil was used in the next step without further purification. 1H NMR (400MHz, CDCl3)δ, ppm 8.11(1H,s), 7.89(1H,s), 4.16-4.06(1H,m), 3.98(2H,d,J=7.7Hz), 1.34-1.22(7H,m), 0.72-0.66(2H,m), 0.42-0.37(2H,m). A solution of 1-(cyclopropylmethyl)-N-isopropyl-1H-pyrazole-4-carbimidoyl chloride in MeCN (10 mL) was added to a solution of ethyl 3-amino-4-cyanopicolinate (1.50 g, 7.85 mmol) in MeCN (20 mL) under a nitrogen atmosphere. The resulting solution was heated at 50 °C. After 140 h, K2CO3 (4.34 g, 31.4 mmol) was added to the reaction mixture, and the resulting mixture was heated at 82 °C for 40 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting solid was loaded onto an 80 g SiO2 cartridge with DCM and eluted with 20–100% EtOAc in cyclohexane. The product was concentrated to give the title compound (0.928 g, 26.5%) as an off-white solid. 1 H NMR (400MHz, CDCl3)δ, ppm 8.86(1H,d,J=4.5Hz), 8.21(1H,s), 7.89(1H,s), 7.87(1H,d,J=4.5Hz), 5.06-4.94(1H,m), 4.09( 2H,d,J=7.3Hz), 1.76(6H,d,J=6.8Hz), 1.43-1.34(1H,m), 0.78-0.72(2H,m), 0.50-0.45(2H,m).

[0455] 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide Synthesized from 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidine-8-carbonitrile using the general nitrile hydrolysis procedure to give the title compound (95 mg, 60%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 9.37(1H,d,J=2.5Hz), 8.86(1H,d,J=4.5Hz), 8.35(1H,s), 8.24(1H,d,J=4.5Hz), 8.10(1H,d,J=2.3Hz), 7.91(1H,s), 4. 84-4.73(1H,m), 4.10(2H,d,J=7.2Hz), 1.63(6H,d,J=6.7Hz), 1.36-1.27(1H,m), 0.60-0.55(2H,m), 0.46-0.41(2H,m). LCMS method 1: room temperature 3.18 min, [MH + ]353.0.

[0456] Example 31 3-Isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide N-Isopropylbenzamide A solution of isopropylamine (7.40 mL, 86.2 mmol) in DCM (30 mL) was added dropwise to a solution of benzoyl chloride (5.00 mL, 43.1 mmol) in DCM (50 mL). After 30 min, the reaction was quenched with water and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (6.36 g, 90%) as a white solid. 1 H NMR (400MHz, CDCl3)δ, ppm 7.76-7.74(2H,m), 7.50-7.45(1H,m), 7.44-7.38(2H,m), 6.03(1H,s), 4.33-4.24(1H,m), 1.27-1.25(6H,m).

[0457] 3-Isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carbonitrile A solution of N-isopropylbenzamide (1.71 g, 10.46 mmol) in thionyl chloride (2 mL) was stirred at 80° C. under an argon atmosphere for 2 hours. The reaction mixture was diluted with toluene (10 mL) and concentrated under reduced pressure (azeotropic drying with toluene (2×10 mL)). The resulting yellow oil of N-isopropylbenzimidoyl chloride was used in the next step without further purification. 1 H NMR(400MHz, CDCl3)δ, ppm 7.99(2H,d,J=7.3Hz), 7.46-7.37(3H,m), 4.22-4.12(1H,m), 1.29(6H,d,J=6.4Hz). A solution of N-isopropylbenzimidoyl chloride in MeCN (10 mL) was added to a solution of ethyl 3-amino-4-cyanopicolinate (2.00 g, 10.46 mmol) in MeCN (30 mL) under a nitrogen atmosphere. The resulting solution was heated at 50 °C. After 96 h, K2CO3 (5.78 g, 41.8 mmol) was added to the reaction mixture, and the resulting mixture was heated at 82 °C for 50 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting solid was loaded onto a 220 g SiO2 cartridge with DCM and eluted with 20–40% EtOAc in cyclohexane. The product was concentrated to give the title compound (1.46 g, 48%) as an off-white solid. 1 H NMR(400MHz, CDCl3)δ, ppm 8.95(1H,d,J=4.5Hz), 7.91(1H,d,J=4.5Hz), 7.60-7.55(5H,m), 4.51-4.43(1H,m), 1.64(6H,d,J=6.8Hz). LCMS method 1: room temperature 4.15 min, [MH + ]291.3.

[0458] 3-Isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carboxamide Synthesized from 3-isopropyl-4-oxo-2-phenyl-3,4-dihydropyrido[3,2-d]pyrimidine-8-carbonitrile using the general nitrile hydrolysis procedure to give the title compound (92 mg, 86%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 9.21(1H,s), 8.93(1H,d,J=4.6Hz), 8.26(1H,d,J=4.6Hz), 8.04(1H,s), 7.7 1-7.68(2H,m), 7.61-7.59(3H,m), 4.28-4.18(1H,m), 1.53(6H,d,J=6.8Hz). LCMS method 1: 3.40 min at room temperature, [MH + ]309.1.

[0459] Synthesis of pyrazole spirodiazetidines tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 5-Isopropyl-1H-pyrazole-3-carboxylic acid (1.6 g, 10.4 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (3.0 g, 10.4 mmol) were suspended in DMF (30 mL). Triethylamine (5.8 mL, 41.6 mmol) was added, followed by the portionwise addition of HATU (9.9 g, 26.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with water and 2-methyl-THF. The layers were separated, and the aqueous layer was extracted with 2-methyl-THF (x2). The combined organic layers were washed with water (x2), then saturated brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting compound was triturated with ethyl acetate to give the title compound (2.0 g, 57%) as a white solid. LCMS method 4: room temperature 1.29 min, [MH + ]335.3.

[0460] Pyrazole spirodiazetidinamides (general synthesis) Pyrazole spirodiazetidinamide basic procedure 1 tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (75 mg, 0.22 mmol) was suspended in DCM (1 mL). To this was added MsOH (30 μL, 0.45 mmol). The resulting solution was stirred at room temperature for 2-4 h. EtN (0.13 mL, 0.90 mmol) was added, followed by the carboxylic acid (0.25 mmol) and HATU (111 mg, 0.3 mmol), in that order. The reaction was stirred at room temperature for an additional 90 min-16 h. The solvent was removed under reduced pressure, and the sample was dissolved in 10% water in DMSO and purified by reverse-phase preparative HPLC.

[0461] Pyrazole spirodiazetidinamide basic procedure 2 tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (290 mg, 0.86 mmol) was deprotected using Amberlyst 15 Hydrogen Form (2 g) in MeOH (20 mL) for 2 h. To this suspension was added 2 M NH3 in MeOH (20 mL) and stirred for 1 h. The reaction mixture was filtered and concentrated to give crude (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptane-2-yl)methanone. The isolated material was divided into portions and coupled with four carboxylic acids. HATU (97 mg, 0.26 mmol) and the carboxylic acid (0.24 mmol) were dissolved in DCM (1 mL) and EtN (35 μL, 0.26 mmol). The mixture was stirred for 10 min. To this was added a solution of (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone (50 mg, 0.21 mmol) and EtN (35 μL, 0.26 mmol) in DCM (2 mL). The reaction mixture was stirred for 16 h, then concentrated under reduced pressure, redissolved in 2-methyl-THF, washed twice with water, then with saturated brine, and dried (NaSO). The resulting solution was concentrated under reduced pressure and purified.

[0462] Pyrazole spirodiazetidinamide basic procedure 3 After stirring for 16 h, the reaction mixture was concentrated under reduced pressure and purified directly by reverse phase chromatography as in general pyrazole spirodiazetidinamide procedure 2.

[0463] Pyrazole spirodiazetidinamide basic procedure 4 To a solution / suspension of carboxylic acid (1 eq) in DCM (0.2 M) was added triethylamine (2.4 eq), followed by HATU (1.2 eq). After stirring the reaction mixture at room temperature for 15 minutes, (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone (1 eq) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product.

[0464] Example 32 1-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]propan-1-one Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and propionic acid using the pyrazolespirodiazetidine general procedure 1. Reverse phase preparative HPLC afforded the title compound (30 mg) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.00(1H,s), 6.37(1H,s), 4.59(2H,br s), 4.29-4.26(2H,m), 4.14(2H,br s), 4.03-4.00(2H,m), 3.00-2.92(1H,m), 2.04(2H,q,J=7.5Hz), 1.22(6H,d,J=6.9Hz), 0.96(3H,t,J=7.5Hz). LCMS method 8: Room temperature 2.77 min [MH + ]291.3.

[0465] Example 33 (5-Isopropyl-1H-pyrazol-3-yl)-[2-(spiro[2.2]pentane-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and spiro[2.2]pentane-2-carboxylic acid using the pyrazole spirodiazetidine general procedure 1. Reverse phase preparative HPLC afforded the title compound (37 mg) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.99(1H,s), 6.37(1H,s), 4.59(2H,s), 4.38-4.37(1H,m), 4.29-4.26(1H,m), 4.16(2H,s), 4.01(2H, d,J=2.0Hz), 2.96-2.92(1H,m), 1.89-1.86(1H,m), 1.27-1.18(6H,m), 0.87-0.82(4H,m), 0.72(2H,s). LCMS method 8: Room temperature 3.16 min [MH + ]329.0.

[0466] Example 34 1-[6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl]-2-methyl-propan-1-one Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 2-methylpropanoic acid using the pyrazolespirodiazetidine general procedure 1. Reverse phase preparative HPLC afforded the title compound (10 mg) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.99(1H,s), 6.37(1H,d,J=1.5Hz), 4.62-4.59(2H,m), 4.36-4.30(2H,m), 4.16-4.14(2H,m), 4.0 3-4.00(2H,m), 3.03-2.92(1H,m), 2.46-2.38(1H,m), 1.23(6H,d,J=6.9Hz), 0.97(6H,d,J=6.8Hz). LCMS method 8: Room temperature 3.01 min [MH + ]305.0.

[0467] Example 35 1-[6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl]-2,2-dimethylpropan-1-one Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and pivalic acid using the pyrazolespirodiazetidine general procedure 1. Reverse phase preparative HPLC afforded the title compound (37 mg) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.00(1H,s), 6.37(1H,s), 4.61(2H,s), 4.54(2H,br s), 4.17-4.15(2H,m), 4.01(2H,br s), 3.03-2.92(1H,m), 1.23(6H,d,J=6.9Hz), 1.11(9H,s). LCMS method 8: Room temperature 3.23 min [MH + ]319.0.

[0468] Example 36 (5-Isopropyl-1H-pyrazol-3-yl)-[2-(4-methylthiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 4-methylthiophene-2-carboxylic acid via pyrazolespirodiazetidine general procedure 2. Purification by reverse phase chromatography afforded the title compound (20 mg, 26%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.99(1H,s), 7.39(1H,s), 7.31(1H,d,J=1.0Hz), 6.37(1H,d,J=1.2Hz), 4.63(4 H,s), 4.21-4.17(4H,m), 3.01-2.91(1H,m), 2.23(3H,s), 1.21(6H,d,J=7.0Hz). LCMS method 1: Room temperature 3.46 min [MH + ]359.1.

[0469] Example 37 [2-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 1-(2,2,2-trifluoroethyl)pyrazole-3-carboxylic acid using pyrazolespirodiazetidine general procedure 2. Purification by reverse-phase preparative HPLC afforded 37.0 mg (42%) of the title compound as a white solid after lyophilization. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.98(1H,s), 7.93(1H,d,J=2.4Hz), 6.71(1H,d,J=2.4Hz), 6.36(1H,s), 5.20(2H,q,J=9. 1Hz), 4.62(4H,d,J=5.4Hz), 4.22-4.15(4H,m), 3.00-2.91(1H,m), 1.21(6H,d,J=6.9Hz). LCMS method 1: Room temperature 3.32 min [MH + ]411.0.

[0470] Example 38 [1-(2,2-Difluoroethyl)pyrazol-3-yl]-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 1-(2,2-difluoroethyl)pyrazole-3-carboxylic acid via pyrazolespirodiazetidine general procedure 2. Purification by reverse phase chromatography afforded the title compound (18.3 mg, 22%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.97(1H,s), 7.88-7.87(1H,m), 6.68(1H,d,J=2.4Hz), 6.43(1H,tt,J=3.7,54.8Hz), 6.38(1H,s), 4.70(2 H,dt,J=3.6,15.0Hz), 4.64(4H,d,J=5.0Hz), 4.22-4.18(4H,m), 3.02-2.91(1H,m), 1.23(6H,d,J=7.0Hz). LCMS method 7: Room temperature 3.27 min [MH + ]393.0.

[0471] Example 39 [2-(1,4-dimethylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 1,4-dimethylpyrazole-3-carboxylic acid via pyrazole spirodiazetidine general procedure 3. After lyophilization, a white solid (46.7 mg, 61%) was obtained. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.97(1H,d,J=0.8Hz), 7.53(1H,s), 6.36(1H,d,J=1.5Hz), 4.62(2H,s), 4.58(2H,s), 4.17-4.14(4H,m), 3.80(3H,s), 2.99-2.92(1H,m), 2.15(3H,s), 1.21(6H,d,J=7.0Hz). LCMS method 1: Room temperature 3.04 min [MH + ]357.1.

[0472] Example 40 N-Isopropyl-6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 0.15 mmol) was suspended in acetonitrile (1 mL). To this was added MsOH (50 μL, 0.75 mmol). The resulting solution was stirred at room temperature for 30 min, followed by EtN (0.21 mL, 1.50 mmol) and isopropyl isocyanate (59 μL, 0.60 mmol). The reaction was stirred at room temperature for an additional 16 h. The solvent was removed under reduced pressure, and the sample was dissolved in 10% water in DMSO and purified by reverse-phase preparative HPLC. This afforded the title compound (27.3 mg, 57%) as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 12.97(1H,s), 6.36(1H,s), 6.10-6.05(1H,m), 4.55(2H,s), 4.10(2H,s), 3.91(4H,s) , 3.73-3.62(1H,m), 2.99-2.92(1H,m), 1.21(6H,d,J=6.9Hz), 1.02(6H,d,J=6.8Hz). LCMS method 7: Room temperature 2.98 min [MH + ]320.0.

[0473] Example 41 N-Ethyl-6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.30 mmol) was suspended in acetonitrile (1 mL). To this was added MsOH (100 μL, 1.5 mmol). The resulting solution was stirred at room temperature for 30 min. EtN (0.42 mL, 3.0 mmol) was added, followed by ethyl isocyanate (50 μL, 3.0 mmol). The reaction was stirred at room temperature for an additional 1 h. The solvent was removed under reduced pressure, and the sample was dissolved in 10% water in DMSO and purified by reverse-phase preparative HPLC to give the title compound (47.6 mg, 52%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.99(1H,s), 6.35(1H,s), 6.34-6.28(1H,m), 4.56(2H,s), 4.10(2H,s), 3.96 -3.87(4H,m), 3.03-2.91(3H,m), 1.21(6H,d,J=6.8Hz), 0.98(3H,t,J=7.1Hz). LCMS method 7: Room temperature 2.92 min [MH + ]306.0.

[0474] Example 42 (5-Isopropyl-1H-pyrazol-3-yl)-[2-(pyrrolidine-1-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.60 mmol) was suspended in acetonitrile (3 mL). MsOH (80 μL, 1.2 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes. EtN (0.5 mL, 3.6 mmol) was added, followed by CDI (160 mg, 1.0 mmol). A half-portion of the reaction mixture was removed. Pyrrolidine (0.25 mL, 3.1 mmol) was added to the reaction mixture. The reaction mixture was heated to 60°C and stirred for 24 hours, then at 80°C for 2 hours and at 100°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the sample was dissolved in 10% water in DMSO and purified by reverse-phase preparative HPLC to give the title compound (29.5 mg, 29%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.98(1H,s), 6.36(1H,s), 4.55(2H,s), 4.11(2H,s), 4.04-4.01(4H,m), 3.2 2-3.16(4H,m), 2.99-2.91(1H,m), 1.78-1.73(4H,m), 1.21(6H,d,J=6.9Hz). LCMS method 7: Room temperature 3.01 min [MH + ]332.3.

[0475] Example 43 N-Ethyl-6-(5-isopropyl-1H-pyrazole-3-carbonyl)-N-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide tert-Butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.30 mmol) was suspended in acetonitrile (2 mL). To this was added MsOH (80 μL, 1.2 mmol). The resulting solution was stirred at room temperature for 1 hour. EtN (0.3 mL, 2.4 mmol) was added, followed by CDI (53 mg, 0.33 mmol). The reaction mixture was heated to 100°C and stirred for 4 hours, then at 120°C for 2 hours. N-Ethylmethylamine (0.26 mL, 3.0 mmol) was added, and the reaction was heated to 120°C for 8 hours, then at 150°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the sample was dissolved in 10% water in DMSO and purified by reverse-phase preparative HPLC to give the title compound (24.2 mg, 25%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.97(1H,s), 6.36(1H,s), 4.56(2H,s), 4.11(2H,s), 4.06-4.00(4H,m), 3.13(2H,q,J =7.1Hz), 3.00-2.90(1H,m), 2.71(3H,s), 1.21(6H,d,J=7.0Hz), 1.01(3H,t,J=7.2Hz). LCMS method 7: Room temperature 2.99 min [MH + ]320.3.

[0476] Example 44 (1-Ethylpyrazol-3-yl)-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone Synthesized from tert-butyl 6-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and 1-ethylpyrazole-3-carboxylic acid via pyrazolespirodiazetidine general procedure 3 to give the title compound (46.7 mg, 61%) as a white solid after lyophilization. 1H NMR (400 MHz, d6-DMSO) δ, ppm 7.81-7.79 (1H, m), 6.58 (1H, d, J = 2.3 Hz), 6.36 (1H, d, J = 1.2 Hz), 4.63 (4H, d, J = 3.7 Hz), 4.21-4.14 (6H, m), 2.99-2.92 (1H, m), 1.38 (3H, t, J = 7.2 Hz), 1.21 (6H, d, J = 7.2 Hz). In addition, one exchangeable proton was not observed. LCMS method 1: Room temperature 3.04 min [MH + ]357.1.

[0477] Example 45 tert-Butyl (2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate tert-Butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol), tert-butyl (2-bromoethyl)carbamate (2.43 g, 10.82 mmol), and potassium carbonate (2.14 g, 15.46 mmol) in DMF (30 mL) was heated at 50 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% ethyl acetate / cyclohexane mixture, to give the title compound (567 mg, 22%) as a white solid. LCMS method 5: room temperature 1.41 min, [MH + -56]282,[MH + -100]238.

[0478] tert-Butyl (2-(4-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate A mixture of 2-bromo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (90 mg, 0.35 mmol), tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (165 mg, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol), cesium carbonate (171 mg, 0.53 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and then heated at 100°C for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-4% MeOH in DCM to give the title compound (80 mg, 59%) as a yellow oil. LCMS method 2: room temperature 1.06 min, [MH + ]388.

[0479] tert-Butyl (2-(4-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate To a solution of tert-butyl (2-(4-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (120 mg, 0.31 mmol) in DMF (3 mL) was added NBS (61 mg, 0.34 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (140 mg, 99%) as a yellow oil. LCMS method 2: room temperature 1.37 min, [MH + ]466&468.

[0480] tert-Butyl (2-(4-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate A mixture of tert-butyl (2-(4-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (140 mg, 0.30 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol), and cesium carbonate (147 mg, 0.45 mmol), dioxane (5 mL), and water (0.5 mL) was degassed with argon and heated at 100° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound (52 mg, 32%) as a yellow oil. LCMS method 4: room temperature 1.34 min, [MH + ]538.

[0481] tert-Butyl (2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate To a solution of tert-butyl (2-(4-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (52 mg, 0.10 mmol) in MeOH (3 mL) was added aqueous HCl (0.4 mL, 1 M, 0.4 mmol), and the reaction mixture was stirred at room temperature for 16 h. An additional aliquot of aqueous HCl (0.4 mL, 1 M, 0.4 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was basified with 7N NH3 in methanol and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-5% (7N NH3 / MeOH) in DCM. The product was repurified by reverse phase preparative HPLC to give the title compound (9 mg, 20%) as a white solid after lyophilization. 1 H NMR (400 MHz, CDCl) δ, ppm 8.17 (2H, s), 7.82 (1H, s), 7.79 (1H, s), 7.67 (1H, s), 4.94 (1H, br s), 4.67 (1H, sept, J = 6.8 Hz), 4.36 (2H, d, J = 5.7 Hz), 3.71–3.61 (2H, m), 1.69 (6H, d, J = 6.8 Hz), 1.44 (9H, s). In addition, one exchangeable proton was not observed. LCMS method 1: Room temperature 3.46 min, [MH + ]454.3.

[0482] Example 46 3-Isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 2-bromo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.39 mmol), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol), cesium carbonate (190 mg, 0.58 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and heated at 100 °C for 16 h. An additional aliquot of tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol) was added, and the reaction was heated for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine, dried (MgSO), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound (50 mg, 42%) as a yellow oil. LCMS method 2: room temperature 1.08 min, [MH + ]303.

[0483] 7-Bromo-3-isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.17 mmol) in DMF (2 mL) was added NBS (32 mg, 0.18 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (45 mg, 71%) as a yellow oil. LCMS method 4: room temperature 1.15 min, [MH + ]381&383.

[0484] 3-Isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 7-bromo-3-isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (45 mg, 0.12 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol), cesium carbonate (58 mg, 0.18 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and heated at 100° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure to give the title compound (83 mg, 156%) as a yellow oil which was used in the next reaction. LCMS method 4: room temperature 1.21 min, [MH + ]453.

[0485] 3-Isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (83 mg, ∼0.12 mmol) in MeOH (3 mL) was added HCl solution (2 mL, 1 M, 2.00 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative HPLC. After lyophilization, the title compound (10 mg, 23%) was obtained as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 13.16(1H,s), 8.29(1H,s), 8.22(2H,s), 7.91(1H,s), 7.76(1H,s), 4.57(1H,sept,J=6 .7Hz), 4.40(2H,t,J=5.3Hz), 3.77(2H,t,J=5.3Hz), 3.27(3H,s), 1.57(6H,d,J=6.8Hz) LCMS method 1: room temperature 2.91 min, [MH + ]369.

[0486] Example 47 N-(2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide N-(2-(4-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide A mixture of 2-bromo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.39 mmol), N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide (100 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol), cesium carbonate (195 mg, 0.60 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon, and the reaction mixture was heated at 100°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% MeOH in DCM to give the title compound (51 mg, 52%) as a yellow oil. LCMS method 4: room temperature 0.85 min, [MH + ]330.

[0487] N-(2-(4-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide To a solution of N-(2-(4-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide (81 mg, 0.25 mmol) in DMF (3 mL) was added NBS (48 mg, 0.27 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure to give the title compound as a yellow oil. The aqueous layer was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give a second batch of the desired product as a yellow oil. Both batches were combined to give the title compound (75 mg, 75%). LCMS method 5: room temperature 0.93 min, [MH + ]408&410.

[0488] N-(2-(4-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide A mixture of N-(2-(4-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide (75 mg, 0.18 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (72 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol), cesium carbonate (90 mg, 0.28 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and heated at 100 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The residue was purified by silica gel chromatography, eluting with 0-10% MeOH in DCM to give the title compound (51 mg, 58%) as a yellow oil. LCMS method 4: room temperature 1.06 min, [MH + ]480.

[0489] N-(2-(4-(3-isopropyl-4-oxo-7-(1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide To a solution of N-(2-(4-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)acetamide (51 mg, 0.11 mmol) in methanol (3 mL) was added aqueous HCl (1 mL, 1 M, 1.00 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was made basic by the addition of 7N NH3 in MeOH, concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% (7N NH3 / MeOH) in DCM, to give the title compound (10 mg, 25%) as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 13.17(1H,s), 8.34(1H,s), 8.27(1H,s), 8.12(1H,s), 8.02(1H,t,J=5.6Hz), 7.92(1H,s), 7.76(1H,s), 4. 58(1H,sept,J=6.8Hz), 4.27(2H,t,J=5.9Hz), 3.50(2H,q,J=5.9Hz), 1.80(3H,s), 1.56(6H,d,J=6.8Hz). LCMS method 1: room temperature 2.48 min, [MH + ]396.

[0490] Example 48 3-Isopropyl-7-(1H-pyrazol-4-yl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.94 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole (409 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (109 mg, 0.09 mmol), cesium carbonate (613 mg, 1.88 mmol), dioxane (5 mL), and water (0.5 mL) was degassed with argon, and the reaction mixture was heated at 100° C. for 16 hours. An additional aliquot of tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) was added, and the reaction mixture was heated for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the title compound (100 mg, 31%) as a yellow oil. LCMS method 5: room temperature 1.18 min, [MH + ]341.

[0491] 7-Bromo-3-isopropyl-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (99 mg, 0.29 mmol) in DMF (4 mL) was added NBS (57 mg, 0.32 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (146 mg, 120%) as a yellow oil. LCMS method 4: room temperature 1.33 min, [MH + ]419&421.

[0492] 3-Isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 7-bromo-3-isopropyl-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (~122 mg, ~0.29 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (136 mg, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol), cesium carbonate (170 mg, 0.52 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and heated at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine, dried (MgSO), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give the title compound (100 mg, 58%) as a yellow oil. LCMS method 2: room temperature 1.25 min, [MH + ]491.

[0493] 3-Isopropyl-7-(1H-pyrazol-4-yl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.20 mmol) in MeOH (3 mL) was added aqueous HCl (4 mL, 1 M, 4.00 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was made basic by the addition of 7N NH in MeOH and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0–5% (7N NH in MeOH) in DCM. The residue was triturated with warm acetonitrile and collected by filtration to give the title compound (20 mg, 24%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.17(1H,s), 8.42(1H,s), 8.33(1H,s), 8.12(1H,s), 7.95(1H,s), 7.77(1H,s), 4.58-4.48(3H,m), 3.04-2.91(2H,m), 1.56(6H,d,J=6.6Hz). LCMS method 1: room temperature 3.54 min, [MH + ]407.

[0494] Example 49 3-Isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.94 mmol), 1-(1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (421 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (109 mg, 0.09 mmol), cesium carbonate (613 mg, 1.88 mmol), dioxane (5 mL), and water (0.5 mL) was degassed with argon and the reaction mixture was heated at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by ISOLUTE®. (登録商標) The residue was purified by silica gel chromatography, loaded onto a HM-N column (Biotage) and eluted with 0-10% MeOH in DCM to give the title compound (114 mg, 33%) as a yellow oil. LCMS method 5: room temperature 1.37 min, [MH + ]349.

[0495] 7-Bromo-3-isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (114 mg, 0.33 mmol) in DMF (3 mL) was added NBS (64 mg, 0.36 mmol) and stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure to give the title compound (149 mg, 105%) as a yellow oil. LCMS method 5: room temperature 1.56 min, [MH + ]427&429.

[0496] 3-Isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A mixture of 7-bromo-3-isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (~140 mg, ~0.32 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (136 mg, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol), cesium carbonate (170 mg, 0.52 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and heated at 100 °C for 2.5 h. The reaction mixture was concentrated under reduced pressure to give ISOLUTE (登録商標) The residue was loaded onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with 0-10% MeOH in DCM. The residue was re-purified by silica gel chromatography eluting with 0-100% ethyl acetate in cyclohexane to give the title compound (44 mg, 25%) as a yellow oil. LCMS method 5: room temperature 1.59 min, [MH + ]499.

[0497] 3-Isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 3-isopropyl-2-(1-(1-phenylethyl)-1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (44 mg, 0.09 mmol) in MeOH (3 mL) was added aqueous HCl (2 mL, 1 M, 2.00 mmol), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was made basic by the addition of 7N NH in MeOH and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0–10% MeOH in DCM, to give the title compound (17 mg, 46%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.16(1H,s), 8.47(1H,s), 8.33(1H,s), 8.11(1H,s), 7.94(1H,s), 7.76(1H,s), 7.43~7.26(5H,m ), 5.79(1H,q,J=7.0Hz), 4.56(1H,sept,J=6.8Hz), 1.89(3H,d,J=7.0Hz), 1.56(6H,t,J=7.1Hz). LCMS method 9: room temperature 3.91 min, [MH + ]415.

[0498] Example 50 7-(1H-imidazol-4-yl)-2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-Isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and (1-isopentylpyrazol-4-yl)boronic acid using Suzuki-Miyaura general procedure 1 to afford the title compound (72 mg, 60%) as a yellow oil. LCMS method 2: room temperature 1.61 min, [MH + ]623.

[0499] 7-(1H-imidazol-4-yl)-2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to afford the title compound (20 mg, 45%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.34(1H,s), 8.34(1H,s), 7.89(1H,s), 7.80(1H,s), 7.71(2H,s), 4.56(1H,sept,J=6.9H z), 4.25(2H,t,J=7.4Hz), 1.76(2H,q,J=7.4Hz), 1.60-1.48(7H,m), 0.93(6H,d,J=6.7Hz). LCMS method 1: room temperature 3.17 min, [MH + ]381.

[0500] Example 51 tert-Butyl (2-(4-(7-(1H-imidazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate tert-Butyl (2-(4-(3-isopropyl-4-oxo-7-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and [1-[2-(tert-butoxycarbonylamino)ethyl]pyrazol-4-yl]boronic acid according to Suzuki-Miyaura general procedure 1 to afford the title compound (63 mg, 47%) as a yellow oil. LCMS method 2: room temperature 1.46 min, [MH + ]696.

[0501] tert-Butyl (2-(4-(7-(1H-imidazol-4-yl)-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate A suspension of tert-butyl (2-(4-(3-isopropyl-4-oxo-7-(1-trityl-1H-imidazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate in methanol (90 mM) was treated with 1N aqueous HCl (6 eq), and the reaction mixture was stirred at room temperature for 21 h. The reaction was quenched with 7N ammonia in methanol, and the reaction mixture was evaporated to dryness. Purification by reverse phase chromatography afforded the title compound (8 mg, 27%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.34(1H,s), 8.26(1H,s), 7.90(1H,s), 7.80(1H,s), 7.73(1H,s), 7.71(1H,s), 7.00(1H,t,J=5.5Hz), 4. 60(1H,sept,J=6.8Hz), 4.26(2H,t,J=6.1Hz), 3.40(2H,d,J=6.1Hz), 1.57(6H,d,J=6.8Hz), 1.35(9H,s). LCMS method 3: room temperature 2.71 min, [MH + ]454.3.

[0502] Example 52 7-(1H-imidazol-4-yl)-3-isopropyl-2-(4-(piperidin-1-yl)phenyl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(4-(piperidin-1-yl)phenyl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and [4-(1-piperidyl)phenyl]boronic acid using Suzuki-Miyaura general procedure 1 to afford the title compound (68 mg, 55%) as a yellow oil. LCMS method 2: room temperature 1.74 min, [MH + ]646.

[0503] 7-(1H-imidazol-4-yl)-3-isopropyl-2-(4-(piperidin-1-yl)phenyl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(4-(piperidin-1-yl)phenyl)-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give the title compound (12 mg, 29%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.29(1H,s), 7.78(1H,s), 7.71(1H,s), 7.58(1H,s), 7.51(2H,d,J=8.6Hz), 7.08(2H,d,J=8. 6Hz), 4.27(1H,sept,J=6.8Hz), 3.33-3.27(4H,m), 1.67-1.55(6H,m), 1.51(6H,d,J=6.8Hz). LCMS method 1: room temperature 3.36 min, [MH + ]404.4.

[0504] Example 53 7-(1H-imidazol-4-yl)-2-(1H-indol-2-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1H-indol-2-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (49 mg, 43%) as a yellow oil from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and indole-2-boronic acid according to Suzuki-Miyaura general procedure 1. LCMS method 2 Room temperature 1.67 min, [MH + ]602.

[0505] 7-(1H-imidazol-4-yl)-2-(1H-indol-2-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(1H-indol-2-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give the title compound (8 mg, 27%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.38(1H,s), 11.86(1H,s), 7.85-7.74(3H,m), 7.70(1H,d,J=8.0Hz), 7.56(1H,d,J=8.0Hz), 7.28(1 H,t,J=7.7Hz), 7.14(1H,t,J=7.7Hz), 6.98(1H,s), 4.59(1H,sept,J=6.8Hz), 1.60(6H,d,J=6.8Hz). LCMS method 1: room temperature 3.43 min, [MH + ]360.2.

[0506] Example 54 2-(1-(2-hydroxy-1-phenylethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (2-Bromo-2-phenylethoxy)(tert-butyl)dimethylsilane To a solution of 2-bromo-2-phenylethan-1-ol (2.00 g, 9.95 mmol) in THF (50 mL), tert-butyldimethylsilyl chloride (1.80 g, 11.94 mmol) and imidazole (0.88 g, 12.93 mmol) were added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were dried (MgSO4) and concentrated under reduced pressure to give the title compound (3.3 g, quant) as a colorless oil. 1 H NMR (400MHz, CDCl3)δ, ppm 7.42-7.25(5H,m), 4.91(1H,t,J=6.9Hz), 4.09(1H,dd,J=10.8,6.7Hz), 3.99(1H,dd,J=10.8,7.1Hz), 0.81(9H,s), 0.00(3H,s), -0.06(3H,s).

[0507] 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), (2-bromo-2-phenylethoxy)(tert-butyl)dimethylsilane (2.44 g, 7.73 mmol), cesium carbonate (5.04 g, 15.46 mmol), and potassium iodide (0.43 g, 2.58 mmol) in DMF (20 mL) was heated at 60 °C for 48 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-70% ethyl acetate in cyclohexane, to give the title compound (394 mg, 18%) as a white solid. 1H NMR (400MHz, CDCl3)δ, ppm 7.91(1H,s), 7.86(1H,s), 7.46-7.25(5H,m), 5.47(1H,dd,J=7.1,5.6Hz), 4.47(1H,dd,J=10. 6,7.1Hz), 4.25(1H,dd,J=10.5,5.6Hz), 1.38(12H,s), 0.87(9H,s), 0.01(3H,s), 0.00(3H,s).

[0508] 2-(1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (41 mg, 26%) as a yellow oil from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to Suzuki-Miyaura general procedure 1. LCMS method 4 Room temperature 1.89 min, [MH + ]629.

[0509] 2-(1-(2-hydroxy-1-phenylethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (78 mg, 0.12 mmol) in MeOH (0.5 mL) A solution of hydrochloric acid in dioxane (4N, 3 mL, 12.00 mmol) was added, stirred at room temperature for 20 minutes, and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography to obtain the title compound (26 mg, 49%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.18(1H,s), 8.53(1H,s), 8.24(2H,s), 7.98(1H,s), 7.77(1H,s), 7.46-7.30(5H,m), 5.64(1H,dd,J=9.0,4.8 Hz), 5.26(1H,br, s), 4.60(1H,sept,J=6.7Hz), 4.36-4.28(1H,m), 4.03-3.96(1H,m), 1.58(6H,t,J=6.6Hz). LCMS method 8: room temperature 3.34 min, [MH + ]431.0.

[0510] Example 55 2-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (63 mg, 79%) as a yellow oil from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole according to Suzuki-Miyaura general procedure 1. LCMS method 4: room temperature 1.52 min, [MH +]477.

[0511] 2-(1-Cyclohexyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one To a solution of 2-(1-cyclohexyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.13 mmol) in MeOH (2 mL), HCl solution (1 M, 3 mL, 3 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography to obtain the title compound (24 mg, 46%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.18(1H,s), 8.36(1H,s), 8.25(2H,s), 7.91(1H,s), 7.77(1H,s), 4.59(1H,sept,J=6.8Hz), 4.30(1H,tt,J=11.5,3 .7Hz), 2.16-2.06(2H,m), 1.91-1.66(5H,m), 1.58(6H,d,J=6.8Hz), 1.51-1.36(2H,m), 1.26(1H,qt,J=12.6,3.5Hz). LCMS method 7: room temperature 4.05 min, [MH + ]393.0.

[0512] Example 56 (5-Isopropyl-1H-pyrazol-3-yl)(3-(6-methyl-4-(p-tolyl)pyridin-2-yl)azetidin-1-yl)methanone tert-Butyl 3-(2-(3-methylisoxazol-5-yl)acetyl)azetidine-1-carboxylate To a solution of 3,5-dimethylisoxazole (2.6 mL, 26.2 mmol) in THF (75 mL) at -78 °C, nBuLi (11.5 mL, 2.5 M, 28.82 mmol) was added at a rate such that the temperature remained below -60 °C. The reaction mixture was warmed to -40 °C, cooled to -78 °C, and stirred for 45 min. tert-Butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (3.20 g, 13.10 mmol) was added and allowed to warm to room temperature over 1 h. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-100% ethyl acetate in cyclohexane, to give the title compound (2.49 g, 68%) as a colorless oil. LCMS method 5: Room temperature 1.42 min, [M-tBu+2H] + 225, [M-Boc+2H] + 181.

[0513] tert-Butyl 3-(4-hydroxy-6-methylpyridin-2-yl)azetidine-1-carboxylate Palladium on carbon (0.25 g, 10%) was added to a solution of tert-butyl 3-(2-(3-methylisoxazol-5-yl)acetyl)azetidine-1-carboxylate (2.49 g, 8.88 mmol) in ethanol (25 mL), and the mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was heated at 45°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% (7N NH3 / MeOH) in DCM and repurified by silica gel chromatography eluting with 0-10% (7N NH3 / MeOH) in ethyl acetate to give the title compound (838 mg, 36%) as a white solid. LCMS method 5: Room temperature 1.00 min, [M-tBu+2H] + 209.

[0514] tert-Butyl 3-(6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)azetidine-1-carboxylate To a suspension of tert-butyl 3-(4-hydroxy-6-methylpyridin-2-yl)azetidine-1-carboxylate (828 mg, 3.11 mmol) and triethylamine (1.3 mL, 9.34 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (1.3 mL, 7.78 mmol) dropwise to dissolve the solid. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-60% ethyl acetate in cyclohexane, to afford the title compound (396 mg, 32%) as a yellow oil. LCMS method 5: Room temperature 2.04 min, [M-tBu+2H] + 341.

[0515] tert-Butyl 3-(6-methyl-4-(p-tolyl)pyridin-2-yl)azetidine-1-carboxylate A mixture of tert-butyl 3-(6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)azetidine-1-carboxylate (234 mg, 0.59 mmol), p-tolylboronic acid (112 mg, 0.83 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and cesium carbonate (308 mg, 0.95 mmol), dioxane (3 mL), and water (0.5 mL) was degassed with argon and heated at 100 °C for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0–100% ethyl acetate in cyclohexane, to give the title compound (152 mg, 76%) as a yellow oil. LCMS method 5: room temperature 1.35 min, [MH + ]339, [M-tBu+2H] +283, [M-Boc+2H] + 239.

[0516] 2-(Azetidin-3-yl)-6-methyl-4-(p-tolyl)pyridine hydrochloride To a solution of tert-butyl 3-(6-methyl-4-(p-tolyl)pyridin-2-yl)azetidine-1-carboxylate (150 mg, 0.44 mmol) in methanol (1 mL), a solution of HCl in dioxane (2.6 mL, 4N, 10.4 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (130 mg, 106%) as a white solid. LCMS method 5: room temperature 0.89 min, [MH + ]239.

[0517] (5-Isopropyl-1H-pyrazol-3-yl)(3-(6-methyl-4-(p-tolyl)pyridin-2-yl)azetidin-1-yl)methanone To a suspension of 2-(azetidin-3-yl)-6-methyl-4-(p-tolyl)pyridine hydrochloride (122 mg, 0.44 mmol), 5-isopropyl-1H-pyrazole-3-carboxylic acid (103 mg, 0.67 mmol), and triethylamine (0.15 mmol, 1.11 mmol) in DMF (3 mL) was added HATU (270 mg, 0.71 mmol). DCM (2 mL) was added to dissolve the solid, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with 5% aqueous LiCl and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-5% (7N NH3 / MeOH) in DCM, to give the title compound (89 mg, 54%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ, ppm 12.97(1H,s), 7.70(2H,d,J=8.1Hz), 7.50-7.42(2H,m), 7.31(2H,d,J=8.0 Hz), 6.40(1H,d,J=1.8Hz), 4.83(1H,t,J=9.2Hz), 4.65(1H,dd,J=9.5,6.3 Hz), 4.35(1H,t,J=9.3Hz), 4.20(1H,dd,J=9.3,6.1Hz), 4.12-4.03(1H,m) , 2.97(1H,sept,J=7.0Hz), 2.53(3H,s), 2.36(3H,s), 1.23(6H,d,J=6.6Hz) LCMS method 1: room temperature 3.39 min, [MH + ]375.1.

[0518] Example 57 (5-Isopropyl-1H-pyrazol-3-yl)(3-(6-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)azetidin-1-yl)methanone tert-Butyl 3-(6-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)azetidine-1-carboxylate A mixture of tert-butyl 3-(6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)azetidine-1-carboxylate (150 mg, 0.38 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (67 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.04 mmol), and cesium carbonate (197 mg, 0.61 mmol) in dioxane (3 mL), and water (0.5 mL) was degassed with argon, and the reaction mixture was heated at 100° C. for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic fractions were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-60% ethyl acetate in cyclohexane, to give the title compound (112 mg, 68%) as a yellow oil. LCMS method 2: room temperature 0.82 min, [MH + ]329, [M-tBu+2H] + 273.

[0519] 2-(azetidin-3-yl)-6-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridine To a solution of tert-butyl 3-(6-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)azetidine-1-carboxylate (112 mg, 0.34 mmol) in methanol (1 mL), a solution of HCl in dioxane (2 mL, 4N, 8 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (130 mg, quant) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 9.59-9.34(2H,m), 8.78(1H,s), 8.42(1H,s), 8.37(1H,s), 7.97(1H,s), 4.52(1H,quin, J=8.5Hz), 4.40-4.31(4H,m), 3.95(3H,s), 2.68(3H,s).

[0520] (5-Isopropyl-1H-pyrazol-3-yl)(3-(6-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)azetidin-1-yl)methanone To a suspension of 2-(azetidin-3-yl)-6-methyl-4-(p-tolyl)pyridine hydrochloride (122 mg, 0.44 mmol), 5-isopropyl-1H-pyrazole-3-carboxylic acid (103 mg, 0.67 mmol), and triethylamine (0.15 mmol, 1.11 mmol) in DMF (3 mL) was added HATU (270 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with 5% aqueous LiCl and saturated brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% (7N NH3 / MeOH) in DCM and repurified by reverse-phase preparative HPLC to give the title compound (13 mg, 10%) as a white solid. 1H NMR (400 MHz, CDCl3) δ, ppm The peaks were 7.84 (1H, d, J = 0.7 Hz), 7.74 (1H, s), 7.15 (1H, s), 7.13-7.12 (1H, m), 6.48 (1H, s), 4.88 (1H, t, J = 9.1 Hz), 4.75 (1H, dd, J = 6.5, 9.0 Hz), 4.57 (1H, t, J = 9.4 Hz), 4.43 (1H, dd, J = 6.3, 10.0 Hz), 4.08-4.01 (1H, m), 3.97 (3H, s), 3.02 (1H, sept, J = 6.9 Hz), 2.55 (3H, s), and 1.30 (6H, d, J = 6.9 Hz). In addition, one exchangeable proton was not observed. LCMS method 7: room temperature 2.47 min, [MH + ]365.0.

[0521] Example 58 7-(1-acetyl-1H-pyrazol-4-yl)-2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-Isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (112 mg, 58%) as a yellow oil from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and (1-isopentylpyrazol-4-yl)boronic acid according to Suzuki-Miyaura general procedure 1. LCMS method 2: room temperature 1.40 min, [MH + ]465.

[0522] 2-(1-Isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one The title compound (93 mg, quantitative yield) was synthesized from 2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one using THP deprotection procedure 1 to give the title compound as a yellow solid. LCMS method 2: room temperature 1.18 min, [MH + ]381. 1 H NMR (400 MHz, d6-DMSO) δ, ppm 8.39 (1H, s), 8.25 (2H, s), 7.91 (1H, d, J = 0.6 Hz), 7.87 (1H, s), 4.65-4.55 (1H, m), 4.29-4.24 (2H, m), 1.76 (2H, dt, J = 7.1, 7.2 Hz), 1.72-1.63 (1H, m), 1.57 (6H, d, J = 6.9 Hz), 0.93 (6H, d, J = 6.1 Hz), plus one exchangeable proton not observed.

[0523] 7-(1-acetyl-1H-pyrazol-4-yl)-2-(1-isopentyl-1H-pyrazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(1-Isopentyl-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (20 mg, 0.05 mmol) was dissolved in pyridine (1.0 mL). Acetic anhydride (10 μL, 0.11 mmol) was added to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were concentrated under reduced pressure, and the residue was purified by reverse phase chromatography to give the title compound (12 mg, 60%) as a white solid. LCMS method 1: room temperature 4.62 min, [MH + ]423. 1H NMR (400MHz, CDCl3)δ, ppm 8.79(1H,s), 8.17(1H,s), 7.78(1H,s), 7.76(1H,s), 7.72(1H,s), 4.69(1H,hept,J=6.8Hz), 4. 28-4.24(2H,m), 2.75(3H,s), 1.92-1.85(3H,m), 1.68(6H,d,J=6.0Hz), 1.02(6H,d,J=6.5Hz).

[0524] Example 59 (1-Cyclopropylpyrazol-3-yl)-[2-(5-isopropyl-1H-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methanone Pyrazole spirodiazetidinamide was synthesized from (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone and 1-cyclopropylpyrazole-3-carboxylic acid using general pyrazole spirodiazetidinamide procedure 4. The crude product was purified by reverse-phase chromatography eluting with 10–98% MeCN in 0.1% NH4OH to afford the title compound (60 mg, 76%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.99(1H,s), 7.86(1H,d,J=2.3Hz), 6.58(1H,d,J=2.6Hz), 6.36(1H,d,J=1.7Hz), 4.66-4.58(4H,m) , 4.21-4.13(4H,m), 3.84-3.78(1H,m), 3.01-2.91(1H,m), 1.22(6H,d,J=6.9Hz), 1.11-0.96(4H,m).

[0525] Example 60 2-(furan-3-yl)-7-(1H-imidazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-(furan-3-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (26 mg, 24%) from 2-chloro-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and furan-3-boronic acid by Suzuki-Miyaura general procedure 1 gave the title compound as a white solid. 1 H NMR (400MHz, CDCl3)δ, ppm 7.97(1H,s), 7.64(1H,d,J=1.4Hz), 7.54(1H,t,J=1.6Hz), 7.52-7.50(2H,m), 7.37-7.31(9H, m), 7.18-7.13(6H,m), 6.50(1H, dd, J=0.9, 1.9Hz), 4.59-4.48(1H,m), 1.64(6H,d,J=6.4Hz).

[0526] 2-(furan-3-yl)-7-(1H-imidazol-4-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(furan-3-yl)-3-isopropyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via trityl deprotection procedure 1 to give the title compound (2.8 mg, 10%) as a white solid. LCMS method 1: room temperature 2.47 min, [MH + ]311.1. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.34(1H,s), 8.32-8.31(1H,m), 7.94(1H,t,J=1.7Hz), 7.79(1H,s), 7.72(1H ,s), 7.69(1H,s), 6.92-6.90(1H,m), 4.48-4.37(1H,m), 1.56(6H,d,J=7.4Hz).

[0527] Example 61 3-Isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and N-methyl-2-tetrahydrofuran-2-yl-ethanamine via SnAr general procedure 3 to afford the title compound (270 mg, 94%) as a yellow oil. LCMS method 4: 1.25 min at room temperature, [MH + ]306.

[0528] 7-Bromo-3-isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one The title compound (340 mg, quantitative yield) was obtained as a yellow oil from 3-isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one using the bromination general procedure 1. LCMS method 4: room temperature 1.44 min, [MH + ]384,386.

[0529] 3-Isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (480 mg, 96%) from 7-bromo-3-isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole using Suzuki-Miyaura general procedure 1. LCMS method 4: room temperature 1.44 min, [MH + ]456.

[0530] 3-Isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A suspension of 3-isopropyl-2-(methyl(2-(tetrahydrofuran-2-yl)ethyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one (419 mg, 0.91 mmol) in MeOH (10 mL) was treated with 1N aqueous HCl (30 eq) and the reaction mixture was stirred at 50 °C for 16 h. The volatiles were concentrated under reduced pressure. The mixture was basified to pH = 8 by adding saturated aqueous NaHCO3. The precipitate was collected by filtration. The aqueous layer was extracted with 10% MeOH in DCM (x3), combined with the precipitate and concentrated under reduced pressure. The residue was dissolved in DCM / MeOH and purified with ISOLUTE (登録商標) Pre-absorbed onto a HM-N column (Biotage) and purified by silica gel chromatography eluting with a 0-5% gradient of MeOH in DCM to give the title compound (108 mg, 32%) as a white solid. LCMS method 1: room temperature 3.48 min, [MH + ]372.3. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.15(1H,s), 8.34(1H,s), 8.12(1H,s), 7.67(1H,s), 4.79-4.69(1H,m), 3.82-3.71(2H,m), 3.60-3.55(1H,m), 3.29-3.2 0(1H,m), 3.19-3.11(1H,m), 2.84(3H,s), 1.99-1.91(1H,m), 1.88-1.70(4H,m), 1.57(6H,d,J=6.7Hz), 1.48-1.38(1H,m). The enantiomers of Example 61 were separated by chiral SFC using LUX Cellulose-4 21 x 250 mm, 5 μm, eluting with 40% IPA / ACN (50 / 50 / 0.1% DEA) / 60% CO2, 100 mL / min, 120 bar, 40°C.

[0531] Example 62 Enantiomer A: white solid 40.6 mg Analytical equipment: Analytical SFC; Column: LUX Cellulose-4 4.6x250mm, 5µm; Mobile phase: 40% IPA / ACN (50 / 50 / 0.1% DEA) / 60% CO2; Flow rate: 5.0mL / min; Pressure: 120bar; Temperature: 40°C; Detector: DAD 230nm; Retention time: 8.3min.

[0532] Example 63 Enantiomer B: white solid 41 mg Analytical equipment: Analytical SFC; Column: LUX Cellulose-4 4.6x250mm, 5µm; Mobile phase: 40% IPA / ACN (50 / 50 / 0.1% DEA) / 60% CO2; Flow rate: 5.0mL / min; Pressure: 120bar; Temperature: 40°C; Detector: DAD 230nm; Retention time: 9.3min.

[0533] Example 64 2-(1H-indol-3-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one tert-Butyl 3-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate Synthesized from 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate according to Suzuki-Miyaura general procedure 1 to afford the title compound (120 mg, 67%) as a brown oil. 1H NMR (400MHz, CDCl3)δ, ppm 8.27(1H,d,J=8.5Hz), 7.92(1H,s), 7.57-7.56(2H,m), 7.54-7.52(1H,m), 7.48-7.4 4(1H,m), 7.38-7.33(1H,m), 4.47-4.36(1H,m), 1.71(9H,s), 1.61(6H,d,J=6.9Hz).

[0534] tert-Butyl 3-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate Synthesized from tert-butyl 3-(3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate using the bromination general procedure 1 to afford the title compound (144 mg, quantitative yield) as an orange oil. 1 H NMR (400MHz, CDCl3)δ, ppm 8.26(1H,d,J=8.8Hz), 7.96(1H,s), 7.56-7.53(2H,m), 7.47-7.44(1H,m), 7.38-7.34(1H,m), 4.49-4.39(1H,m), 1.71(9H,s), 1.60(6H,d,J=6.1Hz).

[0535] tert-Butyl 3-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate Synthesis of the title compound (106 mg, 64%) from tert-butyl 3-(7-bromo-3-isopropyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole according to Suzuki-Miyaura general procedure 1. 1 H NMR (400MHz, CDCl3)δ, ppm 8.28(1H,d,J=9.0Hz), 8.17(1H,s), 8.02(1H,d,J=0.7Hz), 7.93(1H,s), 7.6 9-7.68(1H,m), 7.63-7.61(1H,m), 7.50-7.45(1H,m), 7.39-7.35(1H,m), 5.3 9-5.36(2H,m), 4.53-4.43(1H,m), 4.09-4.03(2H,m), 3.72-3.65(2H,m), 2.1 6-2.05(2H,m), 1.76(9H,s), 1.71-1.67(1H,m), 1.63(6H,dd,J=1.5,6.8Hz).

[0536] 2-(1H-indol-3-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one A suspension of tert-butyl 3-(3-isopropyl-4-oxo-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroimidazo[2,1-f][1,2,4]triazin-2-yl)-1H-indole-1-carboxylate (106 mg, 0.19 mmol) in MeOH (5 mL) was treated with 1N aqueous HCl (30 eq), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was partitioned between DCM / MeOH (9 / 1) and saturated aqueous NaHCO3. The aqueous layer was extracted with 10% MeOH in DCM (x3) and concentrated under reduced pressure. The resulting off-white solid was purified by reverse-phase preparative HPLC to give the title compound (22.5 mg, 32%) as a white solid. LCMS method 7: 3.6 min at room temperature, [MH +]360. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.10(1H,s), 11.83(1H,s), 8.17(2H,s), 7.87(1H,s), 7.79-7.76(2H,m), 7.56(1H,d,J= 7.4Hz), 7.27-7.23(1H,m), 7.19-7.14(1H,m), 4.62-4.52(1H,m), 1.53(6H,d,J=6.1Hz).

[0537] Example 65 3-Isopropyl-2-(1-methyl-1H-pyrazol-3-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-Chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (460 mg, 2.37 mmol) was suspended in phosphorus oxychloride (5.0 mL) and stirred at 120 °C for 48 hours. POCl (5 mL) was added, and the mixture was stirred at 120 °C until completion of the reaction was confirmed by LCMS. Water was added to the reaction mixture, and NaHCO was slowly added dropwise at 40 °C to adjust the pH to 6. DCM was added, and the layers were separated. The aqueous solution was extracted with DCM (x2) using a phase separation cartridge, and the combined organic layers were concentrated under reduced pressure to give the title compound (285 mg, 57%) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ, ppm 7.54-7.52(2H,m), 5.24-5.24(1H,m), 1.67(6H,d,J=6.9Hz).

[0538] 3-Isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-chloro-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole by Suzuki-Miyaura general procedure 1 to afford the title compound (167 mg, 92%) as a yellow solid. 1 H NMR (400MHz, CDCl3)δ, ppm 7.57(1H,d,J=1.0Hz), 7.53(1H,d,J=1.1Hz), 7.51(1H,d,J=2.4Hz), 6.60(1H,d,J=2.4Hz), 4.70-4.60(1H,m), 4.03(3H,s), 1.63(6H,d,J=6.8Hz).

[0539] 7-Bromo-3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one via general bromination procedure 1 to afford the title compound (118 mg, 54%) as a yellow solid. LCMS method 5: room temperature 1.7 min, [MH + ]337,339.

[0540] 3-Isopropyl-2-(1-methyl-1H-pyrazol-3-yl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of 7-bromo-3-isopropyl-2-(1-methyl-1H-pyrazol-3-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole by Suzuki-Miyaura general procedure 1 followed by THP deprotection procedure 1 and purification by precipitation in DMSO / HO (9 / 1) solution afforded 56 mg (35% over two steps) of the title compound as a white solid. 1H NMR(400MHz,d6-DMSO)δ, ppm 13.15(1H,s), 8.31(1H,s), 8.09(1H,s), 7.96(1H,d,J=1.8Hz), 7.79(1H,s), 6.81(1H,d,J=2.3Hz), 4.74-4.64(1H,m), 3.98(3H,s), 1.54(6H,d,J=7.4Hz). LCMS method 3: room temperature 2.87 min, [MH + ]325.1.

[0541] Example 66 2-(1-(tert-butyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 2-Bromo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropylimidazo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (1.0 g, 5.1 mmol) and phosphorus oxybromide (7.4 g, 25.7 mmol) were heated at 135 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3, and sodium bicarbonate was added as a solid at 40 °C until pH = 6. The mixture was extracted with DCM (x3) using a phase separation cartridge, and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in DCM / MeOH and purified with ISOLUTE (登録商標) Pre-absorption onto an HM-N column (Biotage) and purification by silica gel chromatography eluting with 0-20% EtOAc in DCM afforded the title compound (500 mg, 38%) as a fluffy yellow solid. 1 H NMR(400MHz, CDCl3)δ, ppm 7.52-7.51(2H,m), 5.07-5.07(1H,m), 1.68(6H,d,J=6.7Hz).

[0542] 2-(1-(tert-butyl)-1H-pyrazol-3-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound from 2-bromo-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole according to Suzuki-Miyaura general procedure 2 to afford 60 mg (50%) of the title compound as a yellow oil. LCMS method 4: room temperature 1.22 min, [MH + ]301.

[0543] 7-Bromo-2-(1-(tert-butyl)-1H-pyrazol-3-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 2-(1-(tert-butyl)-1H-pyrazol-3-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one via general bromination procedure 1 to give the title compound as a yellow oil. LCMS method 4: room temperature 1.38 min, [MH + ]379,381.

[0544] 2-(1-(tert-butyl)-1H-pyrazol-4-yl)-3-isopropyl-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesized from 7-bromo-2-(1-(tert-butyl)-1H-pyrazol-3-yl)-3-isopropylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole by Suzuki-Miyaura general procedure 2, followed by THP deprotection procedure 1, and purified by reverse-phase preparative HPLC to give 7 mg (8% over two steps) of the title compound as a white solid. 1H NMR (400 MHz, CDCl) δ, ppm 8.17 (2H, s), 7.87 (1H, d, J = 0.8 Hz), 7.81 (1H, d, J = 0.5 Hz), 7.67 (1H, s), 4.73-4.62 (1H, m), 1.69 (9H, s), 1.68 (6H, d, J = 6.1 Hz), plus one unexchangeable proton. LCMS method 8: room temperature 3.91 min, [MH + ]367.0.

[0545] Example 67 3-Isopropyl-2-methyl-7-(1-(5-methylpyridin-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one 3-Isopropyl-2-methylimidazo[2,1-f][1,2,4]triazin-4(3H)-one 1-Amino-N-isopropyl-1H-imidazole-2-carboxamide (200 mg, 1.19 mmol) was suspended in triethyl orthoacetate (2.0 mL) and stirred at 100° C. for 18 h. The reaction was cooled to room temperature, and the volatiles were concentrated under reduced pressure to give an orange sticky solid. The mixture was dissolved in ethanol (0.5 mL), and sodium ethoxide (21% in ethanol, 360 μL, 1.19 mmol) was added. The reaction mixture was heated at 110° C. for 1 h under microwave irradiation. Water was added, and the volatiles were removed under reduced pressure. The mixture was partitioned between DCM and HO. The aqueous layer was extracted with 10% MeOH in DCM (×3), and the combined organic layers were concentrated under reduced pressure to give a pale yellow solid (60 mg, 32%), which was used in the next step without further purification. LCMS method 2: room temperature 0.76 min, [MH + ]193.

[0546] 7-Bromo-3-isopropyl-2-methylimidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound from 3-isopropyl-2-methylimidazo[2,1-f][1,2,4]triazin-4(3H)-one using general bromination procedure 1 gave 70 mg (quantitative yield) of the title compound as a brown solid. 1H NMR(400MHz, CDCl3)δ, ppm 7.48(1H,s), 4.55-4.55(1H,m), 2.60(3H,s), 1.67(1H,d,J=7.2Hz).

[0547] 5-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine 4-Pyrazoleboronic acid pinacol ester (500 mg, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), and 2-fluoro-5-methylpyridine (0.27 mL, 2.58 mmol) were placed in anhydrous DMF (10.0 mL) under argon and stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3)δ, ppm 8.84(1H,d,J=0.7Hz), 8.23-8.21(1H,m), 7.95(1H,d,J=0.6Hz), 7.90(1H,s), 7.85(1H,d,J=8.5Hz), 2.36(3H,s), 1.34(12H,s).

[0548] 3-Isopropyl-2-methyl-7-(1-(5-methylpyridin-2-yl)-1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesis of the title compound (46 mg, 36%) from 7-bromo-3-isopropyl-2-methylimidazo[2,1-f][1,2,4]triazin-4(3H)-one and 5-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine according to Suzuki-Miyaura general procedure 1 using 1M S / HO (2.5 / 0.5 mL) as solvent to afford 46 mg (36%) of the title compound as a white solid. 1H NMR (400MHz, CDCl3)δ, ppm 9.10(1H,s), 8.28-8.26(1H,m), 8.23(1H,d,J=0.7Hz), 7.92(1H,d,J=8.3Hz), 7.68(1H,s ), 7.68-7.65(1H,m), 4.58-4.58(1H,m), 2.65(3H,s), 2.39(3H,s), 1.70(6H,d,J=7.1Hz). LCMS method 1: room temperature 4.37 min, [MH + ]350.2.

[0549] Example 68 6-Isopropyl-3-(5-isopropyl-1H-pyrazole-3-carbonyl)-4-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one Ethyl 2-benzoyl-3-methylbutanoate A solution of ethyl isovalerate (1.1 mL, 7.11 mmol) was placed in anhydrous THF (15 mL) at -78 °C. Under argon, LDA (2 M, 3.9 mL, 7.83 mmol) was added dropwise, and the reaction mixture was stirred at -78 °C for 1 h. A solution of benzoyl chloride (0.83 mL, 7.11 mmol) in anhydrous THF (5 mL) was added dropwise, and the mixture was stirred at -78 °C for 1 h and then at room temperature for 2 h. The volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The solid was dissolved in DCM and purified with ISOLUTE (登録商標) Preabsorbed onto an HM-N column (Biotage) and purified by silica gel chromatography eluting with 0-20% EtOAc in cyclohexane to give the title compound (1.25 g, 75%) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3)δ, ppm 8.04-8.00(2H,m), 7.60-7.56(1H,m), 7.50-7.45(2H,m), 4.14(2H,dq,J=1.3,7.1Hz), 4.09(1H,d, J=9.2Hz), 2.71-2.59(1H,m), 1.18(3H,t,J=7.1Hz), 1.05(3H,d,J=7.4Hz), 0.95(3H,d,J=6.6Hz).

[0550] 3-Bromo-6-isopropyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one Ethyl 2-benzoyl-3-methylbutanoate (1.0 g, 4.27 mmol) and 3-amino-4-bromo-1H-pyrazole (1.0 g, 6.4 mmol) were suspended in 2-MeTHF (20 mL) and a solution of titanium(IV) chloride in DCM (1 M; 4.3 mL, 4.30 mmol) was added. The mixture was heated at 80 °C for 19 h. The precipitate was filtered, and the filtrate was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3 (x2), water, dried (MgSO4), and concentrated under reduced pressure to give a white solid. The solid was dissolved in DCM and purified by silica gel chromatography, eluting with 0–5% MeOH in DCM, to give the title compound (600 mg, 43%) as a gray solid. 1 H NMR (400MHz, CDCl3)δ, ppm 7.84(1H,s), 7.72(1H,s), 7.60-7.55(3H,m), 7.48-7.44(2H,m), 2.81-2.71(1H,m), 1.34(6H,d,J=6.9Hz).

[0551] 3-Bromo-6-isopropyl-4-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one A solution of 3-bromo-6-isopropyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (250 mg, 0.753 mmol) in THF (3.0 mL) was treated with sodium hydride (60%; 36 mg, 0.90 mmol), and after 30 min, iodomethane (0.23 mL, 3.76 mmol) was added. After 18 h, the solvent was removed under reduced pressure, water was added, and the product was extracted with DCM. The combined organic extracts were dried (NaSO) and concentrated under reduced pressure to give a yellow solid. The crude product was triturated with EtOAc-EtO, and the solid was collected by filtration and dried to give the title compound (120 mg, 46%) as a white solid. LCMS method 2: room temperature 1.57 min, [MH + ]346,348.

[0552] 6-Isopropyl-3-(5-isopropyl-1H-pyrazole-3-carbonyl)-4-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one A solution of 3-bromo-6-isopropyl-4-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (42 mg, 0.12 mmol) in THF (1.5 mL) was cooled to -78 °C, and n-butyllithium (1.6 M; 0.083 mL, 0.13 mmol) was added. After 30 min, a pre-cooled solution of 5-isopropyl-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (34 mg, 0.121 mmol) in THF (1.5 mL) was added. The mixture was allowed to warm to room temperature over 18 h. After removing the solvent under reduced pressure, the residue was redissolved in MeOH (3.0 mL), TFA (1.0 mL) was added, and the mixture was heated at 50 °C for 5 h. The reaction mixture was concentrated, loaded onto an SCX-2 cartridge, and eluted with MeOH. The eluent was evaporated, and the resulting crude product was purified by reverse-phase preparative HPLC to obtain the title compound (2.0 mg, 4%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.32(1H,s), 8.59(1H,s), 7.56-7.66(3H,m), 7.46-7.52(2H,m), 6.62(1H,s), 3.29(3H,s), 3. 02(1H,hept,J=7.2Hz), 2.34(1H,hept,J=7.2Hz), 1.26(6H,d,J=6.9Hz), 1.21(6H,d,J=7.0Hz) LCMS method 9: room temperature 4.84 min, [MH + ]404.3.

[0553] Amide Coupling Procedure 1 A solution of cyclopropyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone (2.8 mL (0.22 M), 0.615 mmol), ArCOH (0.677 mmol), and triethylamine (0.51 mL, 3.69 mmol) in DCM (2.0 mL) was treated with HATU (257 mg, 0.677 mmol) and stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase preparative HPLC or reverse-phase chromatography (C), eluting with 10-98% MeCN / HO + 0.1% NHOH. 18 Cartridge).

[0554] Amide Coupling Procedure 2 A solution of the amine (0.472 mmol), ArCOH (0.567 mmol), and DIPEA (0.25 mL, 1.42 mmol) in DCM (10.0 mL) was treated with T3P (0.42 mL, 0.709 mmol) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase preparative HPLC.

[0555] Amide Coupling Procedure 3 A solution of the amine (2.74 mmol), ArCOH (2.74 mmol), and DIPEA (1.40 mL, 8.21 mmol) in DMF (5.0 mL) was treated with HATU (1.093 g, 2.88 mmol) and stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase preparative HPLC or reverse-phase chromatography (C), eluting with 10-98% MeCN / HO + 0.1% NHOH. 18 Purified using a cartridge.

[0556] Amide Coupling Step 4 A solution of the amine (0.548 mmol), ArCOH (0.603 mmol), and triethylamine (0.23 mL, 1.64 mmol) in DCM (2.0 mL) was treated with HATU (229 mg, 0.603 mmol) and stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase preparative HPLC or reverse-phase chromatography (C), eluting with 10-98% MeCN / HO + 0.1% NHOH. 18Purified using a cartridge.

[0557] Amide Coupling Step 5 A solution of the amine (0.439 mmol), ArCOH (1.10 mmol), and triethylamine (0.24 mL, 1.76 mmol) in DMF (3.0 mL) was treated with HATU (334 mg, 0.878 mmol) and stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase chromatography (C) eluting with 10–98% MeCN / HO + 0.1% NHOH. 18 Purification was carried out by means of a cartridge.

[0558] 2,2-Dimethyl-1-(2,6-diazaspiro[3.3]heptan-2-yl)propan-1-one A solution of tert-butyl 6-pivaloyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.20 g, 0.708 mmol) in MeOH (20 mL) was treated with pre-washed Amberlyst 15 (H form, 4.0 g) and stirred at room temperature for 20 h. The mixture was treated with 2 M ammonia in methanol (20 mL), stirred for 2 h, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (130 mg, 100%) as a brown solid. LCMS method 4: room temperature 0.96 min, [MH + ]183.

[0559] (R)-1-(1-hydroxypropan-2-yl)-1H-imidazole-4-carboxylic acid Synthesis was carried out according to literature procedures (WO2013111105A1) using D-alinor to give the title compound as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ, ppm 7.83 (1H, d, J = 1.3 Hz), 7.74 (1H, d, J = 1.3 Hz), 4.25-4.35 (1H, m), 3.50-3.62 (3H, m), 1.37 (3H, d, J = 6.9 Hz), plus one unexchangeable proton.

[0560] (S)-1-(1-hydroxypropan-2-yl)-1H-imidazole-4-carboxylic acid Synthesis was carried out according to literature procedures (WO2013111105A1) using L-alanine to give the title compound as a yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ, ppm 7.72 (1H, d, J = 1.2 Hz), 7.69 (1H, d, J = 1.2 Hz), 4.21-4.31 (1H, m), 3.50-3.62 (3H, m), 1.36 (3H, d, J = 6.9 Hz), plus one unexchangeable proton.

[0561] (R)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylic acid Ethyl (R)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate A solution of (R)-1-(1-hydroxypropan-2-yl)-1H-imidazole-4-carboxylic acid (870 mg, 4.39 mmol) in DCM (10.0 mL) was cooled to 0 °C (ice / water bath) and stirred, followed by the dropwise addition of DAST (1.7 mL, 13.17 mmol). The mixture was allowed to warm to room temperature, solid Na2CO3 (550 mg, 5.19 mmol) was added, and the mixture was stirred for 20 h. After dilution with DCM, the mixture was filtered and placed on Celite. (登録商標) The crude product was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the title compound (120 mg, 13%) as a yellow oil. LCMS method 4: room temperature 0.99 min, [MH + ]201.

[0562] (R)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylic acid A mixture of ethyl (R)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate (140 mg, 0.699 mmol), LiOH·HO (88 mg, 2.10 mmol), THF (6.0 mL), and water (2.0 mL) was stirred and heated at 80 °C for 2 h. The cooled mixture was diluted with EtOAc, adjusted to pH 5 by the addition of aqueous HCl (1N, 2.2 mL), and aqueous NaHCO was added. The layers were separated, and the aqueous layer was concentrated under reduced pressure to give a white solid. This was extracted into 20% IPA in DCM and purified by Celite. (登録商標) The filtrate was evaporated to give the title compound (120 mg, 100%) as a white solid. LCMS method 4: Room temperature 0.19 min 1 H NMR (400 MHz, d6-DMSO) δ, ppm 7.55 (1H, s), 7.38 (1H, s), 4.47-4.69 (3H, m), 1.39 (3H, d, J = 5.6 Hz). In addition, one exchangeable proton was not observed.

[0563] (S)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylic acid Ethyl (S)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate A solution of (S)-1-(1-hydroxypropan-2-yl)-1H-imidazole-4-carboxylic acid (700 mg, 3.53 mmol) in DCM (10.0 mL) was cooled to 0 °C (ice / water bath) and stirred, followed by the dropwise addition of DAST (1.40 mL, 10.59 mmol). The mixture was allowed to warm to room temperature, solid Na2CO3 (550 mg, 5.19 mmol) was added, and the mixture was stirred for 20 h. After dilution with DCM, the mixture was filtered and placed on Celite. (登録商標) The crude product was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the title compound (100 mg, 14%) as a yellow oil. LCMS method 4: room temperature 0.99 min, [MH + ]201.

[0564] (S)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylic acid A mixture of ethyl (S)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate (120 mg, 0.599 mmol), LiOH·HO (75 mg, 1.80 mmol), THF (6.0 mL), and water (2.0 mL) was stirred and heated at 80 °C for 2 h. The cooled mixture was diluted with EtOAc, adjusted to pH 5 by the addition of aqueous HCl (1N, 2.2 mL), and aqueous NaHCO was added. The layers were separated, and the aqueous layer was concentrated under reduced pressure to give a white solid. This was extracted into 20% IPA in DCM and purified by Celite. (登録商標) The filtrate was evaporated to give the title compound (60 mg, 58%) as a white solid. LCMS method 4: Room temperature 0.20 min 1 H NMR (400 MHz, d6-DMSO) δ, ppm 7.58 (1H, s), 7.41 (1H, s), 4.44-4.70 (3H, m), 1.39 (3H, d, J = 6.1 Hz). In addition, one exchangeable proton was not observed.

[0565] 5-Isopropyl-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 5-Isopropyl-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide A mixture of 3-isopropylpyrazole-5-carboxylic acid (750 mg, 4.86 mmol) in DCM (50 mL) was treated with N,O-dimethylhydroxylamine hydrochloride (949 mg, 9.73 mmol), 4-(dimethylamino)pyridine (2.377 g, 19.46 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.865 g, 9.73 mmol) and stirred for 18 h. It was poured into aqueous NaHCO3 and extracted with DCM. The organic extract was washed with saturated brine, dried (Na2SO4), and evaporated to a solid. The crude product was purified by silica gel chromatography, eluting with 0–30% acetone in DCM, to give the title compound (0.20 g, 21%) as an oil. 1H NMR(300MHz,CDCl3)δ, ppm 6.63(1H,s), 3.79(3H,s), 3.39(3H,s), 3.04(1H,hept,J=7.0Hz), 1.30(6H,d,J=6.9Hz) 5-Isopropyl-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide A solution of 5-isopropyl-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (200 mg, 1.01 mmol) and TFA (12 mg, 0.10 mmol) in DMF (2.0 mL) was heated to 85 °C, and 3,4-dihydro-2H-pyran (0.14 mL, 1.52 mmol) was added. The mixture was stirred at 90 °C for 18 h. After removing the solvent under reduced pressure, the crude product was purified by silica gel chromatography eluting with 0–7.5% (2 M ammonia in MeOH) in DCM to give the title compound (0.24 g, 84%) as a viscous material. LCMS method 2: room temperature 1.15 min, [M+Na + ]304.

[0566] 5-(1-cyanopropan-2-yl)-1H-pyrazole-3-carboxylic acid Ethyl 5-(1-cyanoprop-1-en-2-yl)-1H-pyrazole-3-carboxylate Diethyl cyanomethylphosphonate (3.30 mL, 20.58 mmol) was added to a solution of sodium hydride (60%; 823 mg, 20.58 mmol) in THF (40 mL) at 0 °C (ice / water bath). After 30 min, ethyl 3-acetyl-1H-pyrazole-5-carboxylate (750 mg, 4.12 mmol) was added, and the mixture was allowed to warm to room temperature over 18 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and evaporated to give a yellow oil. The crude product was purified by silica gel chromatography, eluting with 0–30% EtOAc in cyclohexane, to give the title compound (0.84 g, 99%) as a white solid. LCMS method 5: room temperature 1.18, 1.21 min, [M - ]204.

[0567] Ethyl 5-(1-cyanopropan-2-yl)-1H-pyrazole-3-carboxylate Ethyl 5-(1-cyanoprop-1-en-2-yl)-1H-pyrazole-3-carboxylate (810 mg, 3.95 mmol) was hydrogenated under a hydrogen atmosphere using a solution of 10% Pd / C (399 mg) in EtOAc (40 mL) for 18 h. The resulting mixture was placed on Celite (登録商標) The mixture was filtered through a filtration oven, and the filtrate was concentrated under reduced pressure to give the title compound (0.81 g, 99%) as a white solid. LCMS method 5: room temperature 1.07 min, [M - ]206.

[0568] 5-(1-cyanopropan-2-yl)-1H-pyrazole-3-carboxylic acid A mixture of ethyl 5-(1-cyanopropan-2-yl)-1H-pyrazole-3-carboxylate (810 mg, 3.91 mmol), lithium hydroxide monohydrate (820 mg, 19.54 mmol), THF (15 mL), and water (15 mL) was stirred for 18 hours. After neutralization with aqueous hydrochloric acid (1N; 20 mL) and an appropriate amount of aqueous NaHCO3, the mixture was concentrated under reduced pressure. The residue was extracted with 5% MeOH / DCM and filtered. The filtrate was evaporated to give the title compound (0.48 g, 68%) as a colorless semi-solid. LCMS method 5: room temperature 0.78 min, [MH + ]180.

[0569] tert-Butyl 6-(1-isopropyl-1H-imidazole-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (288 mg, 1.00 mmol), 1-(propan-2-yl)-1H-imidazole-4-carboxylic acid hydrochloride (191 mg, 1.00 mmol), and DIPEA (775 mg, 6.00 mmol) in DCM (10 mL) was treated with HATU (456 mg, 1.20 mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with NaHCO3 solution and extracted into DCM. The organic extract was washed with water and saturated brine, then dried (Na2SO4), and evaporated to give the title compound (340 mg, 100%) as a brown solid. LCMS method 2: room temperature 0.87 min, [MH + ]335.2.

[0570] Example 69 (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(5-isobutyl-1H-pyrazol-3-yl)methanone Synthesis by amide coupling procedure 1 using cyclopropyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone (2.8 mL (0.22 M), 0.615 mmol) and 3-(2-methylpropyl)-1H-pyrazole-5-carboxylic acid (114 mg, 0.677 mmol) afforded the title compound (71.1 mg, 36%) as an off-white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 12.95(1H,s), 6.35(1H,s), 4.52-4.68(2H,m), 4.36-4.46(2H,m), 4.09-4.23(2H,m), 3.94-4.08(2H,m), 2. 48(2H,d,J=7.1Hz), 1.87(1H,hept,J=6.8Hz), 1.45-1.53(1H,m), 0.86(6H,d,J=6.6Hz), 0.64-0.73(4H,m) LCMS method 8: room temperature 3.17 min, [MH + ]317.0.

[0571] Example 70 (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(5-cyclopropyl-1H-pyrazol-3-yl)methanone Synthesis by amide coupling procedure 1 using cyclopropyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone (2.8 mL (0.22 M), 0.615 mmol) and 3-cyclopropyl-1H-pyrazole-5-carboxylic acid (103 mg, 0.677 mmol) afforded the title compound (46.3 mg, 25%) as a white solid. 1 H NMR(400MHz,d6-DMSO)δ, ppm 13.00(1H,s), 6.26(1H,s), 4.50-4.66(2H,m), 4.34-4.47(2H,m), 4.08-4.22(2H ,m), 3.92-4.07(2H,m), 1.84-1.95(1H,m), 1.43-1.53(1H,m), 0.61-0.99(8H,m) LCMS method 8: room temperature 2.70 min, [MH + ]301.0.

[0572] Example 71 (5-(tert-butyl)-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone Synthesis by amide coupling procedure 1 using cyclopropyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone (2.8 mL (0.22 M), 0.615 mmol) a...

Claims

1. General formula (II-1-1); 【Chemistry 1】 and General formula (II-5-1): 【Chemistry 2】 (In the formula, R ３－１ represents a hydrogen atom, a C1-4 alkyl, a C1-4 haloalkyl or a halogen atom; R ４－１ represents a hydrogen atom, a C1-4 alkyl, or a 5- or 6-membered monocyclic carbocyclic ring; 【Transformation 3】 represents the α-configuration, the β-configuration, or a mixture of the α-configuration and the β-configuration; R １－１Ｙ teeth 【Chemistry 4】 represents; In the group, the arrow indicates the bond to the carbonyl carbon atom; R 6-1 represents C1-4 alkyl optionally substituted by 1 to 4 R 8-1 , C3-8 cycloalkyl, C3-8 cycloalkyl substituted by C1-4 alkyl, C1-4 haloalkyl, or a halogen atom; R 8-1 represents hydroxy, a halogen atom, nitrile, benzyloxy, or a 5- or 6-membered monocyclic carbocyclic ring; R 9-1 represents a hydrogen atom or C1-4 alkyl; R ２－１Ｙ represents unsubstituted cyclopropane or unsubstituted spiro[2,2]pentane; R ２－１Ｓ is 1 to 4 R １３－１ cyclopropane or cyclobutane optionally substituted with 1 to 4 R １４－１ bicyclo[1,1,1]pentane or spiro[2,2]pentane optionally substituted with, or 1 to 4 R １５－１ represents an optionally substituted 5-membered monocyclic heterocycle; R 13-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 14-1 represents C1-4 alkyl, C3-8 cycloalkyl, a halogen atom, or C1-4 haloalkyl; R 15-1 represents C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C3-8 cycloalkyl, a halogen atom, phenyl optionally substituted by 1 to 4 R 16-1 , phenoxy, pyridin-2-yl, 1-methylpyrazol-4-yl, or oxo; R 16-1 represents C1-4 alkyl or C1-4 alkoxy; and a plurality of R 8-1 , R 13-1 , R 14-1 , R 15-1 or R 16-1 may be the same or different.) A compound represented by the general formula selected from the group consisting of: or a salt thereof.

2. The compound has the general formula (II-1-1): 【Transformation 5】 2. The compound according to claim 1, which is a compound represented by the formula: wherein all symbols have the same meanings as defined in claim 1, or a salt thereof.

3. The compound is (1) The compound according to claim 1 or 2, which is N-(1-(5-isopropyl-1H-pyrazole-3-carbonyl)azetidin-3-yl)cyclopropanecarboxamide, or a salt thereof.

4. The compound has the general formula (II-5-1): 【Transformation 6】 2. The compound according to claim 1, which is a compound represented by the formula: wherein all symbols have the same meanings as defined in claim 1, or a salt thereof.

5. The compound is (1) (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (2) (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone; (3) (5-isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (4) (5-isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; or (5) The compound according to claim 1 or 4, which is [2-(4-fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone, or a salt thereof.

6. A pharmaceutical composition comprising a compound represented by a general formula selected from the group consisting of general formulas (II-1-1) and (II-5-1) according to claim 1, or a salt thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, which is a KDM5 inhibitor.

8. The pharmaceutical composition according to claim 6 or 7, which is an agent for preventing and / or treating a KDM5-related disease.

9. The pharmaceutical composition according to claim 8, wherein the KDM5-related disease is cancer or Alzheimer's disease.

10. A preventive and / or therapeutic agent for a KDM5-related disease, comprising as an active ingredient a compound represented by a general formula selected from the group consisting of general formulas (II-1-1) and (II-5-1) according to claim 1, or a salt thereof, wherein the preventive and / or therapeutic agent is used 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.

11. A compound represented by a general formula selected from the group consisting of general formulas (II-1-1) and (II-5-1) according to claim 1, or a salt thereof, for the prevention and / or treatment of a KDM5-related disease.

12. Use of a compound represented by a general formula selected from the group consisting of general formulas (II-1-1) and (II-5-1) according to claim 1, or a salt thereof, for the manufacture of an agent for the prophylaxis and / or treatment of a KDM5-related disease.

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