Compounds having KDM5 inhibitory action and pharmaceutical use 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-mentioned general formula (Z), which has KDM5 inhibitory activity, or a salt thereof, and medical uses thereof. [Background technology]

[0002] Eukaryotic DNA is present in the nucleus as chromatin, a 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, can 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 that demethylates the trimethylated lysine residue at the fourth position of histone H3 protein (H3K4me3). In mammals, including humans, there are four subfamilies, KDM5A, KDM5B, KDM5C and KDM5D, which have 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 known to be highly expressed in cancer tissues in particular. Epigenetic abnormalities in cancer cells are involved in cell proliferation and metastasis, and KDM5 inhibitors have been reported to be effective against cancer cells. Involvement of epigenetic abnormalities, including histone modifications, has also been reported 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 and treating the above-mentioned diseases.

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

[0005] [ka]

[0006] (In the formula, R 1A -R A , halogen atom, -OR A , -SR A , -N(R ’A ) 2 , -CN; Each R 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; Each R ’A are independent, -R A , -C(O)R A , -CO 2 R A and; Ring A A teeth

[0007] [ka]

[0008] and; R 2A and R 3A is 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 , -CO 2 R A and; X A is -N(R 4A )-, -O-, or -S-; R 4A -R A , -C(O)R A , -CO 2 R A , or -S(O) 2 R; R 5A -R A , -C(O)R A , -CO 2 R A and; R 6A -R A , halogen atom, -OR A , -SR A , -N(R ’A ) 2 , -CN (group definitions are excerpted).) or a pharma- ceutically acceptable salt thereof.

[0009] Furthermore, WO2016057924 reports that the 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 group, a 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, an alkyl or a cyclic group; R 5B is H, halo, alkyl, R 6B is H, an alkyl, or a cyclic group; or R 5B and R 6B together 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 their pharmaceutical uses. [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] Means for Solving the Problems The present inventors conducted extensive research to solve the above problems, and as a result, found that a compound represented by general formula (Z) or a salt thereof can solve the above problems. After further investigation, they 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, halogen atom, oxo or 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 - stands for; B is R 2 or R 2-1 -L 2 - stands for; R 1is a hydrogen atom, C1-4 alkyl, nitrile, a 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 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 or 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 9represents 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-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 7-1 represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R 5-1 represents a C1-4 alkyl, a C3-8 cycloalkyl, a C1-4 haloalkyl, or a halogen atom; R 6-1 is 1 to 4 R 8-1represents C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl substituted with C1-4 alkyl, C1-4 haloalkyl, or a halogen atom optionally substituted with R 7-1 represents a C1-4 alkyl, a C3-8 cycloalkyl, a 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; L 1 represents a bond or carbonyl (-C(=O)-); L 2 is a bond, carbonyl (-C(=O)-), -(CH 2 )n-NR 9-1 C(=O)- or -C(=O)NR 10-1 - stands for; 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 C1-4 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 or -S(O) m -(C1-4 alkyl); R 11-1 represents hydroxy, a halogen atom, or a C3-8 cycloalkyl; R 12-1 represents hydroxy, a halogen atom, or a 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, each of which may be substituted with 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 multiple substitutions are made, 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 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 53represents a hydrogen atom or C1-4 alkyl; The other symbols are the same as those described 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 the above [1] or [2]), 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]. The compound according to any one of the above [1] to [3], which is represented by the formula:

[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 or 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 the above [1] to [3], which is represented by the formula:

[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 a 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; JPEG2024175060000014.jpg1683 shows the α-configuration; JPEG2024175060000015.jpg1785 shows the β-configuration; JPEG2024175060000016.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], which is represented by the formula:

[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 the above [1] or

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

[10] or

[11] , which is 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 14-1 or 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

[10] or

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

[10] or

[11] above, which is 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 the above [1]), the compound according to the above [1],

[10] or

[11] , or a salt thereof;

[0062]

[17] The compound (1) The compound according to the above [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 represents 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 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 the above [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 the general formula (Z) according to [1] above or a salt thereof and a pharma- ceutically acceptable carrier;

[0068]

[21] The pharmaceutical composition according to

[20] above, 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 the above

[22] , which is for treating asthma, allergic diseases, inflammation, neurological diseases, hormone-related diseases, conditions associated with organ transplantation, immunodeficiencies, 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 the above

[22] , 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 a 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-associated disease;

[0075]

[27] Use of a compound represented by general formula (Z) according to [1] 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, a 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 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 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 or 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 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-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 a C1-4 alkyl, a C3-8 cycloalkyl, a 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 with R 7-1represents a C1-4 alkyl, a C3-8 cycloalkyl, a 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; L 2 is a bond, carbonyl (-C(=O)-), -(CH 2 ) n -NR 9-1 C(=O)- or -C(=O)NR 10-1 - stands for; 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 C1-4 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 or -S(O) m -(C1-4 alkyl); R 11-1 represents hydroxy, a halogen atom, or a C3-8 cycloalkyl; R 12-1 represents hydroxy, a halogen atom, or a 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 R16-1 phenyl, phenoxy, pyridin-2-yl, 1-methylpyrazol-4-yl, or oxo, each of which may be substituted with 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 or 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; JPEG2024175060000024.jpg1371 represents the α-configuration; JPEG2024175060000025.jpg1275 represents the β-configuration; JPEG2024175060000026.jpg1376 represents the α-configuration, the 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 or 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 or 1 to 4 R 15-1 represents 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 from 1 to 6, and R is an integer from 1 to 6, and R is an integer from 1 to 6, or a salt thereof. Effect of the Invention

[0081] The compound or salt represented by the general formula (Z) disclosed herein (hereinafter collectively referred to as the present compound) has KDM5 inhibitory activity. Therefore, the present compound is effective in inhibiting KDM5 in hyperproliferative diseases, cancer, stroke, diabetes, liver dysfunction, cardiovascular disease, 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, T cell activity, and the like. The compound can be used as a therapeutic and / or prophylactic agent for diseases such as pathological immune conditions accompanied by neurodegeneration, central nervous system diseases, myeloproliferative diseases, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, cognitive dysfunction, cerebrovascular disease, schizophrenia, depression, anxiety disorder, bipolar disorder, autism spectrum disorder, attention deficit hyperactivity disorder, learning disabilities, movement disorders, obsessive-compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disabilities, intellectual disabilities, post-traumatic stress disorder, or hepatitis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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, "C3-8 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 with 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-dimethylcyclohexyl, 4-methyl ... 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 -(C1-4 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, thiazine ... 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, dihydropyra tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane and dioxole rings.

[0100] In the present invention, the "5- or 6-membered monocyclic heterocycle" includes, for example, "a 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- to 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms, and / or 1 sulfur atom" include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropy ...furan, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydrofuran, dihydro tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane and dioxole rings are included.

[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 "5-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-dihydropyrido[3,2-c]pyrimidine, 5,8-dihydropyrido[3,2-d ...d]pyrimidine, 5,8-dihydropyrido[3,2 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 JPEG2024175060000028.jpg1362 represents bonding to this side of the paper (i.e., β-configuration), JPEG2024175060000029.jpg1563 represents bonding to the other side of the paper (i.e., α-configuration), JPEG2024175060000030.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, a nitrile, a carbamoyl, or one to four 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 an optionally substituted 5- or 6-membered monocyclic heterocycle.

[0111] In the present invention, R 2 is preferably 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 is 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 R 1 to R 2 are 5-membered monocyclic aromatic heterocycles 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 preferable 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 preferable 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 is preferably -(CH 2 ) n -NR 9-1 C(=O)- is also included.

[0121] In the present invention, n is preferably, for example, an integer of 0 to 1, 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 Also included are 5- or 6-membered monocyclic heterocycles optionally substituted with:

[0123] In the present invention, a preferred example of the general formula (Z) is the general formula (I):

[0124] [ka]

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

[0126] Or general formula (II):

[0127] [ka]

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

[0129] In the present invention, examples of the general formula (Z) preferably include the 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 meaning as defined above).

[0132] In the present invention, examples of the general formula (Z) preferably include the 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 meaning as defined above).

[0135] In the present invention, a preferable example of the general formula (Z) is the general formula (IA):

[0136] [ka]

[0137] (In the formula, ring A is

[0138] [ka]

[0139] represents Y 1 and Y 2 respectively 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 above.

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

[0141] [ka]

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

[0143] In the present invention, a preferred example of the general formula (Z) is the general formula (II-A):

[0144] [ka]

[0145] (wherein 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; Y 3 represents a carbon atom or a nitrogen atom, and the other symbols have the same meanings as above.

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

[0147] [ka]

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

[0149] In the present invention, examples of the general formula (Z) preferably include the 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 meaning as defined above).

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

[0153] [ka]

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

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

[0156] [ka]

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

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

[0159] [ka]

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

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

[0162] [ka]

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

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

[0165] [ka]

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

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

[0168] [ka]

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

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

[0171] [ka]

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

[0173] In the present invention, or as an example of the 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), preferably, 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 included unless otherwise specified. For example, alkyl groups, alkoxy groups, etc. include straight-chain and branched-chain isomers. Furthermore, isomers in double bonds, rings, and condensed rings (E, Z, cis, and trans isomers), isomers due to the presence of asymmetric carbons, etc. (R and S isomers, α and β isomers, enantiomers, and diastereomers), optically active isomers having optical rotation (D, L, d, and l isomers), polar isomers (high polarity, low polarity) obtained by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any ratio, and racemic mixtures are all included in the present invention. In addition, all isomers due to tautomerism are also included in the present invention.

[0181] [Salts and solvates] The salts of the compounds represented by the general formula (Z) disclosed in the present invention include all pharma- ceutically acceptable salts. The pharma-ceutically 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.], and salts with acidic natural amino acids [e.g., aspartate, glutamate, etc.]).

[0182] The salt also includes quaternary ammonium salts. Quaternary ammonium salts are compounds in which the nitrogen atom of the compound represented by the general formula (Z) is R 0 represents a quaternary 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-mentioned salt, N-oxide or solvate by known methods.

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

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

[0186] The compound represented by the general formula (Z) and its salts may exist in a non-solvated form or in a solvated form with a pharma- ceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compound represented by the general formula (Z) and its salts may be converted into a solvate by a known method.

[0187] The compound of formula (Z) and its salts can form co-crystals with a suitable co-crystal former. The co-crystal is preferably a pharma- ceutically acceptable one formed with a pharma- ceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules with intermolecular interactions other than ionic bonds. 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 compounds of the present invention include the compounds represented by the general formula (Z), salts thereof, solvates (e.g., hydrates), N-oxides thereof, or co-crystals thereof, or solvates (e.g., hydrates) of salts of the compounds represented by the general formula (Z), N-oxides thereof, or co-crystals thereof.

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

[0190] [Prodrug] The prodrug of the compound represented by the general formula (Z) refers to a compound which is converted into the compound represented by the 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, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, a compound in which the amino group of the compound represented by general formula (Z) is 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, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, a compound in which the hydroxyl group of the compound represented by general formula (Z) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated). The prodrug of the compound represented by the general formula (Z) may be one that changes into the compound represented by the 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 the general formula (Z) can be produced by a method known per se. The prodrug of the compound represented by the general formula (Z) may form a salt, such as the above-mentioned acid addition salt, like the compound represented by the general formula (Z), or may form a solvate with water or an alcoholic solvent (e.g., ethanol, etc.).

[0191] [Labeled compound] In the present invention, the compound represented by the general formula (Z) or a salt thereof also includes so-called labeled compounds in which a part or all of the atoms constituting the compound are replaced with an isotope. These labeled compounds can be produced by a method known per se. The isotope used for labeling is, but is 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] The compounds represented by general formula (I) or (II) or salts thereof can be produced by appropriately modifying and combining known methods, such as the methods shown in Schemes I to XII, methods similar thereto, methods shown in the Examples, methods similar thereto, or methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), but are not limited thereto. In each of the following production methods, the raw material compounds may be used in the form of salts. Examples of such salts include those described above as salts of the compounds represented by general formula (I) or (II).

[0193] Cross Coupling Cross-coupling is a known reaction. For example, there is the following method. (1) Suzuki-Miyaura coupling, (2) Stille coupling and (3) Negishi coupling These techniques are described below. (1) Suzuki-Miyaura coupling is a known method for creating carbon-carbon bonds using an organoboron compound and an aryl halide. For example, in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture thereof), a base (e.g., sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), or an aqueous solution or mixture thereof, and a catalyst (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos) 2 PdCl 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(tri-tert-butylphosphine)palladium (Pd(tBu) 3 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, palladium on carbon, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl 2 (dppf)), diallylpalladium dichloride (PdCl 2 (allyl) 2 ), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh 3 ) 2 ), (tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 In the presence of a ligand (e.g., triphenylphosphine (PPh 3 ), tributylphosphine (PBu 3 ), tricyclohexylphosphine (PCy 3), 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.) at room temperature to 150°C.

[0194] (2) Stille coupling is a known method for creating carbon-carbon bonds using an organotin compound and an aryl halide. 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 of these) with an additive (tetrabutylammonium fluoride, tetrabutylammonium chloride, cesium fluoride, lithium fluoride, lithium chloride, potassium fluoride, copper chloride, copper bromide, copper iodide, copper oxide, etc.) or a mixture of these, and a catalyst (e.g., bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos) 2 PdCl 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(tri-tert-butylphosphine)palladium (Pd(tBu) 3 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc)2), palladium black, palladium on carbon, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl 2 (dppf)), diallylpalladium dichloride (PdCl 2 (allyl) 2 ), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh3 ) 2 ), (tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 In the presence of a ligand (e.g., triphenylphosphine (PPh 3 ), tributylphosphine (PBu 3 ), tricyclohexylphosphine (PCy 3 ), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 1,2-bis(diphenylphosphino)ethane (DPPE), 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, at room temperature to 150°C.

[0195] (3) Negishi coupling is a well-known method for creating carbon-carbon bonds using an organozinc compound and an aryl halide. For example, the coupling is carried out in an organic solvent (e.g., benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixture of these solvents) using a catalyst (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium ((A-taPhos) 2 PdCl 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(tri-tert-butylphosphine)palladium (Pd(tBu) 3 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl 2(dppf)), diallylpalladium dichloride (PdCl 2 (allyl) 2 ), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh 3 ) 2 ), (tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), Nickel chloride (NiCl 2 ), Nickel(II) bis(acetylacetonate) (Ni(acac) 2 In the presence of a ligand (e.g., triphenylphosphine (PPh 3 ), tributylphosphine (PBu 3 ), 2-dicyclohexylphosphino-2'-6'-diisopropoxybiphenyl (RuPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), tri(2-furyl)phosphine (trp), terpyridine, etc.) at room temperature to 150°C.

[0196] Amidation Amidation is a known reaction. For example, there is the following method. (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) The reaction via an acyl halide can be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g., oxalyl chloride or thionyl chloride) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or in a non-solvent at about -20°C to reflux temperature. 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) The reaction via a mixed acid anhydride can be carried out, for example, by reacting a carboxylic acid with an acyl halide (e.g., pivaloyl chloride) or a sulfonyl chloride (e.g., p-toluenesulfonyl chloride or methanesulfonyl chloride), or a chloroformate (e.g., ethyl chloroformate, isobutyl chloroformate or phenyl chloroformate) 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 reacting the 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] The 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 preferred results.

[0202] Oxidative halogenation reactions The oxidative halogenation reaction is a known reaction. For example, there is the following method. (1) Oxidative chlorination (2) Oxidative bromination (3) Oxidative iodination These techniques are described below. (1) Oxidative chlorination is carried out using a chlorination reagent (e.g., N-chlorosuccinimide, N-chlorophthalimide, trichloroisocyanuric acid, etc.) and a solvent (e.g., DMF, DMA, THF, DME, CH 3 The reaction can be carried out using a solvent such as toluene, CN, or a mixed solvent of these) in an inert atmosphere at 0° C. to 100° C. (2) Oxidative bromination is carried out using a bromination reagent (e.g., N-bromosuccinimide, N-bromophthalimide, pyridinium bromide perbromide, bromine, etc.) and a solvent (e.g., DMF, DMA, THF, DME, CH 3 The reaction can be carried out using a solvent such as toluene, CN, or a mixed solvent of these) 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, there is the following method. (1) Dehydration and chlorination (2) Dehydration bromination These techniques are described below. (1) Dehydration chlorination is POCl 3 The reaction can be carried out using the above 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) Dehydration bromination is POBr 3 The reaction can be carried out using the above 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 known reaction. For example, there is the following method. (1) SnAr substitution reaction with 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, or a mixture of these) using 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, there is the following method. (1) Reaction via iminochloride (2) Reaction via orthoester (1) The reaction via imino chloride can be carried out by reacting 1-amino-2-imidazolecarboxylic acid with imino chloride 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 of these) 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 part 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 solution of hydrogen chloride in dioxane, trifluoroacetic acid, or methanesulfonic acid) in a solvent (e.g., dioxane, dichloromethane) at 0°C to 40°C. For example, the deprotection reaction of a benzyloxycarbonyl (Z) group can be carried out by hydrogenation in the presence of a catalyst (e.g., palladium on 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. Methods for deprotecting an amino-protecting group are known and are described in detail in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

[0207] Deprotection of Carboxylic Acid Protecting Group The deprotection reaction of the carboxylic acid protecting group can be carried out under suitable conditions 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, a solution of 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 on 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 protecting group for a carboxylic acid is known and is described in detail in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

[0208] Urea formation reaction The urea-forming reaction can be carried out, for example, as follows. (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 is to dissolve one amine and the carbonylation reagent in a solvent (e.g., DCM, CH 3 The second step can be carried out in an inert atmosphere at room temperature to 100° C. in a solvent such as CN, dioxane, or a mixture thereof.

[0209] Protecting groups in reactions I-XII P in Reactions I-XII 1 represents a protecting group for a carboxylic acid. P 1 include 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] SnBu 3 , 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 compound represented by general formula (I).

[0211] Reaction Scheme I

[0212] [ka]

[0213] R in the compound represented by formula (I-1) 3 But, OR 7 , N.H.R. 8 or N(R 8 ) 2 If not, the compound of 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 a compound represented by general formula (IX) and a 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 mixture thereof.

[0219] The compound represented by the general formula (VI) can be produced by subjecting the compound represented by the general formula (IV) and the compound represented by the 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 of these 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 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 , N.H.R. 8 or N(R 8 ) 2 In the case where the compound represented by the general formula (I-1) is a compound represented by the 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 compound represented by the general formula (XI) and the compound represented by the general formulas (XVIII), (XIX) and (XX) can be produced by subjecting the compound represented by the general formula (XI) and the compound represented by the general formula (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 the general formula (XXV) can be produced by subjecting a compound represented by the general formula (XXIII) and a compound represented by the general formula (XXIV) to a pyrazolopyrimidinone cyclization reaction.

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

[0241] The compound represented by the general formula (XXIII) can be produced by subjecting a compound represented by the general formula (XXI) and a compound represented by the 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 from -78°C to room temperature.

[0243] Reaction formula V

[0244] [ka]

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

[0246] The pyridinopyridazinone cyclization reaction can be carried out by reacting an ester of a 3-aminonicotinic acid derivative with an imino chloride 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 the compound represented by general formula (XXVIII) are described in Chemical and Pharmaceutical bulletin, vol 31, #10, p 3490-3464, U.S. Patent No. 5591742 (1997) or U.S. Application Publication No. 2019 / 194174.

[0248] Reaction formulas VI to XII show the synthesis of the compound 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 Scheme VI

[0256] [ka]

[0257] L 1 , L 2 is -C(=O)-, the compounds represented by the general structural formulas (II-3), (II-5), (II-6), (II-9) and (II-10) can be respectively represented by the following reaction formula VI: A ) can be written as

[0258] General formula (II A The compound represented by formula (XXXII) and the compound represented by formula (XXXIII) can be produced by subjecting them 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 a 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 a compound represented by general formula (XXIX) and a 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 the general formula (XXXV) can be produced by subjecting the compound represented by the general formula (XXXIV) to a 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 the general formulae (II-1) and (II-2) can be respectively represented by the following reaction formula VIII: B ) can be written as

[0269] General formula (II B The 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 a 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 Scheme 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 the general formula (XLI) can be produced by subjecting the compound represented by the general formula (XL) to a 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 formula 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 represented by the following reaction formula X: C ) can be written as

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

[0281] The compound represented by the general formula (XLV) can be produced by subjecting the compound represented by the general formula (XLIV) to a 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 a compound represented by general formula (XLIII) and a 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 the general formula (XLVII) can be produced by subjecting the compound represented by the general formula (XXXIII) and the compound represented by the general formula (XLVI) to the above-mentioned amidation reaction.

[0288] Reaction Scheme 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 reaction formula XII: D ) or (II E ) can be written as

[0291] General formula (II D The compound represented by the general formula (XXXV) and the compound represented by the 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 formulae I to XII, each compound 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) can be obtained as a commercially available product or as a product easily prepared by a known method described in, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons, Inc., 1999).

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

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

[0296] The products obtained by the reactions exemplified herein can be purified by conventional purification methods, such as distillation at atmospheric or reduced pressure, 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] Since the compounds of the present invention have low toxicity, they can 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 causing cognitive impairment include chronic platelet aggregation, liver disease, pathological immune states associated with T cell activation, CNS diseases, myeloproliferative disorders, Parkinson's disease, Lewy body disease, 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, the compound exhibits 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 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, for example, agents 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-HT 4 Receptor agonists or partial agonists, histamine H3 antagonists, 5-HT 6 Receptor antagonists, or 5HT 1A Receptor ligands, and NMDA receptor antagonists or modulators, 5-HT 2A Antagonist, 5-HT 7Antagonists, Dl agonists or PAMs, D4 agonists or PAMs, D5 agonists or PAMs, GABA-Aa5 inverse agonists or negative allosteric modulators (NAMs), GABA-Aa2 / 3 agonists or PAMs, mGluR2 modulators (PAMs or NAMs), mGluR3PAMs, mGluR5 Potential disease modifying agents such as PAMs, PDE1 inhibitors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE9 inhibitors, PDE10 inhibitors, GlyTl inhibitors, DAAO inhibitors, ASCI inhibitors, AMPA modulators, SIRT1 activators or inhibitors, AT4 antagonists, GalRl antagonists, GalR3 ligands, adenosine Al antagonists, adenosine A2a antagonists, a2A antagonists or agonists, selective and nonselective norepinephrine reuptake inhibitors (SNRIs), or gamma-secretase inhibitors or modulators, alpha-secretase activators or modulators, amyloid aggregation inhibitors, amyloid antibodies, tau aggregation inhibitors, or tau phosphorylation / kinase inhibitors, tau dephosphorylation / phosphatase activators, mitogen-activated protein kinase kinase 4 (MKK4 / MEK4 / MAP2K4) inhibitors, c-Jun These include N-terminal kinase (JNK) inhibitors, casein kinase inhibitors, MK2 (mitogen-activated protein kinase 2) inhibitors, MARK (microtubule affinity-regulating kinase) inhibitors, CDK5 (cyclin-dependent kinase 5) inhibitors, GSK-3 (glycogen synthase kinase-3) inhibitors and tau-tubulin kinase-1 (TTBK1) inhibitors.

[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 (molecule interacting 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 drugs and / or HMGCoA reductase inhibitors (statins), dimebolins or similar agents, antihistamines, metal binding / chelating drugs, antibiotics, growth hormone secretagogues, cholesterol-lowering drugs, vitamin E, cholesterol absorption inhibitors, cholesterol efflux promoters and / or activators, and insulin 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 one preparation, or may be administered in the form of separate preparations administered by 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 administrations as necessary. In addition, when a time lag is set between administrations, there is no particular restriction on the order of administration, and it is sufficient to appropriately adjust so as to obtain the desired efficacy.

[0307] The dosage of these other drugs used in combination with the compound of the present invention can be appropriately increased or decreased based on the clinically used dosage of the drug or similar drug. In addition, the mixing ratio of the compound of the present invention and the other drugs can be appropriately adjusted in consideration of the age and body weight of the subject, the administration method, administration time, the target disease, symptoms, etc. In general, the other drugs may be combined in the range of 0.01 to 100 parts by weight with 1 part by weight of the compound of the present invention. A plurality of other drugs may be used. In addition to the above-listed drugs, the other drugs may be drugs having the same mechanism as the above-listed drugs. Such drugs include not only those that have been discovered so far, but also those that will 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 the range of 0.1 mg to 300 mg per dose per adult, once to several times a day, or parenterally in the 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 is sufficient, and in other cases a dosage exceeding the range is required.

[0310] In order to use the compound of the present invention as a single agent or as a combination agent of the compound of the present invention and other drugs for the purpose of preventing and / or treating the above-mentioned diseases, the active ingredient is usually formulated together with pharma- ceutically acceptable carriers such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, the pharma- ceutically acceptable carrier means a substance other than the active ingredient that is generally used in the formulation of pharmaceuticals. The pharma- ceutically acceptable carrier is preferably one that does not show pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, the pharma- ceutically acceptable carrier can also be used for the purpose of increasing the usefulness of the active ingredient and the formulation, facilitating formulation, stabilizing the quality, or improving usability. Specifically, a substance such as that described in "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nipposha in 2000, may be appropriately selected according to 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 semi-solids, gargles, 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 semi-solids, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.).

[0312] [Oral formulation] Oral preparations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc. Oral preparations include rapidly disintegrating preparations in which the release of the active ingredient from the preparation is not particularly adjusted, and release-adjusted preparations, such as enteric preparations and sustained-release preparations, in which the release is adjusted according to the purpose by a specific preparation design and manufacturing method. Enteric preparations are preparations designed to release the active ingredient not in the stomach but mainly in the small intestine, for the purpose of preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach, and can usually be manufactured by applying a coating using an acid-insoluble enteric base. Sustained-release preparations are preparations in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or reducing side effects, and can usually be manufactured 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 sugars or sugar alcohols, polymeric compounds, etc., 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 rapid 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, mix them together to make a homogeneous mixture, granulate them using water or a solution containing a binder in an appropriate manner, add lubricants, mix, and compress into a mold; (b) The active ingredient is mixed with additives such as excipients, binders, and disintegrants to form a homogeneous mixture, which is then directly compressed and molded, or the active ingredient and lubricants are added to granules previously prepared with additives, which are then mixed to form a homogeneous mixture, which is then compressed and molded; (c) Add excipients, binders and other additives to the active ingredient, mix them homogeneously, wet the mixture with a solvent, pour it into a mold, and then dry it in an appropriate manner; is used. Film-coated tablets can usually be produced by coating plain tablets with a thin coating of a suitable coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating plain tablets with a coating agent containing sugars or sugar alcohols. Multi-layer tablets can be produced by stacking powders of different compositions in layers and compressing them using an appropriate method. Dry-coated tablets can be produced by covering an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using a known appropriate method. Oral rapid disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of additives, and can be produced in accordance with the manufacturing method of the above-mentioned tablets. In addition, an intraoral rapid disintegrating tablet is a tablet that can be taken by dissolving or disintegrating quickly in the oral cavity; a chewable tablet is a tablet that is taken by chewing; an effervescent tablet is a tablet that dissolves or disperses while effervescently rapidly in water; a dispersible tablet is a tablet that is dispersed in water before taking; and a dissolving tablet is a tablet that is dissolved in water before taking. Effervescent tablets can be produced by using an appropriate acidic substance, carbonate, bicarbonate, etc. as an additive.

[0314] (2) Capsules Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules can be produced by mixing an active ingredient with an additive such as an excipient to make it homogeneous, or by forming it into a granular or shaped form by an appropriate method, and filling the mixture directly or lightly into a capsule. Soft capsules can be produced by encapsulating an active ingredient with an additive and encapsulating it into a certain shape with an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, or the like. Capsules can be made into enteric capsules or sustained-release capsules using a known appropriate method, and colorants, preservatives, and the like can also be added to the capsule base.

[0315] (3) Granules Granules are preparations granulated into a granular form, and include not only those generally called granules, but also effervescent granules, etc. Granules are usually produced using the following (a), (b), or (c) method: (a) The powdered active ingredient is mixed with an excipient, binder, disintegrant, or other additive to obtain a homogeneous mixture, and then granulated by a suitable method; (b) Add excipients and other additives to the active ingredient that has already been prepared into granules and mix until homogeneous; (c) Adding excipients and other additives to the active ingredient that has already been granulated, mixing the mixture, and forming the mixture into granules by a suitable method; The granules can be coated with a coating if necessary, and can be made into enteric granules or sustained-release granules by using a known suitable method. The effervescent granules can be produced by using a suitable acidic substance, carbonate, bicarbonate, etc. as an additive. The effervescent granules refer to granules that dissolve or disperse in water while effervescently foaming. The granules can also be made into fine granules by adjusting the particle size.

[0316] (4) Powders A powder is a preparation in powder form, and can usually be produced by adding an excipient or other additives to an active ingredient, mixing them together, and making them homogenous.

[0317] (5) Oral liquid Oral liquids are preparations in the form of liquid or viscous gel with fluidity, and include those generally referred to as oral liquids, as well as elixirs, suspensions, emulsions, lemonades, etc. Oral liquids can usually be produced by adding additives and purified water to the active ingredient, mixing and dissolving homogeneously, or emulsifying or suspending, and filtering as necessary. Elixirs refer to clear liquid oral liquids containing sweet and aromatic ethanol, and can usually be produced by adding ethanol, purified water, flavorings, and white sugar, other sugars, or sweeteners to a solid active ingredient or its exudate, dissolving it, and filtering or other methods to make it a clear liquid. Suspensions refer to oral liquids in which the active ingredient is finely and homogeneously suspended, and can usually be produced by adding suspending agents or other additives and purified water or oil to a solid active ingredient, suspending it in an appropriate manner, and homogenizing the whole. 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. Note that a lemonade is an oral liquid preparation that is clear and has a sweet and sour taste.

[0318] (6) Syrups A syrup is a viscous liquid or solid preparation containing sugars or sweeteners, and includes syrup preparations. A syrup can usually be produced by adding an active ingredient to a solution of white sugar, other sugars, or sweeteners, or a simple syrup, dissolving, mixing, suspending, or emulsifying the active ingredient, boiling the mixture as necessary, and then filtering it while hot. A syrup preparation is a granular or powdered preparation that becomes a syrup when water is added, and is sometimes called a dry syrup. A syrup preparation can usually be produced using sugars or sweeteners as additives in accordance with the production method of the granules or powders.

[0319] (7) Oral jelly Oral jellies are non-flowable, molded gel-like preparations, and can usually be produced by mixing the active ingredient with an additive 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 certain shape that are applied in 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 method of the tablets. Note that a troche is an oral tablet that is gradually dissolved or disintegrated in the oral cavity and applied locally to the oral cavity, pharynx, etc.; a sublingual tablet is an oral tablet that quickly 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 the 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, and 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) Semi-solid preparation for oral use Oral semi-solid preparations are preparations applied to the oral mucosa, and include creams, gels, ointments, etc. Oral semi-solid preparations can usually be produced by emulsifying an active ingredient together with additives in purified water and oily ingredients such as petrolatum, or by mixing an active ingredient and additives with a polymer gel or oil as a base to make it homogeneous. Creams refer to semi-solid preparations emulsified into oil-in-water or water-in-oil types, and lipophilic preparations emulsified into water-in-oil types are sometimes called oily creams. Creams can usually be produced by forming an oil phase with petrolatum, higher alcohol, etc. as it is or with the addition of an additive such as an emulsifier, and separately forming an aqueous phase with purified water as it is or with the addition of an additive such as an emulsifier, adding an active ingredient to either of the phases, heating each, and emulsifying the oil phase and the aqueous phase together by stirring until the whole is homogeneous. Gels refer to gel-like preparations, and include aqueous gels, oily gels, etc. Aqueous gels can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending it, and then heating and cooling, or adding a gelling agent to crosslink it. Oily gels can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. An ointment refers to a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base, and includes oleaginous ointments, water-soluble ointments, etc. An oleaginous ointment can usually be produced by heating and melting an oleaginous base such as oils, waxes, and hydrocarbons such as paraffin, adding an active ingredient, mixing and dissolving or dispersing it, and mixing and kneading until the whole is homogeneous. A water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole is homogeneous.

[0323] (4) Mouthwash Mouthwashes are liquid preparations that are applied locally to the oral cavity, pharynx, etc., and also include solid preparations that are dissolved when used. 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 when used can usually be produced in accordance with the production methods for tablets or granules.

[0324] [Injectable preparations] (1) Injectables Injections are solutions, suspensions, or emulsions, or solid sterile preparations that are dissolved or suspended just before use and are administered subcutaneously, intramuscularly, or directly into internal tissues or organs such as blood vessels. 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. Injections are usually manufactured using the following method (a) or (b): (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 obtain a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized; (b) 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, etc., to obtain a homogeneous mixture, which is then filtered through a sterile filter, or the homogeneous mixture is prepared under aseptic conditions and filled into a container for injection and sealed; is used. A freeze-dried injection can usually be produced by dissolving the active ingredient as it is, or the active ingredient and additives such as excipients in water for injection, sterilizing and filling it into a container for injection, followed by freeze-drying, or freeze-drying it in a dedicated container and filling it directly into a container. A powder injection can usually be produced by processing it by sterile filtration, followed by adding a powder obtained by crystallization or a sterilized additive to the powder, and filling it into a container for injection. A filled syringe can usually be produced by filling a syringe with the active ingredient as it is, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. A cartridge refers to an injection that is used by putting a cartridge filled with a drug solution into a dedicated syringe, and a cartridge filled with a drug solution can usually be produced by filling the cartridge with the active ingredient as it is, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. An infusion refers to an injection that is usually 100 mL or more and is administered intravenously. The implantable injection refers to a solid or gel-like injection that is applied subcutaneously, intramuscularly, etc., using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. The implantable injection can usually be produced by using a biodegradable polymer compound to make it into pellets, microspheres, or gels. The sustained release injection refers to an injection that is applied 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 making it into a suspension of microspheres using a biodegradable polymer compound.

[0325] [Dialysis preparations] (1) Dialysis agents The dialysis agent is a liquid or solid preparation that dissolves when used, used for peritoneal dialysis or hemodialysis, and includes peritoneal dialysis agents and hemodialysis agents. The peritoneal dialysis agent refers to a sterile dialysis agent used for peritoneal dialysis, and can be produced by adding an additive to an active ingredient, dissolving it in a solvent to a fixed volume, or by filling a container with the active ingredient and the additive, sealing it, and sterilizing it as necessary. In the case of a solid preparation that dissolves when used, it can be produced in accordance with the production method of the above-mentioned tablets or granules. The hemodialysis agent refers to a dialysis agent used for hemodialysis, and can be produced in accordance with the production method of the above-mentioned tablets or granules, and can be produced in accordance with the production method of the above-mentioned tablets or granules. In the case of a solid preparation that dissolves when used, it can be produced in accordance with the production method of the above-mentioned tablets or granules.

[0326] [Inhalation preparations] (1) Inhalants Inhalants are preparations in which the active ingredient is inhaled as an aerosol and applied to the bronchi or lungs, and include powder inhalants, inhalation liquids, inhalation aerosols, etc. Powder inhalants are preparations inhaled as an aerosol of solid particles, prepared so that the inhalation amount is constant. They can usually be produced by making the active ingredient fine particles and mixing them with additives such as lactose as necessary to make them homogeneous. Inhalation liquids are liquid inhalants applied by a nebulizer, etc., and usually can be produced by adding a solvent and an appropriate isotonicity agent, pH regulator, etc. to the active ingredient, mixing them to dissolve or suspend them homogeneously, and filtering as necessary. Inhalation aerosols are metered-dose inhalants that spray a fixed amount of active ingredient together with a propellant filled in a container. Inhalation aerosols can usually be produced by adding a solvent and an appropriate dispersant, stabilizer, etc. to the active ingredient to make a solution or suspension, filling it into a pressure-resistant container together with a liquid propellant, and attaching a metered-dose valve.

[0327] [Ophthalmic preparations] (1) Eye drops Eye drops are sterile preparations in liquid or solid form that are applied to eye tissues such as the conjunctival sac and are dissolved or suspended just before use. Eye drops can usually be 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 homogenous, 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 before use. Ear drops can usually be 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 fine powder nasal drops administered to the nasal cavity, and can usually be produced by making the active ingredient into moderately fine particles and mixing with additives as necessary 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 when used, and can usually be produced by adding a solvent and additives to the active ingredient, dissolving or suspending it, and filtering it as necessary. Additives that can be used for nasal liquids include isotonicity agents and pH adjusters.

[0331] [Rectal preparations] (1) Suppositories Suppositories are semi-solid preparations of a certain shape that are applied rectally and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Suppositories can usually be manufactured by mixing the active ingredient with additives such as dispersants and emulsifiers to make it homogeneous, dissolving or dispersing it homogeneously in a base that has been liquefied by heating, filling a certain amount into a container, and solidifying / molding it. An oily base or a hydrophilic base is usually used as the base for suppositories.

[0332] (2) Semisolid preparation for rectal administration Semisolid rectal preparations are preparations to be applied around or inside the anus, and include rectal creams, rectal gels, rectal ointments, etc. Semisolid rectal preparations can usually be produced by emulsifying an active ingredient together with additives in purified water and oily ingredients such as petrolatum, or by mixing a polymer gel or oil as a base with an active ingredient and additives to make it homogeneous. Rectal creams can usually be produced by using petrolatum, higher alcohols, etc. as they are or with the addition of additives such as emulsifiers to make an oil phase, and separately using purified water as it is or with the addition of additives such as emulsifiers to make an aqueous phase, adding an active ingredient to either of these phases, heating each, and emulsifying by mixing the oil phase and the aqueous phase together until the whole is homogeneous. Rectal gels refer to gel-like preparations, and include aqueous gels, oily gels, etc. Aqueous gels can be produced by adding a polymer compound, other additives, and purified water to the active ingredient, dissolving or suspending it, and then heating and cooling, or adding a gelling agent to crosslink it. Oily gels can be produced by adding and mixing the active ingredient with a liquid oily base such as glycols and 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, and the like. Oleaginous ointments can usually be produced by heating and melting an oleaginous base such as oils, waxes, and hydrocarbons such as paraffin, adding the active ingredient, mixing and dissolving or dispersing it, and mixing and kneading until the whole 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 whole is homogeneous.

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

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

[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 homogenous mixture, and then forming them into a powder.

[0337] (2) Liquid preparations for external use The external liquid preparation is a liquid preparation to be applied to the skin, including the scalp, or to nails, and includes liniments, lotions, etc. External liquid preparations can usually be produced by adding a solvent, additives, etc. to the active ingredient, dissolving, emulsifying, or suspending, and filtering as necessary. The liniment refers to a liquid or muddy external liquid preparation to be rubbed into the skin. The lotion refers to an external liquid preparation in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid, and can usually be produced by homogenizing the entirety as a solution, suspension, or emulsion using the active ingredient, additives, and purified water.

[0338] (3) Sprays A spray is a preparation in which an active ingredient is sprayed onto the skin in the form of a mist, powder, foam, or paste, and includes aerosols for external use, pump sprays, and the like. A spray can usually be produced by preparing a solution or suspension of an active ingredient, filtering it as necessary, and then filling it into a container. An aerosol for external use is a spray that sprays an active ingredient together with a liquefied gas or compressed gas filled in a container. An aerosol for external use can usually be produced by preparing a solution or suspension of an active ingredient, filling it into a pressure-resistant container together with a liquid propellant, and attaching a continuous injection valve. Additives such as dispersants and stabilizers can also be added to an aerosol for external use as necessary. A pump spray is a spray that sprays an active ingredient in a container by a pump. A pump spray can usually be produced by dissolving or suspending an active ingredient and an additive, and attaching a pump to the filled container.

[0339] (4) Ointments Ointments are semi-solid preparations 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, and hydrocarbons such as paraffin, adding an active ingredient, mixing and dissolving or dispersing it, and mixing and kneading until the whole is homogeneous. Water-soluble ointments can usually be produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole is homogeneous.

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

[0341] (6) Gels Gels are gel-like preparations to be applied to the skin, and include aqueous gels, oily gels, etc. Aqueous gels can be produced by adding a polymer compound, other additives, and purified water to the active ingredient, dissolving or suspending it, and then heating and cooling it, or adding a gelling agent to crosslink it. 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.

[0342] (7) Patches Patches are preparations that are applied to the skin, and include tapes, poultices, etc. Patches are usually made by mixing an active ingredient with a base made of a polymeric compound or a mixture of these, making the active ingredient homogenous, and spreading it on a support or liner (release body) and molding it. A release-regulating membrane can also be used to make a transdermal preparation. Patches can also contain additives such as adhesives and absorption promoters, as necessary. Tapes refer to patches that use a base that contains almost no water, and include plasters, plasters, etc. Tapes are usually made by using a water-insoluble natural or synthetic polymeric compound such as resin, plastic, or rubber as a base, making the active ingredient homogenous or by adding additives to the active ingredient, spreading it on a cloth or a plastic film, etc., and molding it. Patches can also be made by encapsulating a mixture of the active ingredient and a base or other additives in a release body made of a release-regulating membrane, a support, and a liner (release body) and molding it. A cataplasm is a patch that uses a water-containing base, and can usually be produced by mixing the active ingredient with purified water, glycerin, or other liquid substance and homogenizing the whole, or by mixing and kneading a natural or synthetic polymer compound such as a water-soluble polymer or water-absorbent polymer with purified water, adding the active ingredient, homogenizing the whole, and spreading it onto a cloth or the like to form the mixture.

[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 are hereby incorporated by reference in their entirety. EXAMPLES

[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 were named according to the IUPAC nomenclature. Naming according to the IUPAC nomenclature can be performed, for example, using ACD / Name (version 2019.2.0, Advanced Chemistry Development Inc.), ACD / Name Batch (version 12.02.45356, Advanced Chemistry Development Inc.) or ChemDraw Professional (version 17.1.0.105 or 18.0.0.231, available from PerkinElmer Inc.). In each of the following examples, the name of the target compound of the example is described 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 with a 5 mm inverse-detected triple resonance probe operating at 400 MHz, or a Bruker Avance DRX 400 spectrometer with a 5 mm inverse-detected triple resonance TXI probe operating at 400 MHz, or a Bruker Avance DPX 300 spectrometer with a standard 5 mm dual frequency probe operating at 300 MHz, or a Bruker Avance 400 MHz with a 5 mm QNP probe H, C, F, P, single Z gradient, 2-channel instrument running TopSpin 2.1, or a Bruker advance III 400 MHz with a 5 mm BBFO Plus probe, single Z gradient, 2-channel instrument running TopSpin 3.1. Shift values ​​were 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 1.7 μm, 100 × 2.1 mm. 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 1.7 μm, 50 × 2.1 mm. 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 1.7 μm, 100 × 2.1 mm. 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 1.7 μm, 50 × 2.1 mm. 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 1.7 μm, 50 × 2.1 mm. Mobile phase (A): 0.1% ammonia water (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 1.8 μm, 100 × 2.1 mm. 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 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 1.7 μm, 100 × 2.1 mm. Mobile phase (A): 0.1% ammonia water (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 3.5 μm, 50 × 4.6 mm. 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 20 x 2.0 mm. Mobile phase (A): 1.5 mL of TFA-4 L of water; Mobile phase (B): 0.75 mL of TFA-acetonitrile solution

[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). Columns used for purification of compounds were Waters Sunfire OBD, Phenomenex Luna Phenyl Hexyl, or Waters Xbridge Phenyl 10μm 19x150mm unless otherwise stated. Appropriate gradients were selected from the solvent system of acetonitrile and MeOH in either acidic or basic conditions. The standard gradient was 5% to 20% MeCN over 1 min, held for 2.5 min, 80% MeCN over 12.5 min, held for 7.5 min, followed by re-equilibration at initial conditions for 3 min. The flow rate was 20ml / min. Prior to the purification step, the compounds were analytically screened. Each sample was run under acidic and basic conditions (2 μl injection, 5 / 95 gradient, 5 min). It was then decided which pH and which concentration gradient to use depending on where the target substances would elute and where separation would be achieved. The modifiers used under acidic / 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. The purification was controlled by monitoring 210 nm to 400 nm using Waters Fractionlynx software, revealing the threshold recovery value at 260 nm and the presence of the target molecular ion observed under the targeted ESI conditions. The collected fractions were analyzed by LCMS (Waters ACQUITY systems with Waters SQD). The fractions containing the target substances were dried overnight in a Genevac freeze dryer. Some compounds undergo a second purification step to obtain the required purity due to the complex mixture. More focused gradient or isocratic conditions may be used for more challenging separations.

[0370] Separation of the enantiomers by supercritical fluid chromatography (SFC) was performed using a Waters Thar Prep 100 preparative SFC system (P200 CO 2 The experiments were performed using either a Waters Thar Investigator semi (Waters Fluid Delivery Module, 2998 UV / VIS detector, 2767 Liquid Handler with Stacked Injection Module) or a Waters Thar Investigator semi (Waters Fluid Delivery Module, 2998 UV / VIS detector, Waters Fraction Collection Module). When the Waters 2767 Liquid Handler was used, it acted 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 columns.

[0372] Under unmodified or basic conditions, the appropriate isocratic method was selected from methanol, ethanol, or isopropanol solvent systems. 2 , 100 ml / min (or appropriate), 120 Bar back pressure, column temperature 40° C., with specific modifier composition as specified during the method development stage.

[0373] All compounds were analytically screened prior to the purification step. Each sample was run through ethanol, methanol and isopropanol under neat and basic conditions (5.0 μL, 5 / 55 gradient over 5 min). If necessary, a secondary screen covering a wide range of solvents such as acetonitrile, ethyl acetate, THF, etc. was also performed. It was then decided which pH and which isocratic conditions to use depending on where the target material elutes and where separation is achieved.

[0374] The modifier used under basic conditions was diethylamine (0.1% V / V). Alternative modifiers such as formic acid (0.1% V / V), acetic acid (0.1% V / V) can be used as acidic modifiers. Purification was controlled by monitoring from 210 to 400 nm using Waters Fractionlynx or Waters Chromscope software to determine the presence of threshold recovery values ​​at the appropriate wavelengths. Collected fractions were analyzed by SFC (Waters / Thar SFC system with Waters SQD or Waters UPCC with 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 prior to 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 0.1% formic acid or 0.1% NH 4 Using either OH modifier, MeCN / H 2 Elute with a gradient of O, C 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 Steps 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 if necessary for completion of 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 NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 ) and concentrated under reduced pressure. The residue was dissolved in DCM and (登録商標) Pre-adsorbed on an HM-N column (Biotage) and diluted with 2N NH 3Purified by silica gel chromatography eluting with MeOH in DCM.

[0380] Suzuki-Miyaura Basic Step 2 Aryl chloride or bromide (1.0 eq), boronic acid or ester (1.3 eq), cesium carbonate (2.5 eq), Pd(PPh 3 ) 4 A mixture of (0.1 eq) of boronic acid and Pd(PPh) in dioxane / water (10:1, 100 mM) was degassed and stirred at 80° C. for 16 h. If necessary, boronic acid and Pd(PPh) were added to the reaction mixture to complete the reaction. 3 ) 4 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 NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 ) and concentrated under reduced pressure. The residue was dissolved in DCM and (登録商標) Pre-adsorbed on an HM-N column (Biotage) and diluted with 2N NH 3 Purified by silica gel chromatography eluting with a gradient of 100% methanol / MeOH in DCM.

[0381] THP Deprotection Step 1 A suspension of the THP-protected compound in methanol (100 mM) was treated with 1 N HCl (aq) (5 eq) and the reaction mixture was stirred at room temperature until the reaction was judged complete 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 Step 1 A suspension of the trityl-protected compound in methanol (200 mM) was treated with 1N HCl(aq) (5 eq) and the reaction mixture was stirred at room temperature for 21 h. The solid was collected by filtration, washed with MeOH and pumped dry. It was further purified by reverse phase chromatography to give 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 under microwave irradiation for 1 h. 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 and then diluted with MeCN / H 2 Dissolve in 10-98% MeCN / H2O / formic acid 2 Purification was performed by reverse phase chromatography (C18 cartridge), eluting with O+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 concentration) 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 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 DMSO / formic acid and purified by 10-98% MeCN / H 2 Purification was performed by reverse phase chromatography (C18 cartridge), eluting with O+0.1% formic acid.

[0386] SnAr Basic Step 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 amine or amine hydrochloride (1.0 eq) in dioxane (0.2 mM) was treated with triethylamine (5 eq) and heated at 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 if necessary to complete the reaction (as determined by LC-MS analysis). The reaction was diluted with DCM and saturated NaHCO 3 The organic layer was partitioned into aqueous saturated sodium bicarbonate (NaHCO 3 The mixture was washed with aqueous solution (x2) and water, added with 100 mL of ethyl acetate, and dried (MgSO 4 ) 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] General procedure for nitrile hydrolysis Nitrile (1 eq) and Perkin's catalyst (5 mol%) in EtOH / H 2 The suspension in 2H2O (9:1, 0.34 M) was heated at 80 °C until complete as determined 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] Working 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 (0.6eq) 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 and then lithium bis(trimethylsilyl)amide (1 M in THF, 510 mL, 0.510 mol) was added dropwise while maintaining the temperature at 10-15 °C. To the resulting solution was added O-(diphenylphosphinyl)hydroxylamine (119 g, 0.510 mol) 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 (x4), 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 dissolved in Et 2 Trituration with O and filtration gave the title compound (61.2 g, 84%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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 the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a yellow oily product, which crystallized by leaving it (21.7 g, quant.). 1 H NMR (400 MHz, CDCl 3 )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 in a microwave reactor for 45 min. 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 was stirred at room temperature until complete dissolution (30-45 min). The reaction 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 (MgSO 4 ) and concentrated under reduced pressure to obtain the title compound (21.4 g, quant.) as an orange paste. 1 H NMR (400 MHz, CDCl 3)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 washed with DCM and saturated NaHCO 3 The organic layer was partitioned between aqueous saturated sodium bicarbonate and aqueous sodium chloride. 3 Wash with aqueous solution (x3) and water, dry (MgSO 4 ) and concentrated under reduced pressure to give a light brown oil which crystallized on standing (20.9 g, 68%). 1 H NMR (400 MHz, CDCl 3 )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 hours. The reaction mixture was diluted with toluene, concentrated under reduced pressure, and then azeotroped with toluene (x2). The residue was dissolved in DCM and saturated NaHCO 3 The mixture was partitioned between aqueous and aqueous solutions. The layers were separated and the aqueous layer was extracted with DCM (x2). The combined organic layers were washed with water, brine and dried (MgSO 4 ) 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 h, after which 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) HM-N column (Biotage) and elution with 0–20% EtOAc in cyclohexane; 200 g SiO 2 The cartridge was dry loaded. 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 (400 MHz, CDCl 3)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 to obtain Pd(PPh 3 ) 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 diluted with DCM and 220 g SiO 2 The cartridge was loaded 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 (400 MHz, CDCl 3 )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 Synthesised 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-furylboronic acid using the 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, 0.6eq 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, d 6 -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, 0.6eq formate 3-Isopropyl-2-phenyl-7-(1-trityl-1H-imidazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4(3H)-one Synthesised from 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 following the 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, 0.6eq 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, d 6 -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 from 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 by 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 It 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 following the trityl deprotection procedure 1, except that TFA (11 eq) was also added to the reaction mixture in 10-98% MeCN / H 2 Reverse phase chromatography (C 18 Cartridge) to afford 17 mg (45%) of the title compound as a white solid. 1 H NMR (400MHz, d 6 -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 Synthesis 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 by 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 and heating the reaction mixture at 120° C. for 30 min under microwave irradiation, followed by additional amine (0.5 eq) and triethylamine (0.8 eq) and heating at 120° C. for another 30 min under microwave irradiation. DCM (0.5 mL) was added 6 h after the addition of TFA and the mixture was stirred at room temperature for a further 40 h. The title compound was isolated as a white solid, 45 mg (75%). 1 H NMR (400MHz, d 6 -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% dispersion in oil, 38 mg, 0.96 mmol) under nitrogen and stirred at room temperature. After 10 min, a portion of this mixture (0.9 mL) was added to a 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 (2.0 mL) under argon, and the reaction mixture was stirred at room temperature for 30 min, after which another portion of the alkoxide solution (0.5 mL) was added and stirred for an additional 30 min before diluting 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 solution and saturated brine, and dried (MgSO 4 ) and then concentrated under reduced pressure to give a yellow viscous substance. This viscous substance was dissolved in DCM and added to ISOLUTE (登録商標) Preliminary adsorption was performed on an HM-N column (Biotage), and 0–4% (2N NH 3 Purification by silica gel chromatography (40 g cartridge) eluting with C13H2O / MeOH in DCM afforded 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, d 6-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. 20% EtOH (+0.1% diethylamine):80% CO 2 The enantiomers of Example 5 were separated by chiral SFC using a YMC Amylose-C column eluting at 15 mL / min, 120 bar, 40° C., DAD 230 nm to give Example 6 and Example 7.

[0406] Example 6 Enantiomer A: white solid 17mg Analytical equipment: Analytical SFC; Column: YMC Amylose-C (4.6x250mm, 5micron); Mobile phase: 20% EtOH (+0.1% diethylamine) / 80% CO 2 ; 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 16mg Analytical equipment: Analytical SFC; Column: YMC Amylose-C (4.6x250mm, 5micron); Mobile phase: 20% EtOH (+0.1% diethylamine) / 80% CO 2 ; 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 following 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. 1 H NMR (400MHz, d 6 -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 from 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 following general SnAr and deprotection procedure 2, except that the reaction was heated at 120° C. for 90 min under microwave irradiation, followed by heating at 80° C. for 72 h under normal heating. Further, amine hydrochloride (0.8 eq), triethylamine (1.5 eq) were added and heated at 120° C. for 60 min under microwave irradiation. The reaction mixture was treated with 8.2 eq TFA. The title compound (57 mg, 40%) was isolated as a white solid. 1 H NMR (400MHz, d 6 -DMSO) δ, ppm 8.02 (1H,s), 7.77 (1H,d,J=1.0Hz), 7.68 (1H,s), 4.70 (1H,hept,J=6.8Hz), 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=6.8Hz), 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. 40% MeCN (+0.1% diethylamine): 60% CO 2 The enantiomers of Example 9 were separated by chiral SFC using a YMC Cellulose-C column eluting at 15 mL / min, 120 bar, 40° C., DAD 230 nm to give Examples 10 and 11.

[0410] Example 10 Enantiomer A: Light yellow-brown solid 8 mg Analytical equipment: Analytical SFC; Column: YMC Cellulose-C (4.6x250mm, 5micron); Mobile phase: 40% MeCN (+0.1% diethylamine) / 60% CO 2; 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 yellow-brown solid 8 mg Analytical equipment: Analytical SFC; Column: YMC Cellulose-C (4.6x250mm, 5micron); Mobile phase: 40% MeCN (+0.1% diethylamine) / 60% CO 2 ; 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 h. Further, N-methyl-4-(tributylstannyl)imidazole (30 μL, 0.090 mmol) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) were added and stirred at 100° C. for 3 hours. The reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted with DCM (×2), and the combined organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried (MgSO 4 ) and concentrated under reduced pressure to give a yellow oil. The oil was diluted with 0-4% (2N NH3 Purification by silica gel chromatography (40 g cartridge) eluting with C12H2O / MeOH in DCM afforded the title compound (35 mg, 32%) as a milky gum. 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. 1 H NMR (400MHz, d 6 -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 give the title compound (34 mg, 45%) as a white solid. 1 H NMR (400MHz, d 6-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 following 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, d 6 -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 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, a small amount of solid was separated by filtration, and the filtrate was purified by hexane (2N NH 3 / MeOH) in DCM and saturated NaHCO 3 The aqueous layer was diluted with DCM (x2) and the layers were separated. The aqueous layer was extracted with DCM (x2) and the combined organic layers were washed with saturated NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 The residue was dissolved in MeOH / DCM and added with ISOLUTE (登録商標) Preliminary adsorption was performed on an HM-N column (Biotage), and then 0–10% 2N NH 3 Purification by silica gel chromatography eluting with a gradient of 1000 ml of methanol / MeOH in DCM afforded the title compound (21 mg, 30%) as a white solid. 1 H NMR (400MHz, d 6 -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 0.6eq 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 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 purified with 2N NH 3 ISOLUTE dissolved in DCM / MeOH solution (登録商標) The sample was pre-adsorbed on an HM-N column (Biotage) and diluted with 0 to 10% 2N NH 3 The product was purified by silica gel chromatography eluting with a gradient of 10–98% MeCN / H 2 Reverse phase chromatography (C 18 Cartridge) to obtain the title compound (34 mg, 52%) as a white solid. 1 H NMR (400MHz, d 6 -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 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 mixture was filtered and the solid was washed with 2N NH 3 ISOLUTE dissolved in DCM / MeOH solution (登録商標) Preliminary adsorption was performed on an HM-N column (Biotage), and then 0–10% 2N NH 3 Purification by silica gel chromatography eluting with a gradient of 1000 ml of methanol / MeOH in DCM afforded the title compound (21 mg, 22%) as a white solid. 1 H NMR (400MHz, d 6 -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 hours. 3 (5 mL) was added and stirred at 120° C. until the completion of the reaction was confirmed by LCMS. Then, water was added and NaHCO 3was added slowly in small portions to pH = 6. DCM was added and the layers were separated. Using a layer separation cartridge, the aqueous solution was extracted with DCM (x2) 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 (400 MHz, CDCl 3 )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 general Suzuki-Miyaura 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 NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 The residue was dissolved in MeOH / DCM and added with ISOLUTE (登録商標) Preabsorb onto a HM-N column (Biotage) and purify by silica gel chromatography eluting with 0-100% EtOAc in cyclohexane to give 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 general Suzuki-Miyaura procedure 1, except that the ratio of dioxane:water 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 1N HCL(aq) (1.2 mL) and stirred at room temperature for 18 h. Concentrated HCl (1.2 mL) was added and the reaction mixture was stirred at room temperature for 4 h. 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 (400MHz, d 6 -DMSO) δ, ppm 8.16 (2H,s), 7.78 (1H,s), 7.35 (1H,d,J=1.4Hz), 7.26 (1H,dd,J=1.7,8.0Hz), 6.68 (1H,d,J=8.1Hz), 4.29 (1H,hept,J=6.8Hz), 3.56 (2H,t,J=8.6Hz), 3.04 (2H,t,J=8.6Hz), 1.50 (6H,d,J=6.8Hz). 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 h, after which an additional 10 mL of MeCN was added and stirring at reflux continued for 24 h. An additional 10 mL of DMAP (0.029 mmol, 0.24 mmol) was added and the reaction mixture was stirred at reflux for 16 h, after which an additional 1.63 g (11.8 mmol) of potassium carbonate and MeCN (10 mL) were added and stirring at reflux continued for 7 h, whereupon LCMS showed the reaction to be 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 and dried (MgSO 4 ) and concentrated under reduced pressure to give a dark brown solid. The solid was dissolved in MeOH / DCM and (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 afforded the title compound (1.49 g, 42%) as a golden viscous oil. 1 H NMR (400MHz, d 6-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 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) under argon and stirred at room temperature for 18 h. Further NBS (87 mg, 0.49 mmol) was added to the reaction mixture and stirred for 1 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 NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 The residue was dissolved in MeOH / DCM and added with ISOLUTE (登録商標) Preabsorbed 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. 1 H NMR (400 MHz, CDCl 3)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 min. Zinc chloride (2.0 M in 2-methyl THF, 0.29 mL, 0.58 mmol) was added dropwise to give a creamy suspension which was stirred at room temperature for 2 h. 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, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and stirring at reflux for 3 h. An additional 15 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and stirred at reflux for 16 h, then cooled to room temperature. EtOAc and saturated aqueous ammonium chloride were added and a small amount of insoluble solid was dissolved by adding 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 (MgSO 4) 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 the 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 1N 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 ether, and dried to give the title compound (17 mg, 41%) as a white solid. 1 H NMR (400MHz, d 6 -DMSO) δ, ppm 9.17 (1H,s), 8.40 (1H,s), 8.08 (1H,s), 8.06 (1H,d,J=1.2Hz), 7.96 (1H,d,J=0.6Hz), 4.63 (1H,hept,J=6.7Hz), 4.10 (2H,d,J=7.2Hz), 1.59 (6H,d,J=6.7Hz), 1.38-1.28 (1H,m), 0.61-0.55 (2H,m), 0.46-0.41 (2H,m), plus three exchangeable protons not observed. 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 and then treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.040 mmol) and stirred at 100° C. for 3 h. An additional portion of [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. Further 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 h at 100° C. EtOAc and water were added and the mixture was washed with celite (登録商標) The layers were separated and the aqueous layer was extracted with EtOAc (x2) and the combined organic layers were washed with water, saturated NaHCO 3 Wash with aqueous solution and saturated saline, then dry (MgSO 4 The residue was dissolved in MeOH / DCM and added with ISOLUTE (登録商標) Pre-adsorption onto a 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 first filtration was washed repeatedly with 10% MeOH / DCM. The solution was washed with water and the aqueous layer was extracted with DCM (x2). The combined DCM extracts were washed with saturated NaHCO 3 It was washed with aqueous solution and saturated saline, dried (MgSO 4 ) and concentrated under reduced pressure to a solid (112 mg). The two solids were combined, dissolved in MeOH / DCM, and added to ISOLUTE (登録商標)Preabsorbed onto a 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, then washed with MeOH / DCM and then 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, d 6 -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, after which ZnCl 2 (1.9 M in 2-MeTHF, 5.86 mL, 11.1 mmol) was added dropwise. The resulting yellow solution was stirred for 30 min and then Pd(PPh 3 ) 4(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 quickly 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 (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The resulting yellow oil was dissolved in DCM and 120 g SiO 2 The cartridge was loaded and eluted with 10-70% EtOAc in DCM. The product containing the desired fraction was concentrated to give the title compound (1.13 g, 53%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 )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 Synthesized 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 1-methylimidazole-5-boronic acid using the Suzuki-Miyaura general procedure 1 to afford 146 mg (77%) of the title compound as a white fluffy solid. 1 H NMR (400 MHz, CDCl 3)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. 1 H NMR (400MHz, d 6 -DMSO) δ, ppm 8.13 (2H,s), 7.91 (1H,d,J=1.2Hz), 7.78 (1H,s), 7.65 (1H,d,J=8.5Hz), 7.51 (1H,d,J=3.3Hz), 7.45 (1H,dd,J=1.7,8.5Hz), 6.59 (1H,d,J=2.6Hz), 4.24-4.13 (1H,m), 3.88 (3H,s), 1.49 (6H,d,J=6.8Hz) plus one exchangeable proton was not observed. LCMS method 1: room temperature 3.80 min, [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 Synthesised 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-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 give 20.8 mg (71%) of the title compound as a white solid. 1 H NMR (400MHz, d 6 -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 Synthesised 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-(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 give 5.5 mg (19%) of the title compound as a white solid. 1 H NMR (400MHz, d 6 -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 the general Suzuki-Miyaura 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 min, [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 give 6.3 mg (9% for 2 steps) of the title compound as a white solid. 1 H NMR (400MHz, d 6 -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. The reaction was stirred for 30 min, after which ZnCl 2 (1.9 M in 2-MeTHF, 0.455 mL, 0.864 mmol) was added dropwise. The resulting yellow solution was stirred for 30 min, after which 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 added quickly 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, saturated brine, and dried (Na 2 SO 4 ) and concentrated under reduced pressure. This crude mixture was diluted with DCM and 24 g SiO 2 The cartridge was loaded and eluted with 0-10% MeOH in DCM. The product containing fractions of interest 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, d 6 -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 give 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 give 15 mg (24% over 2 steps) of the title compound as a white solid. 1 H NMR (400MHz, d 6 -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 Synthesized 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 to afford 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, d 6 -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 following 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, d 6 -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, 0.3eq 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, 0.3eq 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, d 6 -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 NaHCO 3 A saturated solution of sodium hydroxide (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 diluted with CHCl 3 (4×500 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to give the title compound (26.60 g, 40%) as a black oil. 1 H NMR (300 MHz, CDCl 3) 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-formamide acetate A mixture of formic acid (16.3 mL, 433 mmol) and acetic anhydride (39.8 mL, 421 mmol) was heated to 55° C. under nitrogen for 2 h. The reaction was allowed to cool, then added to THF (350 mL) and cooled to less than 10° C. A solution of ethyl 2-amino-2-cyanoacetate (30.0 g, 234 mmol) in THF (350 mL) was added via the dropping funnel over 30 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated under reduced pressure (azeotropic drying with toluene (3×100 mL)). The residue was dissolved in DCM (20 mL) and diluted with 330 g SiO 2 The product was concentrated to give the title compound (13.26 g, 36%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 )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-formamide acetate (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 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting black residue was diluted with DCM (100 mL) and diluted with saturated NaHCO 3 The organic layer was collected and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure.(登録商標) The column was loaded with HM-N (Biotage). 2 The cartridge was loaded and eluted with 20-50% EtOAc in cyclohexane, and the product was concentrated to give the title compound (8.78 g, 55%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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 mixture 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) and diluted with LiOH·H 2 The reaction was treated with 2H2O (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 x 300 mL). The combined organic layers were washed with brine (300 mL) and dried (MgSO 4 ) and concentrated under reduced pressure to give a white solid, which 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 3 ) δ, ppm 8.09 (1H,s), 7.99 (1H,s), 4.03 (2H,d,J=7.2Hz), 1.38-1.26 (1H,m), 0.74-0.68 (2H,m), 0.41 (2H,q,J=5.2Hz). 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 nitrogen. After 4 h, the resulting clear solution was concentrated under reduced pressure (azeotropic drying 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) and saturated NH 4 Cl (40 mL) and dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain the title compound (2.27 g, 91%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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 under argon atmosphere at 80° C. for 2 h. 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. 1 H NMR (400 MHz, CDCl 3 )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 nitrogen atmosphere. The resulting solution was heated at 50° C. After 140 h, K 2 CO 3 (4.34 g, 31.4 mmol) was added to the reaction mixture and the resulting mixture was heated at 82° C. for 40 h. After the reaction was cooled to room temperature, it was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with saturated brine and dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting solid was dissolved in DCM and 80 g SiO 2 The cartridge was loaded 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 (400 MHz, CDCl 3 )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, d 6 -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 (3x50 mL). The combined organic layers were washed with brine and dried (MgSO 4 ) and concentrated under reduced pressure to obtain the title compound (6.36 g, 90%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )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 under an argon atmosphere at 80° C. for 2 hours. The reaction solution 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 (400 MHz, CDCl 3 )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 hours, 2 CO 3 (5.78 g, 41.8 mmol) was added to the reaction mixture and the resulting mixture was heated at 82° C. for 50 h. After the reaction was cooled to room temperature, it was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with saturated brine and dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting solid was dissolved in DCM and 220 g SiO 2 The cartridge was loaded and eluted with 20-40% EtOAc in cyclohexane, and the product was concentrated to give the title compound (1.46 g, 48%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 )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, d 6 -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 portionwise addition of HATU (9.9 g, 26.0 mmol). The reaction 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 and dried (Na 2 SO 4 The resulting compound was triturated with ethyl acetate to obtain the title compound (2.0 g, 57%) as a white solid. LCMS method 4: room temperature 1.29 min, [MH + ]335.3.

[0460] Pyrazole spirodiazetidinamide (general synthesis method) Pyrazole spirodiazetidinium amide 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. Et 3 N (0.13 mL, 0.90 mmol) was added, followed by the carboxylic acid (0.25 mmol) and HATU (111 mg, 0.3 mmol). 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 spirodiazetidinium amide 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. 3 A solution of (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone was added 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]heptan-2-yl)methanone. The isolated material was divided into portions and coupled with four carboxylic acids. HATU (97 mg, 0.26 mmol) and carboxylic acid (0.24 mmol) were dissolved in DCM (1 mL) and Et 3 N (35 μL, 0.26 mmol). The mixture was stirred for 10 min. To this was added (5-isopropyl-1H-pyrazol-3-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone (50 mg, 0.21 mmol) and Et 3A solution of N (35 μL, 0.26 mmol) in DCM (2 mL) was added. The reaction mixture was stirred for 16 hours, concentrated under reduced pressure, redissolved in 2-methyl-THF, washed twice with water, washed with saturated saline, and dried (Na 2 SO 4 The resulting solution was concentrated under reduced pressure and purified.

[0462] Pyrazole spirodiazetidinium amide basic procedure 3 After stirring for 16 h, the reaction mixture was concentrated under reduced pressure and purified directly by reverse phase chromatography as described for pyrazole spirodiazetidinium amide general 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, d 6 -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 pyrazolespirodiazetidine general procedure 1. Reverse phase preparative HPLC afforded the title compound (37 mg) as a white solid. 1 H NMR (400MHz, d 6 -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, d 6-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, d 6 -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 the pyrazolespirodiazetidine general procedure 2. After purification by reverse phase preparative HPLC and lyophilization, 37.0 mg (42%) of the title compound was obtained as a white solid. 1 H NMR (400MHz, d 6 -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, d 6 -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, d 6 -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, then diluted with Et 3 N (0.21 mL, 1.50 mmol) was added followed by 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. 1 H NMR (400MHz, d 6 -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. Et 3N (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, d 6 -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). To this was added MsOH (80 μL, 1.2 mmol). The resulting solution was stirred at room temperature for 30 min. Et 3 N (0.5 mL, 3.6 mmol) was added, followed by CDI (160 mg, 1.0 mmol). A half amount of the reaction mixture was removed. Pyrrolidine (0.25 mL, 3.1 mmol) was added to the reaction solution. The reaction mixture was heated to 60° C. and stirred for 24 hours, then stirred 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 obtain the title compound (29.5 mg, 29%) as a white solid. 1 H NMR (400MHz, d 6-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 h. Et 3 N (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 h, then stirred at 120° C. for 2 h. N-ethylmethylamine (0.26 mL, 3.0 mmol) was added, and the reaction was heated to 120° C. for 8 h, then heated at 150° C. for 3 h. 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, d 6 -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. 1 H NMR (400MHz, d 6 -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 (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a 0 to 100% ethyl acetate / cyclohexane mixture to obtain 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) and 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 h. The reaction was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO 4 ) 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), NBS (61 mg, 0.34 mmol) was 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 fraction was washed with saturated brine, dried (MgSO 4), and concentrated under reduced pressure to obtain 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 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO 4 ) 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), aqueous HCl (0.4 mL, 1 M, 0.4 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. An additional amount of aqueous HCl (0.4 mL, 1 M, 0.4 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 7N NH 3 The residue was diluted with 0-5% (7N NH 3 The product was purified by silica gel chromatography eluting with 1,2-dichloromethane (COOH) in DCM. The product was re-purified by reverse phase preparative HPLC to give, after lyophilization, the title compound (9 mg, 20%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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=6.8Hz), 4.36 (2H,d,J=5.7Hz), 3.71-3.61 (2H,m), 1.69 (6H,d,J=6.8Hz), 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 then heated at 100° C. for 16 hours. An additional aliquot of tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol) was added and the reaction was heated for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine and dried (MgSO 4 ) 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 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO 4 ), and concentrated under reduced pressure to obtain 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) and cesium carbonate (58 mg, 0.18 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and then 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 brine and dried (MgSO 4 ), and concentrated under reduced pressure to obtain 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), HCl solution (2 mL, 1 M, 2.00 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to give the title compound (10 mg, 23%) as a white solid after lyophilization. 1 H NMR (400MHz, d 6 -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) and 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 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO 4 ) 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), NBS (48 mg, 0.27 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fraction was washed with saturated brine and dried (MgSO 4 ) 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) and cesium carbonate (90 mg, 0.28 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and then heated at 100° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). 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), an aqueous HCl solution (1 mL, 1 M, 1.00 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure with 7N NH 3 The residue was made basic by adding a solution of 0-10% (7N NH 3 Purification by silica gel chromatography eluting with C12H2O / MeOH in DCM afforded the title compound (10 mg, 25%) as a white solid. 1 H 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) and 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 saturated brine, dried (MgSO 4 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), NBS (57 mg, 0.32 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fraction was washed with saturated brine and dried (MgSO 4 ) and concentrated under reduced pressure to obtain 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) and cesium carbonate (170 mg, 0.52 mmol), dioxane (3 mL), and water (0.3 mL) was degassed with argon and the reaction mixture was 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 saturated brine and dried (MgSO 4) 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), aqueous HCl (4 mL, 1 M, 4.00 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 7N NH 3 The mixture was made basic by the addition of MeOH solution and concentrated under reduced pressure. The residue was diluted with 0-5% (7N NH 3 The mixture was purified by silica gel chromatography eluting with C12H2O / 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, d 6 -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) and 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 with ISOLUTE. (登録商標) Purify by silica gel chromatography by loading onto a HM-N column (Biotage) and eluting the residue 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), NBS (64 mg, 0.36 mmol) was added 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 and dried (MgSO 4 ) 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) and 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 and purified by ISOLUTE. (登録商標) The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM after loading onto an HM-N column (Biotage). 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), aqueous HCl (2 mL, 1 M, 2.00 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 7N NH3 The mixture was made basic by the addition of a solution of MeOH in DCM and concentrated under reduced pressure, and 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, d 6 -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 The title compound (72 mg, 60%) was obtained as a yellow oil by synthesis 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. 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 give the title compound (20 mg, 45%) as a white solid. 1 H NMR (400MHz, d 6 -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 Synthesised 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 by 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 was evaporated to dryness. Purification by reverse phase chromatography afforded the title compound (8 mg, 27%) as a white solid. 1 H NMR (400MHz, d 6 -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]triazine-4(3H)-one and [4-(1-piperidyl)phenyl]boronic acid using Suzuki-Miyaura general procedure 1 to give 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, d 6 -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 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 by Suzuki-Miyaura general procedure 1 afforded the title compound (49 mg, 43%) as a yellow oil. 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, d 6 -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 (MgSO 4 ) and concentrated under reduced pressure to obtain the title compound (3.3 g, quant) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )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 (MgSO 4 The residue was purified by silica gel chromatography eluting with a 0 to 70% solution of ethyl acetate in cyclohexane to give the title compound (394 mg, 18%) as a white solid. 1 H NMR (400 MHz, CDCl 3)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 was performed using Suzuki-Miyaura general procedure 1 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. 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) solution, hydrochloric acid in dioxane (4N, 3 mL, 12.00 mmol) was added, stirred at room temperature for 20 minutes, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography to obtain the title compound (26 mg, 49%) as a white solid. 1 H NMR (400MHz, d 6 -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 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-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole following Suzuki-Miyaura general procedure 1 to afford the title compound (63 mg, 79%) as a yellow oil. 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 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) was added with HCl solution (1 M, 3 mL, 3 mmol), 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, d 6 -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 was added nBuLi (11.5 mL, 2.5 M, 28.82 mmol) at a rate that kept the temperature 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 NH 4 The mixture was diluted with aqueous Cl and extracted with ethyl acetate (x3). The combined organic fractions were washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a solution of 0 to 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 dissolved in 0-10% (7N NH 3 Purify by silica gel chromatography eluting with 0–10% (7N NH 3 Repurify by silica gel chromatography, eluting with a solution of 100 ml of methanol in ethyl acetate (1:1 / MeOH) 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 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a solution of 0 to 60% ethyl acetate in cyclohexane to give 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 4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a solution of 0 to 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 obtain 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 solids 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, saturated brine and dried (MgSO 4 ) and concentrated under reduced pressure. The residue was diluted with 0 to 5% (7N NH 3 Purification by silica gel chromatography eluting with C12H2O / MeOH in DCM afforded the title compound (89 mg, 54%) as a white solid. 1 H NMR (400MHz, d 6-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 h. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic fractions were washed with saturated brine, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a solution of 0 to 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 obtain the title compound (130 mg, quant) as a white solid. 1 H NMR (400MHz, d 6 -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 fraction was washed with 5% LiCl aqueous solution, saturated brine and dried (MgSO 4 ) and concentrated under reduced pressure. The residue was diluted with 0 to 5% (7N NH 3 Purification by silica gel chromatography eluting with C12H2O / MeOH in DCM and repurification by reverse phase preparative HPLC afforded the title compound (13 mg, 10%) as a white solid. 1 H NMR (400 MHz, CDCl 3) δ, ppm 7.84 (1H,d,J=0.7Hz), 7.74 (1H,s), 7.15 (1H,s), 7.13-7.12 (1H,m), 6.48 (1H,s), 4.88 (1H,t,J=9.1Hz), 4.75 (1H,dd,J=6.5,9.0Hz), 4.57 (1H,t,J=9.4Hz), 4.43 (1H,dd,J=6.3,10.0Hz), 4.08-4.01 (1H,m), 3.97 (3H,s), 3.02 (1H,sept,J=6.9Hz), 2.55 (3H,s), 1.30 (6H,d,J=6.9Hz) plus one exchangeable proton 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 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 afforded the title compound (112 mg, 58%) as a yellow oil. 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 obtained as a yellow solid by synthesizing 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. LCMS method 2: room temperature 1.18 min, [MH + ]381. 1 H NMR (400MHz, d 6 -DMSO) δ, ppm 8.39 (1H,s), 8.25 (2H,s), 7.91 (1H,d,J=0.6Hz), 7.87 (1H,s), 4.65-4.55 (1H,m), 4.29-4.24 (2H,m), 1.76 (2H,dt,J=7.1,7.2Hz), 1.72-1.63 (1H,m), 1.57 (6H,d,J=6.9Hz), 0.93 (6H,d,J=6.1Hz) 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. 1 H NMR (400 MHz, CDCl 3)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 The 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 the pyrazole spirodiazetidinamide general procedure 4. The crude product was diluted with 10-98% MeCN and 0.1% NH 4 Purification by reverse phase chromatography, eluting with OH solution, afforded the title compound (60 mg, 76%) as a white solid. 1 H NMR (400MHz, d 6 -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 (400 MHz, CDCl 3 )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, d 6 -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 according to the general bromination 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 by 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 diluted with saturated NaHCO 3 The mixture was basified to pH=8 by adding aqueous solution of MeOH. 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 diluted with ISOLUTE (登録商標) Pre-adsorbed 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, d 6 -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 mixed in a 40% IPA / ACN (50 / 50 / 0.1% DEA) / 60% CO column using LUX Cellulose-4 21×250 mm, 5 μm.2 The separation was obtained by chiral SFC eluting at 100 mL / min, 120 bar, and 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% CO 2 ; Flow rate: 5.0 mL / min; Pressure: 120 bar; Temperature: 40°C; Detector: DAD 230 nm; Retention time: 8.3 min.

[0532] Example 63 Enantiomer B: white solid 41mg Analytical equipment: Analytical SFC; Column: LUX Cellulose-4 4.6x250mm, 5μm; Mobile phase: 40% IPA / ACN (50 / 50 / 0.1% DEA) / 60% CO 2 ; Flow rate: 5.0 mL / min; Pressure: 120 bar; Temperature: 40°C; Detector: DAD 230 nm; Retention time: 9.3 min.

[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 via Suzuki-Miyaura general procedure 1 to afford the title compound (120 mg, 67%) as a brown oil. 1 H NMR (400 MHz, CDCl 3)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 general bromination procedure 1 to give the title compound (144 mg, quantitative yield) as an orange oil. 1 H NMR (400 MHz, CDCl 3 )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 Synthesized 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 to give the title compound (106 mg, 64%). 1 H NMR (400 MHz, CDCl 3 )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 diluted with DCM / MeOH (9 / 1) and saturated NaHCO 3 The aqueous layer was partitioned between the ethyl acetate solution and the aqueous solution. 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, d 6-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. 3 (5 mL) was added and the mixture was stirred at 120° C. until the completion of the reaction was confirmed by LCMS. Water was added to the reaction mixture, and NaHCO 3 was slowly added dropwise to pH = 6. DCM was added and the layers were separated. Using a layer separation cartridge, the aqueous solution was extracted with DCM (x2) 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 (400 MHz, CDCl 3 )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 via Suzuki-Miyaura general procedure 1 to afford the title compound (167 mg, 92%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )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 Synthesized from 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 the Suzuki-Miyaura general procedure 1 followed by THP deprotection procedure 1 in DMSO / H 2 Purification by precipitation in O (9 / 1) solution afforded 56 mg (35% over two steps) of the title compound as a white solid. 1 H NMR (400MHz, d 6-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 diluted with saturated NaHCO 3 The reaction was quenched with aqueous solution and sodium bicarbonate was added as a solid at 40° C. until pH=6. The mixture was extracted with DCM (×3) using a layer 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) Preabsorbed onto a HM-N column (Biotage) and purified by silica gel chromatography eluting with 0-20% EtOAc in DCM to give the title compound (500 mg, 38%) as a fluffy yellow solid. 1 H NMR (400 MHz, CDCl 3 )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 Synthesised 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 via 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 the general Suzuki-Miyaura procedure 2, followed by THP deprotection procedure 1 and purified by reverse phase preparative HPLC to give 7 mg (8% for 2 steps) of the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3) δ, ppm 8.17 (2H,s), 7.87 (1H,d,J=0.8Hz), 7.81 (1H,d,J=0.5Hz), 7.67 (1H,s), 4.73-4.62 (1H,m), 1.69 (9H,s), 1.68 (6H,d,J=6.1Hz) plus one exchangeable proton not observed. 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. under microwave irradiation for 1 h. Water was added and the volatiles were removed under reduced pressure. The mixture was diluted with DCM and H 2 The mixture was partitioned between 0 and 100 mL of 10% MeOH in DCM (x3) 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 afforded 70 mg (quantitative yield) of the title compound as a brown solid. 1 H NMR (400 MHz, CDCl 3)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 hours. After cooling to room temperature, the mixture was diluted with EtOAc and H 2 The mixture was partitioned between 1000 and 1000 mL of EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with brine and dried (MgSO 4 ) and then concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )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 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, IMS / H 2 Synthesis according to Suzuki-Miyaura general procedure 1 using O (2.5 / 0.5 mL) as solvent afforded 46 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl 3 )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 (2M, 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 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 and dried (MgSO 4 ) and concentrated under reduced pressure. The solid was dissolved in DCM and (登録商標) Preabsorption onto a HM-N column (Biotage) and purification by silica gel chromatography eluting with 0-20% EtOAc in cyclohexane afforded the title compound (1.25 g, 75%) as a yellow oil which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3)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 diluted with EtOAc and saturated NaHCO 3 The organic layer was partitioned between aqueous saturated sodium bicarbonate and aqueous sodium chloride. 3 aqueous solution (x2), washed with water and dried (MgSO 4 ) 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 grey solid. 1 H NMR (400 MHz, CDCl 3 )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 (Na 2 SO 4 ) and concentrated under reduced pressure to give a yellow solid. The crude product was 2 The mixture was triturated with O, 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 removal of 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 obtained 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, d 6-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 Cyclopropyl(2,6-diazaspiro[3.3]heptan-2-yl)methanone (2.8 mL (0.22 M), 0.615 mmol), ArCO 2 A solution of H (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 10-98% MeCN / H 2 O+0.1% NH 4 Reverse phase chromatography (C 18 Cartridge) for purification.

[0554] Amide Coupling Procedure 2 Amine (0.472mmol), ArCO 2 A solution of H (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 Step 3 Amine (2.74mmol), ArCO 2A solution of H (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 10-98% MeCN / H 2 O+0.1% NH 4 Reverse phase chromatography (C 18 Cartridge) for purification.

[0556] Amide Coupling Step 4 Amine (0.548mmol), ArCO 2 A solution of H (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 10-98% MeCN / H 2 O+0.1% NH 4 Reverse phase chromatography (C 18 Cartridge) for purification.

[0557] Amide Coupling Step 5 Amine (0.439mmol), ArCO 2 A solution of H (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 10-98% MeCN / H 2 O+0.1% NH 4 Reverse phase chromatography (C 18 The purification was carried out by using 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 a 2M solution of 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 Synthesized according to literature procedures (WO2013111105A1) using D-allyl to give the title compound as a white solid. 1 H NMR (400MHz, d 6 -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 exchangeable proton not observed.

[0560] (S)-1-(1-hydroxypropan-2-yl)-1H-imidazole-4-carboxylic acid Synthesized according to literature procedures (WO2013111105A1) using L-allyl to give the title compound as a yellow solid. 1 H NMR (400MHz, d 6 -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 exchangeable proton not observed.

[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 dropwise addition of DAST (1.7 mL, 13.17 mmol). The mixture was allowed to warm to room temperature and solid Na 2 CO 3 (550 mg, 5.19 mmol) was added and the mixture was stirred for 20 h. After dilution with DCM, 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 Ethyl (R)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate (140 mg, 0.699 mmol), LiOH H 2 A mixture of 2H2O (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 and brought to pH 5 by the addition of aqueous HCl (1N, 2.2 mL) and NaHCO 3 Aqueous solution 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 precipitated on 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 (400MHz, d 6-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 dropwise addition of DAST (1.40 mL, 10.59 mmol). The mixture was allowed to warm to room temperature and solid Na 2 CO 3 (550 mg, 5.19 mmol) was added and the mixture was stirred for 20 h. After dilution with DCM, 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 Ethyl (S)-1-(1-fluoropropan-2-yl)-1H-imidazole-4-carboxylate (120 mg, 0.599 mmol), LiOH H 2 A mixture of 2H2O (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 and brought to pH 5 by the addition of aqueous HCl (1N, 2.2 mL) and NaHCO 3 Aqueous solution 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 precipitated on 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 (400MHz, d 6 -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 then cooled to 10° C. for 18 h. 3 The organic extract was washed with saturated brine and dried (Na 2 SO 4 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. 1 H NMR (300 MHz, CDCl 3 )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% (2M 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. NH 4 The reaction was quenched with aqueous Cl and extracted with EtOAc. The combined organic extracts were washed with saturated brine and dried (Na 2 SO 4 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 hydrogen atmosphere using a solution of 10% Pd / C (399 mg) in EtOAc (40 mL) for 18 h. The resulting mixture was purified by HPLC using Celite. (登録商標) The mixture was filtered through ethyl acetate and the filtrate was concentrated under reduced pressure to obtain 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 h. Aqueous hydrochloric acid (1N; 20 mL) and an appropriate amount of NaHCO 3 After neutralization with aqueous solution, 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-carboxylate 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 NaHCO 3 The solution was diluted with ethyl acetate and extracted into DCM. The organic extract was washed with water and saturated brine, then dried (Na 2 SO 4 ), 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 via 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 ...

Claims

1. General formula (Z); 【Chemistry 1】 (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, halogen atom, oxo or 5- or 6-membered monocyclic carbocycle; 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 represents a hydrogen atom, a C1-4 alkyl, a nitrile, a halogen atom, a carbamoyl, a C1-4 alkylaminocarbonyl, a C1-4 dialkylaminocarbonyl, 1 to 4 R ４ 5- or 6-membered monocyclic heterocycle optionally substituted by 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 represents a hydrogen atom, 1 to 3 R ５ C1-4 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 amino optionally substituted with 1 to 4 R ９ a 5- or 6-membered monocyclic carbocyclic ring optionally substituted with 1 to 4 R １０ or 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 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-methylcyclopropylcarbonylaminoethyl, tert-butylcarbonylaminoethyl, N-methyl-tert-butylcarbonylaminoethyl, tert-butoxycarbonylaminoethyl, 1-phenylethyl, or 2-hydroxy-1-phenylethyl; R １１ represents a 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 or 1 to 4 R ７－１ represents a 4- to 15-membered bicyclic heterocycle optionally substituted by R ５－１ represents a C1-4 alkyl, a C3-8 cycloalkyl, a C1-4 haloalkyl, or a halogen atom; R ６－１ is 1 to 4 R ８－１ represents a C1-4 alkyl, a C3-8 cycloalkyl, a C3-8 cycloalkyl substituted with a C1-4 alkyl, a C1-4 haloalkyl, or a halogen atom optionally substituted with R ７－１ represents a C1-4 alkyl, a C3-8 cycloalkyl, a 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; L １ represents a bond or carbonyl (-C(=O)-); L ２ represents a bond, carbonyl (-C(=O)-), -(CH ２ ) 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 represents a hydrogen atom, 1 to 4 R １１－１ C alkyl optionally substituted with 1 to 4 R １２－１ C1-4 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 or -S(O) ｍ -(C1-4 alkyl); R １１－１ represents hydroxy, a halogen atom, or a C3-8 cycloalkyl; R １２－１ represents hydroxy, a halogen atom, or a 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, each of which may be substituted with 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 multiple substitutions are made, they may be the same or different; and r represents an integer of 0 to 1. A compound represented by the formula (I), or a salt thereof.

2. The general formula (Z) is the general formula (I); 【Chemistry 2】 (Wherein, general formula (I) represents the following formula: 【Chemistry 3】 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 claim 1. The compound according to claim 1, which is represented by the formula: embedded image or a salt thereof.

3. The general formula (Z) or (I) is the general formula (I-1), (I-5) or (I-7); 【Chemistry 4】 3. The compound according to claim 1 or 2, which is represented by the formula: (wherein all symbols have the same meanings as defined in claim 1 or 2), or a salt thereof.

4. The compound is represented by the general formula (I-1-1); 【Chemistry 5】 (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 claim 1. The compound according to any one of claims 1 to 3, which is represented by the formula: embedded image or a salt thereof.

5. The compound is (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 claims 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.

6. The compound is represented by the general formula (I-5-1); 【Chemistry 6】 (wherein all symbols have the same meanings as defined in claim 1 or 4), or a salt thereof.

7. The compound is (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 claims 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.

8. The compound is represented by the general formula (I-7-1); 【Chemistry 7】 (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 or 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 claim 1 or 2. The compound according to any one of claims 1 to 3, which is represented by the formula:

9. The compound is (1) The compound according to any one of claims 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.

10. The general formula (Z) is the general formula (II); 【Chemistry 8】 (Wherein, general formula (II) represents the following formula: 【Chemistry 9】 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; 【change】 indicates the α-configuration; 【change】 indicates the β-configuration; 【change】 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 in claim 1. The compound according to claim 1, which is represented by the formula: embedded image or a salt thereof.

11. The general formula (Z) or (II) is the general formula (II-1), (II-5), (II-8) or (II-12); 【Chemistry 10】 11. The compound according to claim 1 or 10, which is represented by the formula: (wherein all symbols have the same meanings as defined in claim 1 or 10), or a salt thereof.

12. The compound has the general formula (II-1-1): 【Chemistry 11】 (In the formula, R １－１Ｙ represents the following compound: 【Chemistry 12】 In the group, the arrow represents the bond to the carbonyl carbon atom; R ２－１Ｙ is 1 to 4 R １３－１ or 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 claim 1. The compound according to claim 1, 10 or 11, which is represented by the formula: embedded image or a salt thereof.

13. The compound is (1) The compound according to claim 1 or 10 to 12, which is N-(1-(5-isopropyl-1H-pyrazole-3-carbonyl)azetidin-3-yl)cyclopropanecarboxamide, or a salt thereof.

14. The compound has the general formula (II-5-1): 【Chemistry 13】 (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 １４－１ or 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 claim 10 or 12. The compound according to claim 1, 10 or 11, which is represented by the formula: embedded image or a salt thereof.

15. 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, 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.

16. The compound has the general formula (II-8-1): 【Chemistry 14】 12. The compound according to claim 1, 10 or 11, which is represented by the formula: (wherein all symbols have the same meanings as defined in claim 1), or a salt thereof.

17. The compound is (1) The compound according to claim 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.

18. The compound has the general formula (II-12-1): 【Chemistry 15】 (In the formula, R １－１Ｓ is 1 to 4 R ６－１ represents 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 in claim 10. The compound according to claim 1, 10 or 11, which is represented by the formula: embedded image or a salt thereof.

19. The compound is (1) The compound according to claim 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.

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

21. 21. The pharmaceutical composition of claim 20 which is a KDM5 inhibitor.

22. The pharmaceutical composition according to claim 20 or 21, which is an agent for preventing and / or treating a KDM5-related disease.

23. The pharmaceutical composition of claim 22, wherein the KDM5-related disease is cancer or Alzheimer's disease.

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

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

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

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

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