Novel compounds as hypoxia inducible factor 1 (HIF-1) inhibitors or vascular endothelial growth factor (VEGF) inhibitors and pharmaceutical compositions comprising same

Abstract

The present invention provides a compound as an inhibitor of HIF-1 [alpha] or as an inhibitor against VEGF as a vascularization inducer, and a pharmaceutical composition for preventing or treating HIF-1 [alpha] or VEGF-related diseases comprising the same. The novel compound of the present invention is proved to exhibit an excellent inhibitory effect on the expression of HIF-1 [alpha] and a vascularization-inducing agent VEGF, and thus can be effectively used in the prevention or treatment of diseases associated with HIF-1 [alpha] and a vascularization-inducing agent VEGF.

Description

Technical Field

[0001] The present invention relates to novel compounds as HIF-1 protein inhibitors or VEGF inhibitors, their hydrates, solvates, prodrugs, isomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same. Background Art

[0002] Hypoxia, a pathological condition in which an adequate oxygen supply cannot be achieved, is a typical feature of a variety of incurable diseases (e.g., cancer, heart disease, ischemic disease, and vascular disease). HIF-1 (hypoxia-inducible factor-1) is a transcription factor induced by hypoxia. HIF-1 includes HIF-1α, which is degraded in an oxygen-dependent manner, and HIF-1α induces the expression of genes (e.g., hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGFA, MMP-2, uPAR, and MDR1), thereby obtaining characteristics such as resistance to apoptosis, increased angiogenesis potential, increased cell proliferation potential, and increased cell migration (metastasis) and invasion potential.

[0003] In particular, HIF-1α can be used as a target for the development of therapeutic agents for diseases in which activation of angiogenesis is associated with disease progression, and HIF-1α is a factor that is one of the angiogenesis regulatory proteins and controls angiogenesis in terms of vascular destruction and vascular dysfunction by inducing the expression of VEGF (vascular endothelial growth factor). Angiogenesis is the process in which new capillaries are formed from existing microvessels. Angiogenesis typically occurs during embryonic development, tissue regeneration and wound healing, and corpus luteum development (which is a cyclical change in the female reproductive system), and is also strictly regulated in these cases. In adults, vascular endothelial cells grow very slowly and divide relatively poorly compared to other cell types. The process of angiogenesis generally consists of the following: the reorganization of blood vessels and the generation of new capillaries by the breakdown of the vascular basement membrane by proteases; the migration and proliferation of vascular endothelial cells; and the formation of a lumen through the differentiation of vascular endothelial cells due to stimulation by angiogenesis-promoting factors. However, there are diseases in which angiogenesis is not autonomously regulated and grows pathologically. Excessive angiogenesis can cause diseases such as hemangiomas, angiofibromas, and vascular malformations, as well as cardiovascular diseases such as arteriosclerosis, vascular adhesions, and edematous sclerosis. In particular, excessive angiogenesis has been revealed to play a key role in diseases such as macular degeneration.

[0004] Although various hypotheses have been proposed regarding the cause and pathogenesis of macular degeneration (including neovascularization), they have not yet been clearly identified, and since various studies on diagnosis and treatment are ongoing, there is a continuous demand for the development of new substances for inhibiting neovascularization.

[0005] Purpose of the Invention

[0006] The problem to be solved by the present invention is to provide a novel structural compound that exhibits excellent inhibitory activity against HIF-1α or the angiogenesis inducer VEGF.

[0007] Furthermore, the problem to be solved by the present invention is to provide a pharmaceutical composition for preventing or treating diseases associated with HIF-1α or angiogenesis inducer VEGF, which comprises a compound having a novel structure.

[0008] Furthermore, the present invention aims to provide a method for preventing or treating diseases associated with HIF-1α or angiogenesis inducer VEGF, which comprises the step of administering a compound having a novel structure to a subject or individual in need thereof.

[0009] Furthermore, the problem to be solved by the present invention is to provide a use of a compound having a novel structure in preparing a medicament for preventing or treating diseases associated with HIF-1α or angiogenesis inducer VEGF.

[0010] Problems to be solved by the present invention are not limited to the above-mentioned problems, and other technical problems not mentioned can be clearly understood by ordinary technicians in the field to which the present invention belongs from the following description. Summary of the Invention

[0011] In order to solve the above problems, according to one aspect of the present invention, there is provided a compound represented by the following formula I, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0012] <Formula I>

[0013]

[0014] X is C or N,

[0015] R1 is hydrogen, amino-C 1-3 Alkyl, C 3-8 1 to 2 rings of cycloalkyl (wherein hydrogen is protium or deuterium) or R s , R1 may or may not be replaced by one or more independent R 1a replace,

[0016] where R 1a It is C 1-5 Alkyl, halogen, oxo or -C(O)OR 1b , and R 1b It is hydrogen, C 1-3 an alkyl or arylalkyl group,

[0017] R2 is hydrogen, C 1-3 Alkyl or tri-C 1-3Alkyl-silyl-C 1-3 Alkoxy-C 1-3 alkyl,

[0018] R3 is hydrogen, C 1-3 Alkyl or halogen,

[0019] R4 is hydrogen or C 1-3 alkyl,

[0020] p and q are independently integers 0 or 1,

[0021] When p is 1, R 5a and R 5b are independently hydrogen or C 1-3 Alkyl, or R 5a and R 5b connected to form C 3-6 ring,

[0022] R6 is hydrogen or halogen,

[0023] R7 is hydrogen, halogen, R s 、R u , -NH-aryl, -NH-ring C 3-7 Alkyl, -NHR s 、-NHR u or -NHC(O)R u ,

[0024] R8 is hydrogen, halogen or a 4- to 6-membered heteroaryl group having 1 to 3 N atoms,

[0025] R7 and R8 are independently replaced or not replaced by one or more independent R m replace,

[0026] R m C 1-3 Alkyl (wherein hydrogen is protium or deuterium), C 3-10 Cycloalkyl, C 1-3 Alkoxy, sulfonyl, amino, halogen, cyano, haloalkyl, carbamoyl, carboxyl, aryl (wherein hydrogen is protium or deuterium), arylalkyl, R u or R s , R m By or without one or more independent R n replace,

[0027] R n C 1-3 Alkyl, C 1-3 Alkylsulfonyl, C 1-3 alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, an oxygen bridge or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl,

[0028] R9 and R 10 are independently hydrogen or halogen,

[0029] R s is a 4- to 8-membered saturated heterocycloalkyl group having 1 to 2 heteroatoms selected from N and O,

[0030] R u is a 4- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O and S.

[0031] According to another aspect of the present invention, provided is a pharmaceutical composition for preventing or treating diseases associated with HIF-1α or the angiogenesis inducer VEGF, comprising as an active ingredient a compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0032] According to another aspect of the present invention, a method for preventing or treating a disease associated with HIF-1α or the angiogenesis inducer VEGF is provided, comprising the step of administering to a subject or individual in need thereof a compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0033] According to another aspect of the present invention, provided is the use of a compound represented by formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases associated with HIF-1α or the angiogenesis inducer VEGF.

[0034] According to another aspect of the present invention, there is provided a formulation comprising a compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0035] The novel compounds of the present invention have been demonstrated to exhibit excellent inhibitory effects on the expression of HIF-1α and its downstream gene (angiogenesis inducer VEGF), and thus are shown to be effectively used for preventing or treating diseases associated with HIF-1α and angiogenesis inducer VEGF.

[0036] The effects of the present invention are not limited to the above-mentioned effects, and should be understood to include all effects that can be inferred from the composition of the present invention described in the specification or claims of the present invention. DETAILED DESCRIPTION

[0037] The present invention provides a compound represented by the following formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0038] <Formula I>

[0039]

[0040] X is C or N,

[0041] R1 is hydrogen, amino-C 1-3 Alkyl, C 3-8 1 to 2 rings of cycloalkyl (wherein hydrogen is protium or deuterium) or R s , R1 may or may not be replaced by one or more independent R 1a replace,

[0042] where R 1a It is C 1-5 Alkyl, halogen, oxo or -C(O)OR 1b , and R 1b It is hydrogen, C 1-3 an alkyl or arylalkyl group,

[0043] R2 is hydrogen, C 1-3 Alkyl or tri-C 1-3 Alkyl-silyl-C 1-3 Alkoxy-C 1-3 alkyl,

[0044] R3 is hydrogen, C 1-3 Alkyl or halogen,

[0045] R4 is hydrogen or C 1-3 alkyl,

[0046] p and q are independently integers 0 or 1,

[0047] When p is 1, R 5a and R 5b are independently hydrogen or C 1-3 Alkyl, or R 5a and R 5b connected to form C 3-6 ring,

[0048] R6 is hydrogen or halogen,

[0049] R7 is hydrogen, halogen, R s 、R u , -NH-aryl, -NH-ring C 3-7 Alkyl, -NHR s 、-NHR u or -NHC(O)R u ,

[0050] R8 is hydrogen, halogen or a 4- to 6-membered heteroaryl group having 1 to 3 N atoms,

[0051] R7 and R8 are independently replaced or not replaced by one or more independent R m replace,

[0052] R m C 1-3 Alkyl (wherein hydrogen is protium or deuterium), C 3-10 Cycloalkyl, C 1-3 Alkoxy, sulfonyl, amino, halogen, cyano, haloalkyl, carbamoyl, carboxyl, aryl (wherein hydrogen is protium or deuterium), arylalkyl, R u or R s , R m By or without one or more independent R n replace,

[0053] R n C 1-3 Alkyl, C 1-3 Alkylsulfonyl, C 1-3 alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, an oxygen bridge or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl,

[0054] R9 and R 10 are independently hydrogen or halogen,

[0055] R s is a 4- to 8-membered saturated heterocycloalkyl group having 1 to 2 heteroatoms selected from N and O,

[0056] R u is a 4- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O and S.

[0057] In one embodiment, R1 can be hydrogen, aminomethyl, cyclobutyl, cyclopentyl (wherein hydrogen is protium or deuterium), spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, pyrrolidinyl, tetrahydrofuranyl, or piperidinyl and R 1a It may be methyl, propyl, isopropyl, fluoro, oxo, -C(O)OH, -C(O)O-methyl or -C(O)O-benzyl.

[0058] In one embodiment, R2 can be hydrogen, methyl, or trimethyl-silyl-ethoxy-methyl.

[0059] In one embodiment, R3 can be hydrogen, methyl, ethyl or chloro.

[0060] In one embodiment, R4 can be hydrogen or methyl.

[0061] In one embodiment, R 5a and R 5b may independently be hydrogen or methyl, or R5a and R 5b May be linked to each other to form a cyclopropyl group.

[0062] In one embodiment, R6 may be hydrogen or fluorine.

[0063] In one embodiment, R7 can be hydrogen, Br, piperazinyl, diazepanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, isothiazolyl, triazolyl, oxadiazolyl, -NH-phenyl, -NH-cyclopentyl, -NH-piperidinyl, -NH-pyrrolyl, -NH-thienyl, -NH-pyrazolyl, -NH-isothiophene Azolyl, -NH- oxadiazolyl, -NH-thiadiazolyl, -NH-pyridinyl or -NHC(O)-pyrazolyl.

[0064] In one embodiment, R8 can be hydrogen, fluoro, chloro or pyrazolyl.

[0065] In one embodiment, R m can be methyl (wherein hydrogen is protium or deuterium), methoxy, sulfonyl, amino, fluoro, chloro, cyano, trifluoromethyl, difluoroethyl, trifluoroethyl, carbamoyl, carboxyl, cyclopentyl, cyclohexyl, phenyl (wherein hydrogen is protium or deuterium), benzyl, thienyl, furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl or tetrahydrofuranyl and R n It can be methyl, ethyl, methylsulfonyl, methoxy, fluorine, chlorine, iodine, bromine, cyano, trifluoromethyl, carbamoyl, carboxyl, acetyl, phenyl, benzyl, an oxygen bridge or methylcarboxyl-(8-cyclopentyl-7H-purine-6-carboxamido)-ethyl.

[0066] In one embodiment, R9 can be hydrogen, fluorine or chlorine.

[0067] In one embodiment, R 10 It can be hydrogen or fluorine.

[0068] Unless otherwise specified, the following definitions apply to compounds of formula I.

[0069] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group, preferably C 1-10 Alkyl. Some examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, among others.

[0070] The term "cycloalkyl" as used herein refers to a partially or fully saturated monocyclic or condensed ring hydrocarbon, and C 3-10Monocyclic, bicyclic or tricyclic functional groups. Some examples of monocyclic functional groups in cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexynyl, etc. Bicyclic functional groups in cycloalkyl groups include bicycloalkyl and spiro functional groups, and some specific examples include bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, spiro[2.3]hexyl, spiro[3.3]heptyl, etc.

[0071] As used herein, the term "hydroxy" or "hydroxyl" is defined as -OH, and unless otherwise specified, the term "alkoxy" refers to an alkyloxy group in which the hydrogen atom of the hydroxy group is replaced by 1 to 10 alkyl atoms.

[0072] As used herein, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0073] As used herein, the terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0074] The term "heteroatom" as used herein means N, O or S.

[0075] The term "aryl" as used herein means an aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused to one or more other rings. 5-12 Aryl, and more preferably C 5-10 Aryl. For example, aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like. Also included are groups in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocyclic ring, such as indanyl or tetrahydrobenzopyranyl.

[0076] The term "heteroaryl" or "aromatic heterocycle" as used herein means a 3- to 12-membered, more preferably a 5- to 10-membered aromatic hydrocarbon forming a monocyclic or fused ring containing one or more heteroatoms selected from N, O and S as ring atoms and which may be fused to a benzo or C 3-8 For example, heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, Oxazolyl, iso Oxazolyl, tetrazolyl, indolyl, indazolyl, iso Azolyl, oxazolyl, thiazolyl, isothiazolyl, furyl, benzofuranyl, thienyl, benzothiazolyl, benzo oxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, etc.

[0077] As used herein, the term "heterocycloalkyl" refers to a non-aromatic alkyl ring that is a non-aromatic carbocyclic ring containing one or more heteroatoms (e.g., N, O, or S) within the ring. The ring may be 5-, 6-, 7-, or 8-membered and / or may be fused to another ring (e.g., a cycloalkyl or aromatic ring). Some examples of such compounds include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, Oxazolidinyl, isocyanate oxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl and dioxolanyl alkyl.

[0078] Arylalkyl, alkylaryl and heteroarylalkyl refer to groups formed by combining aryl and alkyl or heteroaryl and alkyl as defined above, and examples thereof include, but are not limited to, benzyl, thienylethyl and pyrimidinylmethyl.

[0079] The term "Cbz" as used herein refers to carbobenzoyl.

[0080] Some representative examples of compounds of formula I according to the present invention are as follows:

[0081] [1] 8-cyclopentyl-N-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0082] [2] 8-cyclopentyl-N-(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0083] [3] 8-cyclopentyl-N-(3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0084] [4] (S)-8-cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide,

[0085] [5] 8-cyclopentyl-N-(3-fluoro-5-(1-methyl-1H-pyrazole-4-carboxamido)benzyl)-7H-purine-6-carboxamide,

[0086] [6] 8-cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-7H-purine-6-carboxamide,

[0087] [7] 8-cyclopentyl-N-(3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0088] [8] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0089] [9] N-(3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0090]

[10] 8-cyclopentyl-N-(3-fluoro-5-(pyridin-3-ylamino)benzyl)-7H-purine-6-carboxamide,

[0091]

[11] 8-cyclopentyl-N-(3-fluoro-5-(1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0092]

[12] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0093]

[13] 8-cyclopentyl-N-(3-fluorobenzyl)-7H-purine-6-carboxamide,

[0094]

[14] N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0095]

[15] 8-cyclopentyl-N-(3-fluoro-5-(phenylamino)benzyl)-7H-purine-6-carboxamide,

[0096]

[16] 8-cyclopentyl-N-(3-fluoro-5-(pyridin-4-ylamino)benzyl)-7H-purine-6-carboxamide,

[0097]

[17] 8-cyclopentyl-N-(3-fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0098]

[18] 8-cyclopentyl-N-(3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0099]

[19] 8-cyclopentyl-N-(3-fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0100]

[20] N-(3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0101]

[21] 8-cyclopentyl-N-(3-fluoro-5-((4-fluorophenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0102]

[22] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide,

[0103]

[23] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0104]

[24] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0105]

[25] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0106]

[26] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0107]

[27] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0108]

[28] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0109]

[29] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0110]

[30] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0111]

[31] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0112]

[32] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0113]

[33] 8-cyclopentyl-N-(3-fluoro-5-((2-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0114]

[34] 8-cyclopentyl-N-(3-fluoro-5-((3-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0115]

[35] 8-cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0116]

[36] 8-cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7-methyl-7H-purine-6-carboxamide,

[0117]

[37] N-(3-(1-(3-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0118]

[38] 8-cyclopentyl-N-(3-fluoro-5-(isothiazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0119]

[39] 8-cyclopentyl-N-(3-fluoro-5-(furan-2-yl)benzyl)-7H-purine-6-carboxamide,

[0120]

[40] 8-cyclopentyl-N-(3-fluoro-5-(thien-3-yl)benzyl)-7H-purine-6-carboxamide,

[0121]

[41] 8-cyclopentyl-N-(3-fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide,

[0122]

[42] 8-cyclopentyl-N-(3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0123]

[43] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0124]

[44] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0125]

[45] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0126]

[46] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0127]

[47] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0128]

[48] ​​8-cyclopentyl-N-(3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0129]

[49] 3-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid,

[0130]

[50] N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0131]

[51] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)-7H-purine-6-carboxamide,

[0132]

[52] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)-7H-purine-6-carboxamide,

[0133]

[53] N-(3-(1-(4-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0134]

[54] 4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid,

[0135]

[55] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7-methyl-7H-purine-6-carboxamide,

[0136]

[56] 8-cyclopentyl-N-(2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0137]

[57] 8-cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0138]

[58] N-(3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0139]

[59] N-(3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0140]

[60] 8-cyclopentyl-N-(3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0141]

[61] 2-chloro-8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0142]

[62] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride,

[0143]

[63] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide,

[0144]

[64] Benzyl (R)-2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate,

[0145]

[65] (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride,

[0146]

[66] (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide,

[0147]

[67] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-isopropylpyrrolidin-2-yl)-7H-purine-6-carboxamide,

[0148]

[68] (R)-N-(3-fluorobenzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide,

[0149]

[69] benzyl 4-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)piperidine-1-carboxylate,

[0150]

[70] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(piperidin-4-yl)-7H-purine-6-carboxamide hydrochloride,

[0151]

[71] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpiperidin-4-yl)-7H-purine-6-carboxamide,

[0152]

[72] benzyl ((6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)methyl)carbamate,

[0153]

[73] 8-(aminomethyl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0154]

[74] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0155]

[75] Benzyl 3-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate,

[0156]

[76] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-3-yl)-7H-purine-6-carboxamide hydrochloride,

[0157]

[77] 8-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0158]

[78] 8-(bicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0159]

[79] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-3-yl)-7H-purine-6-carboxamide,

[0160]

[80] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0161]

[81] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0162]

[82] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0163]

[83] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0164]

[84] (E1, E2) 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0165]

[85] (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-2-yl)-7H-purine-6-carboxamide,

[0166]

[86] (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide,

[0167]

[87] N-(3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0168]

[88] (S)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide,

[0169]

[89] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-3-yl)-7H-purine-6-carboxamide,

[0170]

[90] (R)-8-cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide,

[0171]

[91] (S)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[0172]

[92] 8-(3,3-difluorocyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0173]

[93] 2-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide,

[0174]

[94] 8-cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethyl)-7H-purine-6-carboxamide,

[0175]

[95] 8-cyclopentyl-N-(2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0176]

[96] 8-cyclopentyl-N-(4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0177]

[97] 8-(3,3-dimethylcyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0178]

[98] 8-(6,6-difluorospiro[3.3]hept-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0179]

[99] 8-(bicyclo[1.1.1]pentan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0180]

[100] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[3.3]hept-2-yl)-7H-purine-6-carboxamide,

[0181]

[101] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7H-purine-6-carboxamide,

[0182]

[102] (A, B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclobutyl)-7H-purine-6-carboxamide,

[0183]

[103] (A, B) methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate,

[0184]

[104] N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0185]

[105] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-7H-purine-6-carboxamide,

[0186]

[106] 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylic acid,

[0187]

[107] 2-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide,

[0188]

[108] 8-cyclopentyl-N-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0189]

[109] 8-cyclopentyl-N-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0190]

[110] (A, B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclopentyl)-7H-purine-6-carboxamide,

[0191]

[111] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[2.3]hexan-5-yl)-7H-purine-6-carboxamide,

[0192]

[112] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-N-methyl-7H-purine-6-carboxamide,

[0193]

[113] 8-(bicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0194]

[114] 8-(bicyclo[2.2.1]hept-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0195]

[115] 8-(bicyclo[2.1.1]hex-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0196]

[116] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7H-purine-6-carboxamide,

[0197]

[117] 8-cyclopentyl-N-(3-fluoro-5-(1-(thien-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0198]

[118] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0199]

[119] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0200]

[120] N-(3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0201]

[121] 8-cyclopentyl-N-(3-fluoro-5-(iso oxazol-3-ylamino)benzyl)-7H-purine-6-carboxamide,

[0202]

[122] N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0203]

[123] N-(3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0204]

[124] 8-cyclopentyl-N-(3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0205]

[125] N-(3-(1′-benzyl-1′H-[1,4′-bipyrazol]-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0206]

[126] N-(3-((4-carbamoylphenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0207]

[127] ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate,

[0208]

[128] 8-cyclopentyl-N-(3-fluoro-5-(1′-methyl-1′H-[1,4′-bipyrazol]-4-yl)benzyl)-7H-purine-6-carboxamide,

[0209]

[129] 8-cyclopentyl-N-(3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0210]

[130] 8-cyclopentyl-N-(3-fluoro-5-(thien-3-ylamino)benzyl)-7H-purine-6-carboxamide,

[0211]

[131] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)benzyl)-7H-purine-6-carboxamide,

[0212]

[132] 8-cyclopentyl-N-(3-fluoro-5-(5-(4-fluorophenyl)-1,3,4- oxadiazole-2-yl)benzyl)-7H-purine-6-carboxamide,

[0213]

[133] 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoic acid,

[0214]

[134] N-(3-((1,3,4- oxadiazole-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0215]

[135] 8-cyclopentyl-N-(3-(cyclopentylamino)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0216]

[136] N-(3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0217]

[137] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)benzyl)-7H-purine-6-carboxamide,

[0218]

[138] 8-cyclopentyl-N-(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0219]

[139] N-(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0220]

[140] 8-cyclopentyl-N-(3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0221]

[141] 8-cyclopentyl-N-(3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0222]

[142] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0223]

[143] 8-cyclopentyl-N-(3-fluoro-5-(1-(1-oxothiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0224]

[144] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0225]

[145] 8-cyclopentyl-N-(3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0226]

[146] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0227]

[147] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0228]

[148] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(phenyl-d5)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0229]

[149] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)benzyl)-7H-purine-6-carboxamide,

[0230]

[150] methyl 2-(8-cyclopentyl-7H-purine-6-carboxamido)-3-(4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)phenyl)propanoate,

[0231]

[151] 8-cyclopentyl-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0232]

[152] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide and

[0233]

[153] 8-(Cyclopentyl-2,2,3,3,4,4,5,5-d8)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide.

[0234] The compound represented by the above formula I according to the present invention can be prepared and used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts to promote in vivo absorption or increase solubility, and therefore the above prodrugs, hydrates, solvates and pharmaceutically acceptable salts also fall within the scope of the present invention.

[0235] The term "prodrug" as used herein refers to a substance that is converted into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they can be biologically active when administered orally, whereas the parent drug may not be. Compared to the parent drug, prodrugs can have improved solubility in pharmaceutical compositions. For example, prodrugs can be hydrolyzable esters and pharmaceutically acceptable salts thereof in vivo of a compound according to the present invention. Another example of prodrugs can be a short peptide (polyamino acid), which is connected to an acidic group that is metabolized to display the active site of a peptide.

[0236]

[0046] The term "hydrate" as used herein means a compound of the present invention or a salt thereof having a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0237] As used herein, the term "solvate" refers to a compound of the invention or a salt thereof having a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefore include those that are volatile, non-toxic, and / or suitable for administration to humans.

[0238] The term "isomer" as used herein means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different in structure or space. Such isomers include structural isomers and stereoisomers, such as tautomers, and stereoisomers such as R or S isomers, geometric isomers (trans, cis) and diastereomers with an asymmetric carbon center. All of these isomers and mixtures thereof are also included within the scope of the present invention. In particular, when a compound of formula I has optical isomers, stereoisomers, regioisomers or rotational isomers, these are also included in the compound of formula I, and can be obtained as a single product according to synthesis and separation methods known per se. For example, when a compound of formula I includes optical isomers, the optical isomers split from the compound are also included in the compound of formula I. Optical isomers can be prepared by methods known per se.

[0239] As used herein, the term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. Pharmaceutically acceptable salts include acid addition salts formed from acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylates include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine. The compound of formula 1 according to the present invention can be converted into a salt thereof by a conventional method.

[0240] The synthetic methods of Examples 1 to 153 are exemplified as methods for preparing the compounds of Formula I of the present invention, and these synthetic methods of Examples 1 to 153 do not limit the methods for preparing the compounds of Formula I according to the present invention. The synthetic methods of Examples 1 to 153 are merely exemplary, and it is obvious that they can be easily modified by those skilled in the art according to specific substituents.

[0241] The present invention also provides a pharmaceutical composition for preventing or treating diseases related to HIF-1α (hypoxia-inducible factor 1α) or VEGF (vascular endothelial growth factor), which comprises as an active ingredient a compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0242] The present invention also provides a method for preventing or treating diseases associated with HIF-1α or the angiogenesis inducer VEGF, comprising the step of administering to a subject or individual in need thereof a compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0243] The present invention also provides use of a compound represented by formula I, a hydrate, a solvate, a prodrug, an isomer or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating diseases associated with HIF-1α or the angiogenesis inducer VEGF.

[0244] In one embodiment, diseases associated with HIF-1α or VEGF can be prevented or treated by inhibiting angiogenesis.

[0245] In one embodiment, inhibition of angiogenesis can be achieved by inhibiting HIF-1α expression or inhibiting VEGF expression.

[0246] In one embodiment, the disease associated with HIF-1α or VEGF is at least one selected from the group consisting of stroke, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head and neck cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal cancer, skin cancer, fallopian tube cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, oral cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, ureteral cancer, spleen cell carcinoma, renal pelvis cancer, medulloblastoma, neuroblastoma, brain tumor, central nervous system cancer. Tumors, melanoma, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, cancer, cervical cancer, thyroid cancer, blood cancer, renal cell carcinoma, hepatocellular carcinoma, metastatic cancer, hemangioma, pyogenic granuloma, Kaposi's sarcoma, hemangioendothelioma, solid tumors, follicular cysts, endometriosis, uterine sclerosis, ovarian hypertension, overactive ovaries, uterine dysfunction, warts, keloids, allergic edema, atherosclerosis, peritoneal sclerosis, heart dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, bone and cartilage destruction, malignant fibrous histiocytoma of bone, osteomyelitis, pannus Growth, liver fibrosis, pulmonary fibrosis, fibrosis, NASH (non-alcoholic steatohepatitis), pneumonia, asthma, rhinitis, pulmonary hypertension, ischemic acute kidney injury, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, inflammatory neurodegenerative diseases, vascular diseases related to nicotine addiction, chronic kidney disease, retinopathy of prematurity, diabetic retinopathy, corneal transplant rejection, ischemic retinopathy, erythroderma, proliferative retinopathy, psoriasis, hemophilic joints, keloids, wound granulation, vascular adhesions, Autoimmune diseases, angiofibroma, retrolental fibroplasia, cataract, glaucoma, macular degeneration, age-related macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, neovascular glaucoma, neovascular macular degeneration, retinal artery occlusion, retinal vein occlusion, retinoblastoma, optic pathway and hypothalamic glioma, rhabdomyosarcoma, histiosarcoma, inflammation, corneal ulcer, proliferative vitreoretinopathy, sclerosis, asthma, periodontal disease, allergic dermatitis, Alzheimer's disease disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' orbitopathy, leukomalacia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and Behçet's colitis.

[0247] In one embodiment, the angiogenesis-related disease is at least one selected from the group consisting of cancer, cervical cancer, blood cancer, renal cell carcinoma, hepatocellular carcinoma, metastatic cancer, hemangioma, pyogenic granuloma, Kaposi's sarcoma, hemangioendothelioma, follicular cyst, endometriosis, uterine sclerosis, ovarian hypertension, ovarian overactivity, uterine dysfunction, warts, keloids, allergic edema, atherosclerosis, peritoneal sclerosis, cardiac dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, bone and Cartilage destruction, osteomyelitis, pannus growth, liver fibrosis, NASH (non-alcoholic steatohepatitis), pneumonia, asthma, rhinitis, pulmonary hypertension, ischemic acute kidney injury, glomerulonephritis, chronic kidney disease, retinopathy of prematurity, diabetic retinopathy, glaucoma, macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' orbitopathy and leukomalacia. Angiogenesis-related diseases can be neovascular eye diseases, such as retinopathy of prematurity, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization or intraocular neovascularization. Angiogenesis-related diseases can be macular degeneration.

[0248] In one embodiment, the HIF-1α or angiogenesis inducer VEGF-related disease can be a neovascular eye disease, and the neovascular eye disease can be at least one selected from the following: corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, neovascular glaucoma, proliferative diabetic retinopathy, neovascular macular degeneration and retinopathy of prematurity.

[0249] The neovascular eye disease may be macular degeneration, which may be neovascular age-related macular degeneration (neovascular AMD) or non-neovascular age-related macular degeneration (non-neovascular AMD).

[0250] The present invention also provides a preparation comprising the compound represented by Formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0251] The above additives may include pharmaceutically acceptable carriers, such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and may be formulated into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral preparations such as external solutions, external suspensions, external emulsions, gels (ointments, etc.), inhalants, sprays, and injections. In the case of oral tablets, carriers (such as lactose and corn starch) and lubricants (such as magnesium stearate) are generally added. In the case of oral capsules, lactose and / or dried corn starch may be used as diluents. When an oral aqueous suspension is desired, the active ingredient may be combined with an emulsifier and / or suspending agent. If necessary, specific sweeteners and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is generally prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute should be adjusted to impart isotonicity to the preparation. The composition according to the present invention can be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline at a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local injection. The preparation can be formulated in a variety of forms (e.g., as a single dose or multidose dosage form).

[0252] The subject to which the pharmaceutical composition of the present invention is administered may be, for example, humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, cats, dogs, mice, rats, rabbits or guinea pigs, and may be, for example, mammals such as humans, but is not limited thereto.

[0253] In addition, the pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by the following routes: for example, skin, transdermal, ocular, intraperitoneal, rectal or intravenous, intramuscular, subcutaneous, intrauterine epidural, intracerebroventricular injection or by topical administration. Topical administration to the eye includes, for example, direct administration to the eye, or administration around the eye, behind the eye, under the retina, central retina, outside the fovea, under the conjunctiva, in the vitreous, intracameral or on the choroid. The pharmaceutical composition can be administered by an insertion device.

[0254] The dosage of the active ingredient included in the pharmaceutical composition of the present invention varies according to the patient's condition and body weight, the degree of the disease, the form of the active ingredient, the route of administration and the administration period, and can be appropriately adjusted according to the patient. For example, the active ingredient can be administered at a dosage of 0.0001 to 1000 mg / kg, preferably 0.001 to 100 mg / kg per day, and administration can be administered once a day or divided into several times. In addition, based on the gross weight of the composition, the pharmaceutical composition of the present invention can contain 0.001 to 90% weight percent active ingredient.

[0255] Hereinafter, the present invention will be described in more detail through preparation examples, embodiments and experimental examples. However, the following preparation examples, embodiments and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0256] Preparation Example 1

[0257] 1.1 Preparation of 8-cyclopentyl-7H-purine-6-carbonitrile

[0258]

[0259] 6-chloro-8-cyclopenta-7H-purine (1.5g, 6.73mmol), KCN (1.32g, 20.3mmol) and sodium p-toluenesulfinate (1.2g, 6.75mmol) are dissolved in sulfolane (25mL) and stirred 3 hours at 160 to 163 ℃.After reaction mixture is cooled to room temperature, silica gel is added to absorb all sulfolanes.Silica gel is loaded with solid state, and residue is passed through silica gel column chromatography (0 to 5% MeOH in DCM) purifying, to obtain the title compound (5.43g, 71%) as yellow solid.

[0260] LC-MS, m / z 214 [M+H] +

[0261] 1.2 Preparation of methyl 8-cyclopentyl-7H-purine-6-carboxylate

[0262]

[0263] The 8-cyclopentyl-7H-purine-6-carbonitrile (5.40 g, 25.3 mmol) obtained in the above preparation example 1.1 was dissolved in MeOH (220 mL) and TMSCl (trimethylsilyl chloride, 33.5 mL) was added. The mixture was stirred at 70° C. for 4.5 hours and quenched with saturated NaHCO 3 aqueous solution. The aqueous layer was extracted with DCM, and the organic layer was separated and dried over MgSO 4 . After concentration, the obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (3.66 g, 59%) as a white solid.

[0264] LC-MS, m / z 247 [M+H] +

[0265] 1.3. Preparation of 8-cyclopentyl-7H-purine-6-carboxylic acid

[0266]

[0267] The 8-cyclopentyl-7H-purine-6-carboxylic acid methyl esters (3.65 g, 14.8 mmol) obtained in above preparation example 1.2 was dissolved in MeOH (111 mL), 2M NaOH (47.0 mL) was added and stirred at room temperature. After 3.5 hours, the reaction mixture was acidified with 1M HCl (approximately pH 2), the gained solid was filtered and washed with hexane. The solid was dried under vacuum to obtain the title compound (3.02 g, 88%) as a white solid.

[0268] 1 H NMR (400MHz, CD3OD) δ9.00 (s, 1H), 3.58-3.44 (m, 1H), 2.26-2.16 (m, 2H), 2.09-1.98 (m, 2H), 1.98-1.88 (m, 2H), 1.85-1.72 (m, 2H).

[0269] LC-MS, m / z 233 [M+H] +

[0270] Example 1

[0271] 1.1 3-Fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzonitrile

[0272]

[0273] 3-Bromo-5-fluorobenzonitrile (200 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (393 mg, 1.50 mmol) and Pd(dppf)Cl ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 36.6 mg, 0.05 mmol) were dissolved in dioxane (3.4 mL), and 2M KCO (1.25 mL) was added and degassed with N for 10 minutes. The reaction mixture was stirred at 80° C. for 2 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in CHCl) to obtain the title compound (100 mg, 39%) as a white solid.

[0274] LC-MS, m / z 256 [M+H] +

[0275] 1.2(3-Fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0276]

[0277] 3-Fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzonitrile (90 mg, 0.35 mmol) obtained in Example 1.1 above was dissolved in THF (5 mL), cooled to 0° C., LAH solution (2.0 M in THF; 0.35 mL) was added, and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., quenched by the addition of H O (2 mL), and adjusted to pH 10 with 2 M NaOH solution. EtOAc (5 mL) was added, stirred for 1 hour, and filtered to remove solids. The filtrate was concentrated, redissolved in EtOAc, dried over MgSO , and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (0 to 10% MeOH in CH Cl ) to obtain the title compound (44 mg, 49%) as an oil.

[0278] LC-MS, m / z 260 [M+H] +

[0279] 1.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0280]

[0281] 8-Cyclopentyl-7H-purine-6-carboxylic acid (15 mg, 0.07 mmol) obtained in Preparation Example 1.3 above, (3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)methanamine (17 mg, 0.07 mmol) and T3P (propylphosphonic anhydride, a 50 wt% solution in EtOAc, 128 mg) were dissolved in ethyl acetate (3 mL), DIPEA (N,N-diisopropylethylamine, 30 μL) was added, and the mixture was stirred at 50° C. After 12 hours, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (25 mg, 81%) as a white solid.

[0282] 1H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.53 (s, 1H), 7.34 (d, J=12Hz, 1H), 7.11 (d, J=8 .0Hz, 1H), 4.70 (s, 2H), 3.50-3.45 (m, 1H), 2.18 (m, 2H), 2.03-2.01 (m, 2H), 1.91 (m, 2H), 1.77-1.74 (m, 2H).

[0283] LC-MS, m / z 474 [M+H] +

[0284] Example 2

[0285] 2.1 3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzonitrile

[0286]

[0287] By the same procedure as in Example 1.1, using 3-bromo-5-fluorobenzonitrile (200 mg, 1.00 mmol), 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (387 mg, 1.50 mmol), Pd(dppf)Cl2(([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 36.6 mg, 0.05 mmol), 2M K2CO3 (1.25 mL) and dioxane (3.4 mL), the title compound (251 mg, 100%) was obtained as a white solid.

[0288] LC-MS, m / z 252 [M+H] +

[0289] 2.2(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[0290]

[0291] By the same procedure as in Example 1.2, using 3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzonitrile (251 mg, 1.00 mmol) and LAH solution (2.0 M in THF; 1.0 mL), the title compound (193 mg, 76%) was obtained as a yellow syrup.

[0292] LC-MS, m / z 256 [M+H] +

[0293] 2.3 8-Cyclopentyl-N-(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[0294]

[0295] The title compound (3.4 mg, 11%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (15.0 mg, 0.07 mmol), (3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine (16.6 mg, 0.07 mmol), T3P (50 wt% solution in EtOAc, 355 mg) and DIPEA (76 μL).

[0296] 1 H NMR (400MHz, CDCl3) δ10.38 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.11 (d, J = 9.6Hz, 1H), 6.97 (d, J = 9.0Hz, 1H), 6.29-5.92 (m, 1H ), 4.71 (d, J=6.2Hz, 2H), 4.49 (td, J=13.5, 4.1Hz, 2H), 3.49-3.37 (m, 1H), 2 .30-2.17(m,2H), 2.11-2.00(m,2H), 1.97-1.85(m,2H), 1.83-1.72(m,2H).

[0297] LC-MS, m / z 470 [M+H] +

[0298] Example 3

[0299] 3.1 3-Fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzonitrile

[0300]

[0301] By the same procedure as in Example 1.1, using 3-bromo-5-fluorobenzonitrile (200 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (414 mg, 1.50 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), 2M K2CO3 (1.25 mL) and dioxane (3.4 mL), the title compound (269 mg, 100%) was obtained as a white solid.

[0302] LC-MS, m / z 270 [M+H] +

[0303] 3.2(3-Fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0304]

[0305] By the same procedure as in Example 1.2, using 3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzonitrile (269 mg, 1.00 mmol) and LAH solution (2.0 M in THF; 1.0 mL), the title compound (222 mg, 81%) was obtained as a light yellow syrup.

[0306] LC-MS, m / z 274 [M+H] +

[0307] 3.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0308]

[0309] The title compound (8.7 mg, 27%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (15.0 mg, 0.07 mmol), (3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)methanamine (17.8 mg, 0.07 mmol), T3P (50 wt% solution in EtOAc, 128 mg) and DIPEA (30 μL).

[0310] 1H NMR (400MHz, CDCl3) δ10.35 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.26 (s, 1H), 7.12 (d, J=9.1Hz, 1H), 6.99 ( d, J=8.8Hz, 1H), 4.76-4.69 (m, 4H), 3.47-3.38 (m, 1H), 2.29-2.19 (m, 2H), 2.11-2.00 (m, 2H), 1.97-1.85 (m, 2H), 1.83-1.71 (m, 2H).

[0311] LC-MS, m / z 488[M+H] +

[0312] Example 4

[0313] 4. tert-Butyl (S)-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[0314]

[0315] To tert-butyl (S)-(1-(3-bromophenyl)ethyl)carbamate (200 mg, 0.70 mmol) in 1,4-dioxane (3 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 mg, 1.0 mmol) and 2M KCO aqueous solution (1.2 mL, 2.4 mmol). The mixture was degassed with N gas for 10 minutes, PdCl(dppf) (26 mg, 0.035 mmol) was added, and the reaction was allowed to proceed at 80° C. After 3 hours, the reaction solution was diluted with H O, extracted three times with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to obtain the title compound (60 mg, 30%) as a light solid.

[0316] LC-MS, m / z 302[M+H] +

[0317] 4.2(S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-amine

[0318]

[0319] To the solution of 1-(3-(1-methyl isophthalic acid H-pyrazole-4-yl) phenyl) ethyl) carbamate (60mg, 0.20mmol) in DCM (1mL) at 0 ℃, TFA (0.2mL) is added dropwise.Reaction temperature is gradually warmed to room temperature and stirred for 1 hour.After the reaction is complete, the mixture is saturated with Na cO the aqueous solution is quenched and extracted three times with DCM (1% MeOH).The filtrate is concentrated and purified by silica gel column chromatography (0 to 3% MeOH in DCM) to obtain title compound (20mg, 50%).

[0320] 1 H NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.33 (dt, J=15.2, 7.6Hz, 2H), 7.20 (d, J=7.0Hz, 1H), 4.15 (q, J=6.6Hz, 1H), 3.94 (s, 3H), 1.43 (d, J=6.6Hz, 3H).

[0321] 4.3(S)-8-Cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[0322]

[0323] The title compound (13 mg, 63%) was obtained by the same method as in Example 1.3 using (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethanamine (10 mg, 0.050 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (12 mg, 0.050 mmol), T3P (50 wt% solution in EtOAc, 89 μL, 0.15 mmol) and DIPEA (34 μL, 0.20 mmol).

[0324] 1 H NMR (400MHz, DMSO-d6) δ13.12 (s, 1H), 9.38 (s, 1H), 8.94 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.27 (d, J=6.4Hz, 2H), 5.23-5.17 (m, 1H), 3.83 (s, 3H), 3.45 (s, 1H), 2.04 (s, 2H), 1.90 (s, 2H), 1.77 (s, 2H), 1.62 (d, J=4.8Hz, 2H), 1.58 (d, J=6.8Hz, 3H).

[0325] LC-MS, m / z 416[M+H] +

[0326] Example 5

[0327] 5.1 N-(3-cyano-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0328]

[0329] 3-Amino-5-fluorobenzonitrile (119 mg, 0.87 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.79 mmol) and T3P (50 wt% solution in EtOAc, 1.52 g, 2.39 mmol) were dissolved in ethyl acetate (15 mL), DIPEA (333 μL, 1.91 mmol) was added and stirred at 50°C. After 12 hours, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (85 mg, 44%) as a yellow solid.

[0330] LC-MS, m / z 245 [M+H] +

[0331] 5.2 N-(3-(Aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0332]

[0333] To a solution of N-(3-cyano-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide (55 mg, 0.23 mmol) in EtOH (1 mL) was added 10% palladium on carbon (Pd / C; 50 mg) and AcOH (50% in water; 0.5 mL). The mixture was stirred at room temperature under an H atmosphere overnight. The reaction mixture was filtered through a pad of celite and concentrated to obtain the title compound (56 mg, crude).

[0334] LC-MS, m / z 249 [M+H] +

[0335] 5.3 8-Cyclopentyl-N-(3-fluoro-5-(1-methyl-1H-pyrazole-4-carboxamido)benzyl)-7H-purine-6-carboxamide

[0336]

[0337] The title compound (5 mg, 13%) was obtained by the same method as in Example 1.3 using N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide (22 mg, 0.086 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (20 mg, 0.086 mmol), T3P (50 wt% solution in EtOAc, 154 μL, 0.26 mmol), and DIPEA (58 μL, 0.34 mmol).

[0338] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.94 (s, 1H), 9.75 (s, 1H), 8.94 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.61 (d, J=11.4Hz, 1H), 7.40 (s, 1 H), 6.89 (d, J=9.8Hz, 1H), 4.53 (d, J=6.0Hz, 2H), 3.86 (d, J=7.8Hz, 3H), 3.47 (s, 1H), 2.05 (m, 2H), 1.91 (m, 2H), 1.79 (m, 2H), 1.64 (m, 2H).

[0339] LC-MS, m / z 463[M+H] +

[0340] Example 6

[0341] 6.1 tert-Butyl (1-(3-bromophenyl)cyclopropyl)carbamate

[0342]

[0343] To a solution of 1-(3-bromophenyl)cyclopropylamine (300mg, 1.4mmol) in THF (6mL) was added Boc O (370mg, 1.7mmol) and Na CO (300mg, 2.8mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with H O, extracted three times with DCM, and the organic layer was dried over MgSO and concentrated. The gained residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to obtain the title compound (437mg, 99%).

[0344] LC-MS, m / z 313 [M+H] +

[0345] 6. tert-Butyl (1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)carbamate

[0346]

[0347] The title compound (4 mg, 99%) was obtained by the same procedure as in Example 4.1 using tert-butyl (1-(3-bromophenyl)cyclopropyl)carbamate (430 mg, 1.4 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (430 mg, 2.1 mmol), 2M aqueous K2CO3 solution (2.4 mL, 4.8 mmol), PdCl2(dppf) (50 mg, 0.069 mmol) and 1,4-dioxane (5 mL).

[0348] LC-MS, m / z 314 [M+H] +

[0349] 6.3 1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropane-1-amine

[0350]

[0351] The title compound (318 mg, crude) was obtained by the same procedure as in Example 4.2 above using tert-butyl (1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)carbamate (430 mg, 1.4 mmol) and TFA (2 mL).

[0352] LC-MS, m / z 214 [M+H] +

[0353] 6.4 8-Cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-7H-purine-6-carboxamide

[0354]

[0355] The title compound (83 mg, 90%) was obtained by the same procedure as in Example 1.3 using 1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropylamine (69 mg, 0.32 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (50 mg, 0.22 mmol), T3P (50 wt% solution in EtOAc, 380 μL, 0.65 mmol), DIPEA (150 μL, 0.86 mmol) and EtOAc (5 mL).

[0356] 1H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.84 (s, 1H), 8.96 (s, 1H), 8.08 (s, 1H ), 7.80 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 7.6Hz, 1H), 7.25 (t, J = 7.7Hz, 1H), 7. 18(d, J=7.8Hz, 1H), 3.84(s, 3H), 3.50-3.43(m, 1H), 2.07(d, J=12.4Hz, 2H) , 1.92 (dd, J=12.2, 7.4Hz, 2H), 1.80 (s, 2H), 1.69-1.61 (m, 2H), 1.36 (s, 4H).

[0357] LC-MS, m / z 428[M+H] +

[0358] Example 7

[0359] 7.1 3-Fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzonitrile

[0360]

[0361] The title compound (194 mg, 99%) was obtained by the same procedure as in Example 4.1 using 3-bromo-5-fluorobenzonitrile (148 mg, 0.74 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.1 mmol), 2M K2CO3 aqueous solution (1.3 mL, 2.6 mmol), PdCl2(dppf) (27 mg, 0.037 mmol) and 1,4-dioxane (3 mL).

[0362] LC-MS, m / z 264 [M+H] +

[0363] 7.2(3-Fluoro-5-(1-phenyl-1H-pyrazol-4-yl)phenyl)methanamine

[0364]

[0365] At 0 ° C, 3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzonitrile (100 mg, 0.38 mmol) was added to THF (3 mL), followed by LAH solution (2.0 M in THF, 380 μL, 0.76 mmol). The mixture was stirred at room temperature for 1 hour under N2 atmosphere. After the reaction was complete, the mixture was quenched with 1M NaOH (pH=8 to 9), filtered through a celite pad, and washed several times with EtOAc. The filtrate was dried over Na2SO4, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (70 mg, 70%).

[0366] LC-MS, m / z 268[M+H] +

[0367] 7.3 8-Cyclopentyl-N-(3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0368]

[0369] The title compound (13 mg, 72%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)phenyl)methanamine (10 mg, 0.037 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (9 mg, 0.037 mmol), T3P (50 wt% solution in EtOAc, 67 μL, 0.11 mmol), DIPEA (25 μL, 0.15 mmol) and EtOAc (1 mL).

[0370] 1 H NMR (400MHz, DMSO-d6) δ13.18(s, 1H), 9.78(s, 1H), 9.06(s, 1H), 8.97(s, 1H ), 8.25 (s, 1H), 7.88 (d, J = 8.3Hz, 2H), 7.60 (s, 1H), 7.55-7.48 (m, 3H), 7.34 ( t, J=7.2Hz, 1H), 7.07 (d, J=9.3Hz, 1H), 4.61 (d, J=5.8Hz, 2H), 3.52-3.47 (m, 1H), 2.08 (d, J=7.8Hz, 2H), 1.94 (d, J=7.7Hz, 2H), 1.81 (s, 2H), 1.66 (s, 2H).

[0371] LC-MS, m / z 482[M+H] +

[0372] Example 8

[0373] 8.1 3-Fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile

[0374]

[0375] 3-Bromo-5-fluorobenzonitrile (260 mg, 1.3 mmol), 1-methyl-1H-pyrazol-4-amine (100 mg, 1.0 mmol), BINAP (240 mg), Pd2(dba)3 (180 mg) and sodium tert-butoxide (190 mg) were added to toluene (4 mL) and stirred at 100°C for 1 hour. After the reaction was complete, the mixture was diluted with H2O, extracted three times with EtOAc, and the organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by amino silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (160 mg, 58%).

[0376] LC-MS, m / z 217 [M+H] +

[0377] 8.2 N-(3-(Aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine

[0378]

[0379] By the same procedure as in Example 7.2, using 3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile (140 mg, 0.65 mmol), LAH solution (2.0 M in THF, 0.7 mL, 1.3 mmol) and THF (4 mL) to obtain the title compound (100 mg, 70%).

[0380] LC-MS, m / z 221[M+H] +

[0381] 8.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[0382]

[0383] The title compound (132 mg, 37%) was obtained by the same procedure as in Example 1.3 using N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine (180 mg, 0.82 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (190 mg, 0.82 mmol), T3P (50 wt% solution in EtOAc, 1.5 mL, 2.5 mmol), DIPEA (560 μL, 3.3 mmol) and EtOAc (5 mL).

[0384] 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 9.64 (s, 1H), 8.93 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.25 (s, 1H), 6.56 (s, 1H), 6.38 (d, J=9.4Hz, 1H), 6.3 1 (d, J=11.8Hz, 1H), 4.40 (d, J=6.3Hz, 2H), 3.73 (s, 3H), 3.46 (s, 1H), 2. 05(d, J=5.7Hz, 2H), 1.93-1.87(m, 2H), 1.77(s, 2H), 1.67-1.60(m, 2H).

[0385] LC-MS, m / z 435[M+H] +

[0386] Example 9

[0387] 9.1 3-(1-phenyl-1H-pyrazol-4-yl)-5-fluorobenzonitrile

[0388]

[0389] By the same procedure as in Example 1.1, using 3-bromo-5-fluorobenzonitrile (200 mg, 1.00 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (426 mg, 1.5 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol) and dioxane (3.4 mL) to obtain the title compound (276 mg, 99%) as a white solid.

[0390] LC-MS, m / z 277 [M+H] +

[0391] 9.2(3-(1-Benzyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[0392]

[0393] By the same procedure as in Example 1.2, using 3-(1-phenyl-1H-pyrazol-4-yl)-5-fluorobenzonitrile (260 mg, 0.94 mmol), LAH solution (2.0 M in THF, 0.94 mL, 1.88 mmol) and THF (5 mL), the title compound (104 mg, 39%) was obtained as an oil.

[0394] LC-MS, m / z 282 [M+H] +

[0395] 9.3 N-(3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0396]

[0397] The title compound (17 mg, 57%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (14 mg, 0.06 mmol), (3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine (17 mg, 0.06 mmol), T3P (50 wt% solution in EtOAc, 128 mg, 0.20 mmol), DIPEA (29 μL, 0.17 mmol) and ethyl acetate (3 mL).

[0398] 1 H NMR (400MHz, CD3OD) δ8.93 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.40 (s, 1H), 7.32-7.17 (m, 6H), 6.99 (d, J=12 Hz, 1H), 5.32 (s, 2H), 4.65 (s, 2H), 3.48-3.44 (m, 1H), 2.17 (m, 2H), 2.00 (m, 2H), 1.89 (m, 2H), 1.74 (m, 2H).

[0399] LC-MS, m / z 496[M+H] +

[0400] Example 10

[0401] 10.1 3-Fluoro-5-(pyridin-3-ylamino)benzonitrile

[0402]

[0403] 3-Bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), pyridin-3-amine (100 mg, 1.06 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol) and K2CO3 (318 mg, 2.3 mmol) were added to dioxane (5 mL) and stirred at 80°C. After 12 hours, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (190 mg, 89%) as a white solid. LC-MS, m / z 214 [M+H] +

[0404] 10.2 N-(3-(Aminomethyl)-5-fluorophenyl)pyridin-3-amine

[0405]

[0406] By the same procedure as in Example 1.2, using 3-fluoro-5-(pyridin-3-ylamino)benzonitrile (180 mg, 0.83 mmol) and LAH solution (2.0 M in THF, 0.84 mL), the title compound (70 mg, 38%) was obtained as an oil.

[0407] LC-MS, m / z 218 [M+H] +

[0408] 10.3 8-Cyclopentyl-N-(3-fluoro-5-(pyridin-3-ylamino)benzyl)-7H-purine-6-carboxamide

[0409]

[0410] The title compound (25 mg, 32%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (42 mg, 0.18 mmol), N-(3-(aminomethyl)-5-fluorophenyl)pyridin-3-amine (40 mg, 0.18 mmol), T3P (50 wt% solution in EtOAc, 355 mg, 0.56 mmol) and DIPEA (76 μL, 0.45 mmol).

[0411] 1H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.24 (m, 1H), 6.96 (s , 1H), 6.69(m, 2H), 4.61(s, 2H), 3.48-3.44(m, 1H), 2.18(m, 2H), 2.01(m, 2H), 1.91(m, 2H), 1.77(m, 2H).

[0412] LC-MS, m / z 432[M+H] +

[0413] Example 11

[0414] 11.1 3-Fluoro-5-(1H-pyrazol-4-yl)benzonitrile

[0415]

[0416] The title compound (360 mg, 29%) was obtained by the same procedure as in Example 1.1 using 3-bromo-5-fluorobenzonitrile (1.3 g, 6.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 10 mmol), 2M K2CO3 aqueous solution (12 mL, 24 mmol), Pd(dppf)Cl2 (240 mg, 0.33 mmol) and dioxane (24 mL).

[0417] LC-MS, m / z 188 [M+H] +

[0418] 11.2 (3-Fluoro-5-(1H-pyrazol-4-yl)phenyl)methanamine

[0419]

[0420] By the same procedure as in Example 7.2, using 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (247 mg, 1.3 mmol), LAH solution (2.0 M in THF, 1.3 mL, 2.6 mmol) and THF (4 mL), the title compound (364 mg, crude) was obtained.

[0421] LC-MS, m / z 192 [M+H] +

[0422] 11.3 8-Cyclopentyl-N-(3-fluoro-5-(1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0423]

[0424] The title compound (136 mg, 21%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1H-pyrazol-4-yl)phenyl)methanamine (364 mg, crude), 8-cyclopentyl-7H-purine-6-carboxylic acid (364 mg, 1.6 mmol), T3P (50 wt% solution in EtOAc, 2.8 mL, 4.8 mmol), DIPEA (1.0 mL, 6.3 mmol) and EtOAc (15 mL).

[0425] 1 H NMR (400MHz, DMSO-d6) δ13.14(s, 1H), 12.98(s, 1H), 9.72(s, 1H), 8.94(s , 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.33 (d, J=9.8Hz, 1H), 6.97 ( d, J=9.6Hz, 1H), 4.55 (d, J=6.2Hz, 2H), 3.45 (d, J=8.2Hz, 1H), 2.05 (d, J= 8.3Hz, 2H), 1.90 (dd, J=12.4, 7.4Hz, 2H), 1.78 (s, 2H), 1.68-1.60 (m, 2H).

[0426] LC-MS, m / z 406[M+H] +

[0427] Example 12

[0428] 12.1 3-Fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzonitrile

[0429]

[0430] 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (100 mg, 0.53 mmol), 4-iodopyridine (219 mg, 1.0 mmol), CuI (10 mg, 0.053 mmol), K CO (220 mg, 1.6 mmol) and NMP (1 mL) were added to a sealed tube for microwave use and stirred at 150° C. for 4 hours. After confirming that compound 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile was completely consumed by LC-MS, the mixture was quenched with saturated NaHCO aqueous solution, extracted three times with DCM (1% MeOH), and the organic layer was dried over Na SO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 50% EtOAc in normal hexane) to obtain the title compound (41 mg, 29%).

[0431] 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.87 (d, J = 10.6Hz, 1H), 7.58 (d, J = 8.1Hz, 1H).

[0432] LC-MS, m / z 265 [M+H] +

[0433] 12.2(3-Fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine

[0434]

[0435] The title compound (42 mg, crude) was obtained by the same procedure as in Example 7.2 using 3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzonitrile (41 mg, 0.16 mmol), LAH solution (2.0 M in THF, 0.16 mL, 0.31 mmol) and THF (1 mL).

[0436] LC-MS, m / z 265 [M+H] +

[0437] 12.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0438]

[0439] The title compound (5 mg, 7%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine (42 mg, crude), 8-cyclopentyl-7H-purine-6-carboxylic acid (36 mg, 0.16 mmol), T3P (50 wt% solution in EtOAc, 280 μL, 0.47 mmol), DIPEA (110 μL, 0.63 mmol) and EtOAc (3 mL).

[0440] 1H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.80 (s, 1H), 9.25 (s, 1H), 8.93 (s, 1H), 8.66 (d, J=6.2Hz, 2H), 8.37 (s, 1H), 7.87 (d, J=6.2Hz, 2H), 7.60 (s, 1H), 7.49 (d , J=9.6Hz, 1H), 7.09 (d, J=9.4Hz, 1H), 4.60 (d, J=6.4Hz, 2H), 3.48-3.43 (m, 1H ), 2.09-2.01(m, 2H), 1.94-1.87(m, 2H), 1.81-1.73(m, 2H), 1.67-1.59(m, 2H).

[0441] LC-MS, m / z 483 [M+H] +

[0442] Example 13

[0443] 8-Cyclopentyl-N-(3-fluorobenzyl)-7H-purine-6-carboxamide

[0444]

[0445] By the same procedure as in Example 1.3, using 8-cyclopentyl-7H-purine-6-carboxylic acid (114 mg, 0.49 mmol), (3-fluorophenyl)methanamine (100 mg, 0.49 mmol), T3P (50 wt% solution in EtOAc, 2.87 mmol) and DIPEA (206 μL, 1.18 mmol) to obtain the title compound (130 mg, 78%) as a white solid.

[0446] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.36 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.16 (d, J = 12Hz, 1H), 6.99 (m, 1H), 4.68 (s, 2H), 3.49 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0447] LC-MS, m / z 340 [M+H] +

[0448] Example 14

[0449] N-(3-Bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0450]

[0451] The title compound (250 mg, 92%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (150 mg, 0.65 mmol), (3-bromo-5-fluorophenyl)methanamine (158 mg, 0.77 mmol), T3P (50 wt% solution in EtOAc, 1.21 g, 3.81 mmol) and DIPEA (272 μL, 1.56 mmol).

[0452] 1 H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 7.42 (m, 1H), 7.25 (d, J=8.0Hz, 1H), 7.18 (d, J=12H z, 1H), 4.65 (s, 2H), 3.49 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0453] LC-MS, m / z 419[M+H] +

[0454] Example 15

[0455] 15.1 3-Fluoro-5-(phenylamino)benzonitrile

[0456]

[0457] By the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), aniline (100 mg, 1.07 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL) the title compound was obtained as a white solid (200 mg, 94%).

[0458] LC-MS, m / z 213 [M+H] +

[0459] 15.23-(Aminomethyl)-5-fluoro-N-phenylaniline

[0460]

[0461] By the same procedure as in Example 1.2, using 3-fluoro-5-(phenylamino)benzonitrile (200 mg, 0.94 mmol) and LAH solution (2.0 M in THF, 0.94 mL), the title compound (140 mg, 69%) was obtained as an oil.

[0462] LC-MS, m / z 217 [M+H] +

[0463] 15.3 8-Cyclopentyl-N-(3-fluoro-5-(phenylamino)benzyl)-7H-purine-6-carboxamide

[0464]

[0465] The title compound (50 mg, 84%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (32 mg, 0.14 mmol), 3-(aminomethyl)-5-fluoro-N-phenylaniline (30 mg, 0.14 mmol), T3P (propylphosphonic anhydride, 50 wt% solution in EtOAc, 266 mg, 0.42 mmol) and DIPEA (N,N-diisopropylethylamine, 57 μL, 0.34 mmol).

[0466] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.19 (m, 2H), 7.08 (d, J=8.0Hz, 2H), 6.87 (m, 2H), 6.64 (d, J=8.0Hz, 1H), 6.56 (d, J=12Hz, 1H), 4.59 (s, 2H), 3.48-3.46 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H).

[0467] LC-MS, m / z 431[M+H] +

[0468] Example 16

[0469] 16.1 3-Fluoro-5-(pyridin-4-ylamino)benzonitrile

[0470]

[0471] By the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), pyridin-4-amine (100 mg, 1.07 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL) the title compound (182 mg, 85%) was obtained as a white solid.

[0472] LC-MS, m / z 214 [M+H] +

[0473] 16.2 N-(3-(Aminomethyl)-5-fluorophenyl)pyridin-4-amine

[0474]

[0475] By the same procedure as in Example 1.2, using 3-fluoro-5-(pyridin-4-ylamino)benzonitrile (160 mg, 0.75 mmol) and LAH solution (lithium aluminum hydride, 2.0 M in THF, 0.75 mL), the title compound (130 mg, 88%) was obtained as an oil.

[0476] LC-MS, m / z 218 [M+H] +

[0477] 16.3 8-Cyclopentyl-N-(3-fluoro-5-(pyridin-4-ylamino)benzyl)-7H-purine-6-carboxamide

[0478]

[0479] The title compound (40 mg, 51%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (42 mg, 0.18 mmol), N-(3-(aminomethyl)-5-fluorophenyl)pyridin-4-amine (40 mg, 0.18 mmol), T3P (50 wt% solution in EtOAc, 355 mg, 0.56 mmol) and DIPEA (76 μL, 0.45 mmol).

[0480] 1H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.11 (d, J = 4.0Hz, 2H), 7.09 (s, 1H), 6.98 (d, J = 8.0Hz, 2H), 6.87 ( d, J=12Hz, 2H), 4.66 (s, 2H), 3.48-3.46 (m, 1H), 2.19 (m, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H).

[0481] LC-MS, m / z 432 [M+H] +

[0482] Example 17

[0483] 17.1 3-Fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzonitrile

[0484]

[0485] The title compound (80 mg, 29%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 3-(trifluoromethyl)aniline (177 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0486] LC-MS, m / z 281[M+H] +

[0487] 17.2 3-(Aminomethyl)-5-fluoro-N-(3-(trifluoromethyl)phenyl)aniline

[0488]

[0489] By the same procedure as in Example 1.2, using 3-fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzonitrile (80 mg, 0.29 mmol) and LAH solution (2.0 M in THF, 0.29 mL), the title compound (50 mg, 62%) was obtained as an oil.

[0490] LC-MS, m / z 285 [M+H] +

[0491] 17.3 8-Cyclopentyl-N-(3-fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0492]

[0493] The title compound (30 mg, 37%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (37 mg, 0.16 mmol), 3-(aminomethyl)-5-fluoro-N-(3-(trifluoromethyl)phenyl)aniline (45 mg, 0.16 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[0494] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.33-7.26 (m, 3H), 7.08 (d, J=8.0Hz, 1H), 6.96 (s, 1H), 6.70-6 .66 (m, 2H), 4.62 (s, 2H), 3.50-3.46 (m, 1H), 2.19 (m, 2H), 2.02 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0495] LC-MS, m / z 499[M+H] +

[0496] Example 18

[0497] 18.1 3-((4-(Dimethylamino)phenyl)amino)-5-fluorobenzonitrile

[0498]

[0499] The title compound (210 mg, 82%) was obtained as a white solid by the same method as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), N1,N1-dimethylbenzene-1,4-diamine (150 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL). LC-MS, m / z 256 [M+H] +

[0500] 18.2 N-1-(3-(aminomethyl)-5-fluorophenyl)-N4,N4-dimethylbenzene-1,4-diamine

[0501]

[0502] By the same procedure as in Example 1.2, using 3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzonitrile (100 mg, 0.39 mmol) and LAH solution (lithium aluminum hydride, 2.0 M in THF, 0.39 mL), the title compound (80 mg, 79%) was obtained as an oil.

[0503] LC-MS, m / z 260 [M+H] +

[0504] 18.3 8-Cyclopentyl-N-(3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzyl)-7H-purine-6-carboxamide

[0505]

[0506] The title compound (31 mg, 44%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (35 mg, 0.15 mmol), N1-(3-(aminomethyl)-5-fluorophenyl)-N4,N4-xylene-1,4-diamine (40 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol), and DIPEA (N,N-diisopropylethylamine, 66 μL, 0.39 mmol).

[0507] 1 H NMR (400MHz, CD3OD) δ8.93 (s, 1H), 7.97 (s, 1H), 6.96 (m, 2H), 6.66 (m, 2H), 6.40 (m, 2H), 4.53 (s, 2H) , 3.46-3.44(m, 1H), 2.98(s, 3H), 2.85(s, 3H), 2.19(m, 2H), 2.01(m, 2H), 1.90(m, 2H), 1.76(m, 2H).

[0508] LC-MS, m / z 474 [M+H] +

[0509] Example 19

[0510] 19.1 3-Fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzonitrile

[0511]

[0512] The title compound (280 mg, 96%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 4-(methylsulfonyl)aniline (188 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0513] LC-MS, m / z 291[M+H] +

[0514] 19.2 3-(Aminomethyl)-5-fluoro-N-(4-(methylsulfonyl)phenyl)aniline

[0515]

[0516] By the same procedure as in Example 1.2, using 3-fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzonitrile (100 mg, 0.34 mmol) and LAH solution (2.0 M in THF, 0.34 mL), the title compound (72 mg, 82%) was obtained as an oil.

[0517] LC-MS, m / z 295 [M+H] +

[0518] 19.3 8-Cyclopentyl-N-(3-fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0519]

[0520] The title compound (32 mg, 45%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (35 mg, 0.15 mmol), 3-(aminomethyl)-5-fluoro-N-(4-(methylsulfonyl)phenyl)aniline (40 mg, 0.14 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[0521] 1H NMR (400MHz, CD3OD) δ8.94 (s, 1H), 7.69 (d, J=8Hz, 2H), 7.17 (d, J=8Hz, 2H), 7.05 (s, 1H), 6.78 (m, 2H ), 4.63 (s, 2H), 3.49-3.45 (m, 1H), 3.02 (s, 3H), 2.18 (m, 2H), 2.00 (m, 2H), 1.90 (m, 2H), 1.76 (m, 2H).

[0522] LC-MS, m / z 509 [M+H] +

[0523] Example 20

[0524] 20.1 3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzonitrile

[0525]

[0526] The title compound (100 mg, 38%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 4-chloro-2-fluoroaniline (160 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0527] LC-MS, m / z 265 [M+H] +

[0528] 20.2 N-(3-(Aminomethyl)-5-fluorophenyl)-4-chloro-2-fluoroaniline

[0529]

[0530] By the same procedure as in Example 1.2, using 3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzonitrile (90 mg, 0.34 mmol) and LAH solution (2.0 M in THF, 0.34 mL), the title compound (50 mg, 55%) was obtained as an oil.

[0531] LC-MS, m / z 269[M+H] +

[0532] 20.3 N-(3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0533]

[0534] The title compound (60 mg, 83%) was obtained as a white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (35 mg, 0.15 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-4-chloro-2-fluoroaniline (40 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[0535] 1 H NMR (400MHz, CD3OD) δ8.92 (s, 1H), 7.24 (t, J=8.0Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 6.8 2(s, 1H), 6.58(m, 2H), 4.58(s, 2H), 3.48-3.41(m, 1H), 2.16(m, 2H), 2.00(m, 2H), 1.89(m, 2H), 1.74(m, 2H).

[0536] LC-MS, m / z 483 [M+H] +

[0537] Example 21

[0538] 21.13-Fluoro-5-((4-fluorophenyl)amino)benzonitrile

[0539]

[0540] The title compound (90 mg, 36%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 4-fluoroaniline (122 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0541] LC-MS, m / z 231[M+H] +

[0542] 21.23-(Aminomethyl)-5-fluoro-N-(4-fluorophenyl)aniline

[0543]

[0544] By the same procedure as in Example 1.2, using 3-fluoro-5-((4-fluorophenyl)amino)benzonitrile (90 mg, 0.34 mmol) and LAH solution (2.0 M in THF, 0.34 mL), the title compound (20 mg, 22%) was obtained as an oil.

[0545] LC-MS, m / z 235 [M+H] +

[0546] 21.3 8-Cyclopentyl-N-(3-fluoro-5-((4-fluorophenyl)amino)benzyl)-7H-purine-6-carboxamide

[0547]

[0548] The title compound (8 mg, 28%) was obtained as a viscous oil by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (15 mg, 0.06 mmol), 3-(aminomethyl)-5-fluoro-N-(4-fluorophenyl)aniline (15 mg, 0.06 mmol), T3P (50 wt% solution in EtOAc, 124 mg, 0.20 mmol) and DIPEA (27 μL, 0.16 mmol).

[0549] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.07 (m, 2H), 6.93 (t, J=8.0Hz, 2H), 6.80 (s, 1H), 6.53 (t, J= 8.0Hz, 2H) 4.58 (s, 2H), 3.50-3.46 (m, 1H), 2.19 (m, 2H), 2.01 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0550] LC-MS, m / z 449[M+H] +

[0551] Example 22

[0552] 22.1 N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide

[0553]

[0554] To a solution of N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (30 mg, 0.072 mmol) in THF (1 mL) was added NaH (60% dispersion in mineral oil) (4 mg, 0.11 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was cooled to 0°C, (2-(chloromethoxy)ethyl)trimethylsilane (19 μL, 0.11 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with H2O, extracted three times with EtOAc, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 30% EtOAc in n-hexane) to obtain the title compound (25 mg, 64%).

[0555] 1 H NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8.15-8.09 (m, 2 H), 7.68-7.63 (m, 2H), 7.57 (s, 1H), 7.34 (d, J=9.2Hz, 1H), 7.12 (d, J=9.7Hz, 1H) ,5.74(s,2H),4.78(s,2H),3.66-3.56(m,3H),2.19-2.12(m,2H),2.07-2.00(m, 2H), 1.84-1.77(m, 2H), 1.74-1.67(m, 2H), 0.91(t, J=8.0Hz, 2H), -0.07(s, 9H).

[0556] LC-MS, m / z 637[M+H] +

[0557] 22.2 N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide

[0558]

[0559] The title compound (12 mg, 52%) was obtained by the same procedure as in Example 4.1 using N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide (20 mg, 0.037 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile (16 mg, 0.055 mmol), 2M aqueous K2CO3 solution (0.07 mL, 0.128 mmol), PdCl2(dppf) (1 mg, 0.002 mmol) and 1,4-dioxane (1 mL).

[0560] 1 H NMR (400MHz, CD3OD) δ8.99 (s, 1H), 8.76 (s, 1H), 8.19 (s, 1H), 8.15-8.09 (m, 2H) , 7.68-7.63 (m, 2H), 7.57 (s, 1H), 7.34 (d, J = 9.2Hz, 1H), 7.12 (d, J = 9.7Hz, 1H), 5.74(s, 2H), 4.78(s, 2H), 3.66-3.56(m, 3H), 2.19-2.12(m, 2H), 2.07-2.00(m, 2H), 1.84-1.77(m, 2H), 1.74-1.67(m, 2H), 0.91(t, J=8.0Hz, 2H), -0.07(s, 9H).

[0561] LC-MS, m / z 637[M+H] +

[0562] Example 23

[0563] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0564]

[0565] To a solution of N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide (10 mg, 0.016 mmol) in EtOH (2 mL) was added 2N aqueous HCl solution (0.4 mL, 0.39 mmol), and the mixture was stirred at 80 ° C for 4 hours. The reaction solution was neutralized with 2N NaOH aqueous solution, and EtOH was evaporated. The reaction mixture was diluted with H O, extracted three times with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (6 mg, 75%).

[0567] 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 9.76 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.33 (d, J = 9.9Hz, 2H), 8.22 (d, J = 7.5Hz, 1H), 7.80-7.71 (m, 2H), 7.5 8 (s, 1H), 7.46 (d, J = 10.1Hz, 1H), 7.10-7.04 (m, 1H), 4.59 (d, J = 6.2Hz, 2H ), 3.51-3.44(m, 1H), 2.05(s, 2H), 1.91(s, 2H), 1.78(s, 2H), 1.64(s, 2H) -

[0568] LC-MS, m / z 507 [M+H] +

[0569] Example 24

[0570] 24.13-Fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzonitrile

[0571]

[0572] To a solution of 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (65 mg, 0.35 mmol) in 1,4-dioxane (2 mL) was added NaH (60% dispersion in mineral oil) (17 mg, 0.70 mmol) at 0°C, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was cooled to 0°C, 1-(bromomethyl)-4-(methylsulfonyl)benzene (173 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with H2O, extracted three times with EtOAc, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 50% EtOAc in n-hexane) to obtain the title compound (110 mg, 89%).

[0573] LC-MS, m / z 356 [M+H] +

[0574] 24.2(3-Fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0575]

[0576] The title compound (40 mg, 36%) was obtained by the same procedure as in Example 7.2 using 3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzonitrile (110 mg, 0.31 mmol), LAH solution (2.0 M in THF, 310 μL, 0.62 mmol) and THF (1 mL).

[0577] LC-MS, m / z 360[[M+H] +

[0578] 24.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0579]

[0580] The title compound (12 mg, 23%) was obtained by the same procedure as in Example 1.3 using 3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzonitrile (40 mg, 0.11 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (22 mg, 0.093 mmol), T3P (50 wt% solution in EtOAc, 830 μL, 0.28 mmol), DIPEA (40 μL, 0.23 mmol) and EtOAc (1 mL).

[0581] 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 9.74 (s, 1H), 8.94 (s, 1H), 8.36 (s, 1H), 7. 97 (s, 1H), 7.89 (d, J = 8.2Hz, 2H), 7.47-7.42 (m, 3H), 7.32 (d, J = 10.1Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 5.46 (s, 2H), 4.55 (d, J=5.8Hz, 2H), 3.46 (s, 1H), 3.17 (s, 3H), 2 .05 (d, J=10.3Hz, 2H), 1.91 (d, J=7.7Hz, 2H), 1.78 (s, 2H), 1.63 (d, J=5.1Hz, 2H).

[0582] LC-MS, m / z 574 [M+H] +

[0583] Example 25

[0584] 25.1 tert-Butyl 3-bromo-5-fluorobenzylcarbamate

[0585]

[0586] By the same procedure as in Example 6.1, using (3-bromo-5-fluorophenyl)methanamine (2 g, 9.802 mmol), (Boc)2O (30% in THF, 4.3 g, 19.6040 mmol) and DCM (20 mL), the title compound (2.95 g, 99%) was obtained as a colorless clear liquid.

[0587] 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.13 (d, J = 8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.92 (broad peak, 1H), 4.29 (d, J = 5.6 Hz, 1H), 1.47 (s, 9H).

[0588] 25. tert-Butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate

[0589]

[0590] To tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5g, 1.64mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazoles (0.48g, 2.47mmol) and Na cO (0.61g, 5.85mmol) add DMF (7.5mL) and H o (3mL), and by mixture N degassed 10 minutes.Then, add Pd(PPh ) (0.095g, 0.082mmol) and reactant mixture is stirred at 140 ℃ and spend the night.To reactant mixture, add ethyl acetate and H o, extract, and by organic layer through MgSO dry and concentrate.Gained residue is passed through silica gel column chromatography (0 to 65% EtOAc in normal hexane) purifying to obtain the title compound (374mg, 78%) as light yellow solid.

[0591] 1 H NMR (400 MHz, CD3OD) δ 7.98 (broad peak, 2H), 7.32 (s, 1H), 7.21 (d, J=9.6 Hz, 1H), 6.85 (d, J=9.2 Hz, 1H), 4.24 (s, 2H), 1.47 (s, 9H).

[0592] LC-MS, m / z 292[M+H] +

[0593] 25. tert-Butyl 3-(3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0594]

[0595] DMSO (1.5 mL) was added to tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 4-iodoanisole (60 mg, 0.26 mmol), CuI (3.3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol) and KCO (35.6 mg, 0.26 mmol), and the mixture was stirred at 110° C. for 8 hours. After the reaction was complete, H O was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to obtain the title compound (59.6 mg, 87%) as a light brown solid.

[0596] 1H NMR (400MHz, CDCl3) δ8.06 (s, 1H), 7.94 (s, 1H), 7.62 (d, J=8.8Hz, 2H), 7.24 (s, 1H), 7.25 (s, 1H), 7.13 (d, J=10Hz, 1H), 7.0 (d, J=8.8Hz, 2H), 6.89 (d, J=9.2Hz, 2H), 4.34 (d, J=5.2Hz, 2H), 3.86 (s, 3H), 1.48 (s, 9H).

[0597] 25.4-(3-Fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0598]

[0599] tert-Butyl (3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)carbamate (57.5 mg, 0.14 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (1.2 mL) was added, and the mixture was stirred at room temperature for one hour. After completion of the reaction, the process of diluting with DCM and concentrating was repeated five times to obtain the title compound (56 mg, crude) as a dark brown viscous liquid.

[0600] LC-MS, m / z 298 [M+H] +

[0601] 25.5 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0602]

[0603] By the same method as in Example 1.3, 8-cyclopentyl-7H-purine-6-carboxylic acid (33.6 mg, 0.14 mmol), (3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (56 mg), T3P (50 wt% solution in EtOAc, 138 mg, 0.43 mmol), DIPEA (110 μ L) and DMF (2 mL) to afford the title compound (27.1 mg, 37% yield in 2 steps) as a light yellow foam.

[0604] 1H NMR (400MHz, DMSO-d6) δ13.18 (1H, broad peak), 9.77 (t, J=6.8Hz, 1H), 8.96 (d, J=11.2Hz, 2H), 8.19 (s, 1H), 7.78 (2H, J=9.2Hz, 2H), 7.58 (s, 1H), 7.47 ( d, J=9.6Hz, 1H), 7.07 (m, 3H), 4.61 (d, J=6.4Hz, 2H), 3.49 (m, 1H), 2.12 -2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0605] LC-MS, m / z 512 [M+H] +

[0606] Example 26

[0607] 26. tert-Butyl (3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0608]

[0609] The title compound (67 mg, 89%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 4-iodobenzotrifluoride (70 mg, 0.26 mmol), CuI (3.3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (35.6 mg, 0.26 mmol) and DMSO (1.5 mL).

[0610] 1 H NMR (400MHz, CDCl3) δ8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.75 (d, J = 8.4Hz, 2H), 7.26 (s , 1H), 7.14 (d, J=9.6Hz, 1H), 6.92 (d, J=9.2Hz, 1H), 4.96 (broad peak, 1H), 4.36 (d, J=5.6Hz, 2H), 1.48 (s, 9H).

[0611] 26.2(3-Fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0612]

[0613] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate (62.9 mg, 0.14 mmol), trifluoroacetic acid (1.2 mL) and DCM (4 ml) to obtain the title compound (56 mg, crude) as a dark brown viscous liquid.

[0614] LC-MS, m / z 336[M+H] +

[0615] 26.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0616]

[0617] The title compound (31 mg, 39% yield in 2 steps) was obtained as a light yellow foam by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (34 mg, 0.14 mmol), (3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (63 mg), T3P (50 wt% solution in EtOAc, 138 mg, 0.43 mmol), DIPEA (110 μL) and DMF (2 mL).

[0618] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (1H, broad peak), 9.79 (m, 1H), 9.23 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.52 ( d, J=10Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 4.62 (d, J=6.0Hz, 2H), 3.59-3.43 (m, 1H ), 2.12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0619] LC-MS, m / z 550 [M+H] +

[0620] Example 27

[0621] 27. tert-Butyl 1(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0622]

[0623] The title compound (345 mg, 87%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (300 mg, 1.03 mmol), 1-fluoro-4-iodobenzene (343 mg, 1.54 mmol), CuI (20 mg, 0.103 mmol), L-proline (24 mg, 0.206 mmol), K2CO3 (214 mg, 1.54 mmol) and DMSO (3 mL).

[0624] 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.96 (s, 1H), 7.69 (dd, J=8.8, 4.4Hz, 2H), 7.24 (s, 1H), 7.18 (t, J=8 Hz, 2H), 7.13 (d, J=9.6Hz, 1H), 6.90 (d, J=8.8Hz, 1H), 4.93 (s, 1H), 4.35 (d, J=5.6Hz, 2H), 1.48 (s, 9H).

[0625] LC-MS, m / z 386[M+H] +

[0626] 27.2(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0627]

[0628] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate (345 mg, 0.89 mmol), trifluoroacetic acid (3 mL) and DCM (9 ml), the title compound was obtained as an off-white solid (350 mg, crude).

[0629] LC-MS, m / z 286[M+H] +

[0630] 27.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0631]

[0632] 8-Cyclopentyl-7H-purine-6-carboxylic acid (208 mg, 0.89 mmol), (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (350 mg, crude) and T3P (50 wt% solution in EtOAc, 850 mg, 2.67 mmol) were dissolved in DMF (4.5 mL), DIPEA (690 μL) was added, and stirred at room temperature overnight. Ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 3% MeOH in DCM) to give the title compound (319 mg, 71% yield in 2 steps) as a light yellow foam.

[0633] 1 H NMR (400 MHz, DMSO-d6) δ 13.2 (1H, broad), 9.77 (t, J = 5.6 Hz, 1H), 9.04 (s, 1H), 8.98 (s, 1H), 8.25 (s, 1H), 7.91 (dd, J = 9.2, 4.8 Hz, 2H), 7.59 (s, 1H), 7.48 (d, J = 9.6 Hz, 1H). H), 7.39 (t, J=8.8Hz, 2H), 7.08 (d, J=9.6Hz, 1H), 4.61 (d, J=6.4Hz, 2H), 3.49 (m, 1H), 2.12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0634] LC-MS, m / z 500[M+H] +

[0635] Example 28

[0636] 28. tert-Butyl (3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0637]

[0638] The title compound (59 mg, 78%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 4-bromophenylmethylsulfone (60.5 mg, 0.26 mmol), CuI (3.3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (35.6 mg, 0.26 mmol) and DMSO (1.5 mL).

[0639] 1 H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 8.07 (d, J = 8.8Hz, 2H), 8.03 (s, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.15 ( d, J=9.2Hz, 1H), 6.94 (d, J=9.6Hz, 1H), 4.96 (s, broad peak), 4.36 (d, J=6Hz, 2H), 3.11 (s, 3H), 1.49 (s, 9H).

[0640] 28.2(3-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0641]

[0642] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate (56 mg, 0.13 mmol), trifluoroacetic acid (0.43 mL) and DCM (1.3 ml) the title compound (58 mg, crude) was obtained.

[0643] LC-MS, m / z 346[M+H] +

[0644] 28.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0645]

[0646] The title compound was obtained as a white solid (56 mg, 80% yield in 2 steps) by the same procedure as in Example 27.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (30 mg, 0.13 mmol), T3P (50 wt% solution in EtOAc, 120 mg, 0.38 mmol), (3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (58 mg), DIPEA (96 μL, 0.57 mmol) and DMF (3 mL).

[0647] 1 H NMR (400MHz, DMSO-d6) δ13.18 (1H, brs), 9.79 (t, J=6.4Hz, 1H), 9.26 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.15 (d, J=8.4Hz, 2H), 8.09 (d, J=8.4Hz, 2H), 7.62 (s, 1H), 7. 52 (d, J = 10Hz, 1H), 7.10 (d, J = 10Hz, 1H), 4.61 (d, J = 6Hz, 2H), 3.50 (m, 1H), 3.27 (s , 3H), 2.12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0648] LC-MS, m / z 560 [M+H] +

[0649] Example 29

[0650] 29.13-Fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzonitrile

[0651]

[0652] The title compound (86 mg, 72%) was obtained by the same procedure as in Example 24.1 using 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (65 mg, 0.35 mmol), NaH (60% dispersion in mineral oil) (17 mg, 0.70 mmol) and 1,4-dioxane (2 mL).

[0653] LC-MS, m / z 346[M+H] +

[0654] 29.2(3-Fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0655]

[0656] The title compound (50 mg, 57%) was obtained by the same procedure as in Example 7.2 using 3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzonitrile (86 mg, 0.25 mmol), LAH solution (2.0 M in THF, 250 μL, 0.50 mmol) and THF (1 mL).

[0657] LC-MS, m / z 350 [M+H] +

[0658] 29.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0659]

[0660] The title compound (5.7 mg, 8%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)phenyl)methanamine (50 mg, 0.14 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (28 mg, 0.12 mmol), T3P (50 wt% solution in EtOAc, 213 μL, 0.36 mmol), DIPEA (51 μL, 0.30 mmol) and DMF (2 mL).

[0661] 1 H NMR (400MHz, DMSO-d6) δ13.14 (s, 1H), 9.73 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.9 6 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.57 (d, J=7.5Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7 .42 (s, 1H), 7.32 (d, J=9.9Hz, 1H), 6.99 (d, J=9.6Hz, 1H), 5.44 (s, 2H), 4.55 (d, J=6 .1Hz, 2H), 3.48-3.43(m, 1H), 2.04(s, 2H), 1.90(s, 2H), 1.78(s, 2H), 1.63(s, 2H).

[0662] LC-MS, m / z 564 [M+H] +

[0663] Example 30

[0664] 30.1 3-Fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzyl

[0665]

[0666] The title compound (62 mg, 88%) was obtained by the same procedure as in Example 25.3 using 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (50 mg, 0.27 mmol), 2-iodopyridine (66 mg, 0.32 mmol), CuI (1 mg, 0.0053 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (7 μL, 0.053 mmol), K2CO3 (78 mg, 0.56 mmol) and 1,4-dioxane (3 mL).

[0667] LC-MS, m / z 265 [M+H] +

[0668] 30.2(3-Fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)phenyl)methanamine

[0669]

[0670] By the same procedure as in Example 7.2, using 3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile (62 mg, 0.24 mmol), LAH solution (2.0 M in THF, 0.24 mL, 0.47 mmol) and THF (1 mL), the title compound (66 mg, crude) was obtained, which was used in the next reaction without isolation and purification.

[0671] LC-MS, m / z 269[M+H] +

[0672] 30.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0673]

[0674] The same method as in Example 1.3 was used, using (3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)phenyl)methanamine (66 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (57 mg, 0.25 mmol), T3P (EtOAc) and 4-nitropropane. cThe title compound (7 mg, 6%) was obtained from a 50 wt% solution in 4% paraformaldehyde (5%, 1.8 mL, 0.74 mmol), DIPEA (110 μL, 0.62 mmol) and DMF (2 mL).

[0675] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.79 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H) , 8.51 (d, J=4.3Hz, 1H), 8.35 (s, 1H), 8.05-7.95 (m, 2H), 7.70 (s, 1H), 7.59 (d , J=10.3Hz, 1H), 7.43-7.37 (m, 1H), 7.08 (d, J=9.5Hz, 1H), 4.61 (d, J=6.1Hz, 2H), 3.52-3.46(m, 1H), 2.07(m, 2H), 1.94(m, 2H), 1.80(m, 2H), 1.66(m, 2H).

[0676] LC-MS, m / z 483 [M+H] +

[0677] Example 31

[0678] 31. tert-Butyl (3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0679]

[0680] The title compound (291 mg, 77%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (300 mg, 1.0 mmol), 3-iodopyridine (320 mg, 1.5 mmol), CuI (20 mg, 0.10 mmol), L-proline (24 mg, 0.21 mmol), K2CO3 (213 mg, 1.5 mmol) and DMSO (5 mL).

[0681] LC-MS, m / z 369[M+H] +

[0682] 31.2(3-Fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0683]

[0684] By the same method as in Example 25.4, tert-butyl 3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (291 mg, 0.79 mmol), TFA (3 mL) and DCM (7 mL) were used to obtain the title compound (300 mg), which was used in the next reaction without isolation and purification.

[0685] LC-MS, m / z 269[M+H] +

[0686] 31.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0687]

[0688] The title compound (210 mg, 56%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (300 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (180 mg, 0.79 mmol), T3P (50 wt% solution in EtOAc, 1.4 mL, 2.4 mmol), DIPEA (0.6 mL, 3.6 mmol) and DMF (3.5 mL).

[0689] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.80 (s, 1H), 9.20-9.13 (m, 2H), 8.98 ( s, 1H), 8.56 (d, J=4.5Hz, 1H), 8.34 (s, 1H), 8.27 (d, J=8.4Hz, 1H), 7.64-7.55 ( m, 2H), 7.50 (d, J = 10.3Hz, 1H), 7.10 (d, J = 8.9Hz, 1H), 4.62 (d, J = 5.9Hz, 2H), 3.55-3.46 (m, 1H), 2.07 (s, 2H), 1.97-1.89 (m, 2H), 1.81 (s, 2H), 1.66 (s, 2H).

[0690] LC-MS, m / z 483 [M+H] +

[0691] Example 32

[0692] 32. tert-Butyl 1(3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0693]

[0694] The title compound (59 mg, 92%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 5-iodopyrimidine (41 mg, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0695] LC-MS, m / z 370 [M+H] +

[0696] 32.2-(3-Fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0697]

[0698] By the same method as in Example 25.4, tert-butyl 3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzylcarbamate (57 mg, 0.15 mmol), TFA (0.7 mL) and DCM (2 mL) were used to obtain the title compound (61 mg, crude), which was used in the next reaction without isolation and purification.

[0699] LC-MS, m / z 270 [M+H] +

[0700] 32.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0701]

[0702] The same method as in Example 1.3 was used, using (3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (59 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (36 mg, 0.15 mmol), T3P (EtOAc) and 1H-pyrazole-4-yl)phenyl. c The title compound (44 mg, 59%) was obtained by mixing a 50 wt% solution in 4% paraformaldehyde (5%, 280 μL, 0.47 mmol), DIPEA (120 μL, 0.70 mmol) and DMF (2 mL).

[0703] 1H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 9.77 (t, J=6.1Hz, 1H), 9.32 (s, 2H), 9.16 (d, J=16.5Hz, 2H), 8.96 (s, 1H), 8.39 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=9.5Hz, 1H), 7.09 (d, J=9.2Hz, 1H), 4.60 (d, J=6.1Hz, 2H), 3.52-3.44 (m , 1H), 2.04 (s, 2H), 1.94-1.87 (m, 2H), 1.78 (s, 2H), 1.63 (d, J=4.8Hz, 2H).

[0704] LC-MS, m / z 484 [M+H] +

[0705] Example 33

[0706] 33.1 3-Fluoro-5-((2-methoxyphenyl)amino)benzonitrile

[0707]

[0708] The title compound (80 mg, 30%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 2-methoxyaniline (135 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0709] LC-MS, m / z 243 [M+H] +

[0710] 33.23-(Aminomethyl)-5-fluoro-N-(2-methoxyphenyl)aniline

[0711]

[0712] By the same procedure as in Example 1.2, using 3-fluoro-5-((2-methoxyphenyl)amino)benzonitrile (80 mg, 0.33 mmol) and LAH solution (2.0 M in THF, 0.33 mL), the title compound (55 mg, 68%) was obtained as an oil.

[0713] LC-MS, m / z 247 [M+H] +

[0714] 33.3 8-Cyclopentyl-N-(3-fluoro-5,4-(2-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0715]

[0716] The title compound (40 mg, 72%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (28 mg, 0.12 mmol), 3-(aminomethyl)-5-fluoro-N-(2-methoxyphenyl)aniline (30 mg, 0.12 mmol), T3P (50 wt% solution in EtOAc, 244 mg, 0.39 mmol) and DIPEA (27 μL, 0.31 mmol).

[0717] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.22 (d, J=8Hz, 1H), 6.94-6.86 (m, 3H), 6.75 (t, J=8.0Hz, 1H), 6.63 (d, J=12Hz, 1H), 6.56 (d, J=12Hz, 1H), 4.59 (s, 2H), 3.83 (s, 3H), 3.50-3.46 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0718] LC-MS, m / z 461[M+H] +

[0719] Example 34

[0720] 34.1 3-Fluoro-5,4-(3-methoxyphenyl)amino)benzonitrile

[0721]

[0722] The title compound (110 mg, 45%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 3-methoxyaniline (135 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0723] LC-MS, m / z 243 [M+H] +

[0724] 34.2 3-(Aminomethyl)-5-fluoro-N-(3-methoxyphenyl)aniline

[0725]

[0726] By the same procedure as in Example 1.2, using 3-fluoro-5-((3-methoxyphenyl)amino)benzonitrile (110 mg, 0.45 mmol) and LAH solution (2.0 M in THF, 0.45 mL), the title compound (70 mg, 63%) was obtained as an oil.

[0727] LC-MS, m / z 247 [M+H] +

[0728] 34.3 8-Cyclopentyl-N-(3-fluoro-5-((3-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0729]

[0730] The title compound (50 mg, 60%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (42 mg, 0.18 mmol), 3-(aminomethyl)-5-fluoro-N-(3-methoxyphenyl)aniline (45 mg, 0.18 mmol), T3P (50 wt% solution in EtOAc, 366 mg, 0.59 mmol) and DIPEA (80 μL, 0.92 mmol).

[0731] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.06 (t, J=8Hz, 1H), 6.91 (s, 1H), 6.65-6.61 (m, 3H), 6.57 (d, J=8.0Hz, 1H), 6.43 (d, J=8.0Hz, 1H), 4.60 (s, 2H), 3.65 (s, 3H), 3.50-3.46 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0732] LC-MS, m / z 461[M+H] +

[0733] Example 35

[0734] 35.1 3-Fluoro-5-((3-methoxyphenyl)amino)benzonitrile

[0735]

[0736] The title compound (130 mg, 53%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 4-methoxyaniline (135 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0737] LC-MS, m / z 243 [M+H] +

[0738] 34.2 3-(Aminomethyl)-5-fluoro-N-(4-methoxyphenyl)aniline

[0739]

[0740] By the same procedure as in Example 1.2, using 3-fluoro-5-((4-methoxyphenyl)amino)benzonitrile (100 mg, 0.41 mmol) and LAH solution (2.0 M in THF, 0.41 mL), the title compound (55 mg, 54%) was obtained as an oil.

[0741] LC-MS, m / z 247 [M+H] +

[0742] 35.3 8-Cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0743]

[0744] The title compound (45 mg, 67%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (34 mg, 0.15 mmol), 4-(aminomethyl)-5-fluoro-N-(3-methoxyphenyl)aniline (37 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 300 mg, 0.48 mmol) and DIPEA (80 μL, 0.75 mmol).

[0745] 1H NMR (400MHz, CD3OD) δ8.94 (s, 1H), 7.03 (d, J=8Hz, 2H), 6.78 (d, J=12Hz, 2H), 6.70 (s, 1H), 6.46 (d, J=12H z, 2H), 4.56 (s, 2H), 3.71 (s, 3H), 3.50-3.46 (m, 1H), 2.19 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H).

[0746] LC-MS, m / z 461[M+H] +

[0747] Example 36

[0748] 8-Cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7-methyl-7H-purine-6-carboxamide

[0749]

[0750] 8-Cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide (20 mg, 0.043 mmol) was dissolved in DMF (1 mL), CH 1 (2.7 μL, 0.043 mmol) and K CO (30 mg, 0.22 mmol) were added, and the mixture was stirred at 40° C. for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and the solid was removed by filtration. After the filtrate was concentrated, the resulting residue was purified by silica gel column chromatography (CH Cl 0 to 5% MeOH) to obtain the title compound (16 mg, 78%) as a white solid.

[0751] 1 H NMR (400MHz, CD3OD) δ8.93 (s, 1H), 7.03 (d, J=8Hz, 2H), 6.78 (m, 3H), 6.52 (m, 2H), 4.61 (s, 2H), 3 .87(s, 3H), 3.74(s, 3H), 3.55-3.51(m, 1H), 2.15(m, 2H), 2.00(m, 2H), 1.83(m, 2H), 1.73(m, 2H).

[0752] LC-MS, m / z 475 [M+H] +

[0753] Example 37

[0754] N-(3-(1-(3-Carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0755]

[0756] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (Example 23) (40 mg, 0.079 mmol) was dissolved in DMSO (2 mL), and KCO (22 mg, 0.16 mmol) and HO (35% aqueous solution, 105 μL) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with HO, extracted three times with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 10% MeOH in DCM) to obtain the title compound (33 mg, 81%).

[0757] 1 H NMR (400MHz, DMSO-d6) δ13.18 (1H, broad peak), 9.78 (t, J=6.4Hz, 1H), 9.14 (s, 1H).8.98 ( s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8.4Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.63-7.50 (m, 4H), 7.07 (d, J=9.2Hz, 1H), 4.61 (d, J=6.4Hz, 2H), 3.49 (m, 1H), 2.12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0758] LC-MS, m / z 525 [M+H] +

[0759] Example 38

[0760] 38.1 tert-Butyl 3-fluoro-5-(isothiazol-4-yl)benzylcarbamate

[0761]

[0762] The title compound (63 mg, 63%) was obtained as a white solid by the same procedure as in Example 4.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole (104 mg, 0.49 mmol), PdCl2(dppf) (12 mg, 0.016 mmol), 2M K2CO3 aqueous solution (0.085 mL) and 1,4-dioxane (1.5 mL).

[0763] LC-MS, m / z 309[M+H] +

[0764] 38.2-(3-Fluoro-5-(isothiazol-4-yl)phenyl)methanamine, trifluoroacetate

[0765]

[0766] By the same procedure as in Example 25.4, using tert-butyl 3-fluoro-5-(isothiazol-4-yl)benzylcarbamate (61 mg, 0.20 mmol), trifluoroacetic acid (0.7 mL) and DCM (2 mL), the title compound (94 mg, crude) was obtained.

[0767] 38.3 8-Cyclopentyl-N-(3-fluoro-5-(isothiazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0768]

[0769] The title compound (56 mg, 68% yield in 2 steps) was obtained as a white solid by the same procedure as in Example 27.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (46 mg, 0.20 mmol), T3P (50 wt% solution in EtOAc, 189 mg, 0.59 mmol), (3-fluoro-5-(isothiazol-4-yl)phenyl)methanamine, trifluoroacetate (94 mg), DIPEA (151 μL, 0.89 mmol) and DMF (2 mL).

[0770] 1H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.80 (t, J = 6.4Hz, 1H), 9.42 (s, 1H), 9.07 (s, 1H), 8.98 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 10Hz, 1H) , 7.18 (d, J=9.2Hz, 1H), 4.63 (d, J=6Hz, 2H), 3.50 (m, 1H), 2.12-2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0771] LC-MS, m / z 423 [M+H] +

[0772] Example 39

[0773] 39.1 tert-Butyl 3-fluoro-5-(furan-2-yl)benzylcarbamate

[0774]

[0775] By the same procedure as in Example 4.1, using tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (96 mg, 0.49 mmol), PdCl2(dppf) (12 mg, 0.016 mmol), 2M K2CO3 aqueous solution (0.085 mL) and 1,4-dioxane (1.5 mL) to obtain the title compound (53 mg, 55%) as a yellow liquid.

[0776] 39.2(3-Fluoro-5-(furan-2-yl)phenyl)methanamine, trifluoroacetate

[0777]

[0778] By the same procedure as in Example 25.4, using tert-butyl 3-fluoro-5-(furan-2-yl)benzylcarbamate (51 mg, 0.18 mmol), trifluoroacetic acid (0.6 mL) and DCM (1.8 mL), the title compound (41 mg, crude) was obtained.

[0779] 39.3 8-Cyclopentyl-N-(3-fluoro-5-(furan-2-yl)benzyl)-7H-purine-6-carboxamide

[0780]

[0781] The title compound (56 mg, 80% yield in 2 steps) was obtained as a white solid by the same procedure as in Example 27.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (41 mg, 0.20 mmol), (3-fluoro-5-(furan-2-yl)phenyl)methanamine, trifluoroacetate (54 mg), T3P (50 wt% solution in EtOAc, 168 mg, 0.53 mmol), DIPEA (135 μL, 0.79 mmol) and DMF (4 mL).

[0782] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.82 (m, 1H), 8.97 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 9.6Hz, 1H), 7.13 (d, J = 9.2Hz, 1H), 7.04 (d, J=3.2Hz, 1H), 6.62-6.61 (m, 1H), 4.59 (d, J=6.4Hz, 2H), 3.50 (m, 1H), 2.1 2-2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0783] LC-MS, m / z 406[M+H] +

[0784] Example 40

[0785] 40.1 tert-Butyl (3-fluoro-5-(thien-3-yl)benzyl)carbamate

[0786]

[0787] The title compound (60 mg, 59%) was obtained as a light yellow liquid by the same procedure as in Example 4.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (104 mg, 0.49 mmol), PdCl2(dpPf) (12 mg, 0.016 mmol), 2M K2CO3 aqueous solution (0.085 mL) and 1,4-dioxane (1.5 mL).

[0788] 40.2-(3-Fluoro-5-(thiophen-3-yl)phenyl)methylamine, trifluoroacetate

[0789]

[0790] The title compound (63 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(thiophen-3-yl)benzyl)carbamate (60 mg, 0.20 mmol), trifluoroacetic acid (0.67 mL) and DCM (2 mL).

[0791] 40.3 8-Cyclopentyl-N-(3-fluoro-5-(thien-3-yl)benzyl)-7H-purine-6-carboxamide

[0792]

[0793] The title compound (54 mg, 65% yield in 2 steps) was obtained as a white solid by the same procedure as in Example 27.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (46 mg, 0.20 mmol), (3-fluoro-5-(thiophen-3-yl)phenyl)methanamine, trifluoroacetate (63 mg), T3P (50 wt% solution in EtOAc, 188 mg, 0.59 mmol), DIPEA (151 μL, 0.89 mmol) and DMF (2 mL).

[0794] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.80 (t, J=6.8Hz, 1H), 8.97 (s, 1H), 7.94 (m, 1H), 7.66 (m, 1H), 7.60 (s, 1H), 7.56 (d, J=4.4Hz, 1H), 7.47 (d, J =11.2Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 4.60 (d, J = 6Hz, 2H), 3.50 (m, 1H), 2. 12-2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0795] LC-MS, m / z 422[M+H] +

[0796] Example 41

[0797] 41.1 3-Fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzonitrile

[0798]

[0799] The title compound (210 mg, 75%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), 4-(trifluoromethyl)aniline (177 mg, 1.1 mmol), Xantphos (30 mg, 0.05 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), K2CO3 (318 mg, 2.3 mmol) and dioxane (5 mL).

[0800] LC-MS, m / z 281[M+H] +

[0801] 41.2 3-(Aminomethyl)-5-fluoro-N-(4-(trifluoromethyl)phenyl)aniline

[0802]

[0803] By the same procedure as in Example 1.2, using 3-fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzonitrile (200 mg, 0.71 mmol) and LAH solution (2.0 M in THF, 0.71 mL), the title compound (70 mg, 35%) was obtained as an oil.

[0804] LC-MS, m / z 285 [M+H] +

[0805] 41.3 8-Cyclopentyl-N-(3-fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0806]

[0807] The title compound (6 mg, 9%) was obtained as a viscous oil by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (30 mg, 0.13 mmol), 3-(aminomethyl)-5-fluoro-N-(4-(trifluoromethyl)phenyl)aniline (37 mg, 0.13 mmol), T3P (50 wt% solution in EtOAc, 300 mg, 0.48 mmol) and DIPEA (80 μL, 0.75 mmol).

[0808] 1H NMR (400MHz, CD3OD) δ8.93 (s, 1H), 7.41 (d, J = 8Hz, 2H), 7.15 (d, J = 8Hz, 2H), 6.99 (s, 1H), 6.76 (d, J = 8Hz, 1H) , 6.70 (d, J=12Hz, 1H), 4.61 (s, 2H), 3.48-3.44 (m, 1H), 2.19 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.74 (m, 2H).

[0809] LC-MS, m / z 499[M+H] +

[0810] Example 42

[0811] 42. tert-Butyl (3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0812]

[0813] The title compound (45 mg, 68%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 4-iodo-2-methylpyridine (44 mg, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0814] LC-MS, m / z 383[M+H] +

[0815] 42.2(3-Fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0816]

[0817] By the same method as in Example 25.4, tert-butyl 3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzylcarbamate (45 mg, 0.12 mmol), TFA (333 μL) and DCM (1 mL) were used to obtain the title compound (47 mg, crude), which was used in the next reaction without isolation and purification.

[0818] LC-MS, m / z 283 [M+H] +

[0819] 42.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0820]

[0821] The title compound (44 mg, 59%) was obtained by the same procedure as in Example 27.3 using (3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (47 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (27 mg, 0.12 mmol), T3P (50 wt% solution in EtOAc, 210 μL, 0.35 mmol), DIPEA (90 μL, 0.53 mmol) and DMF (2 mL).

[0822] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.79 (s, 1H), 9.25 (s, 1H), 8.98 (s, 1H), 8. 54 (d, J=5.5Hz, 1H), 8.37 (s, 1H), 7.79 (s, 1H), 7.70 (d, J=5.3Hz, 1H), 7.63 (s, 1H) ), 7.51 (d, J=9.7Hz, 1H), 7.12 (d, J=9.0Hz, 1H), 4.63 (d, J=5.8Hz, 2H), 3.56-3.4 5(m, 1H), 2.55(s, 3H), 2.07(s, 2H), 1.98-1.89(m, 2H), 1.81(s, 2H), 1.66(s, 2H).

[0823] LC-MS, m / z 497 [M+H] +

[0824] Example 43

[0825] 43. tert-Butyl (3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0826]

[0827] The title compound (61 mg, 89%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 5-iodo-2-methoxypyridine (32 μL, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0828] LC-MS, m / z 399[M+H] +

[0829] 43.2(3-Fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0830]

[0831] By the same method as in Example 25.4, tert-butyl 3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (61 mg, 0.15 mmol), TFA (670 μL) and DCM (2 mL) were used to obtain the title compound (4 mg, crude), which was used in the next reaction without isolation and purification.

[0832] LC-MS, m / z 299[M+H] +

[0833] 43.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0834]

[0835] The title compound (42 mg, 54%) was obtained by the same procedure as in Example 27.3 using (3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (64 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (36 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 270 μL, 0.46 mmol), DIPEA (120 μL, 0.69 mmol) and DMF (2 mL).

[0836] 1H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.76 (s, 1H), 8.95 (d, J=3.5Hz, 2H), 8.64 (d, J=2.6H z, 1H), 8.23 ​​(s, 1H), 8.16 (dd, J=8.9, 2.7Hz, 1H), 7.55 (s, 1H), 7.44 (d, J=10.1Hz, 1H), 7.05 (d, J=9.2Hz, 1H), 6.98 (d, J=8.9Hz, 1H), 4.59 (d, J=6.0Hz, 2H), 3.88 (s, 3H), 3.52-3.42 (m , 1H), 2.05 (d, J=7.8Hz, 2H), 1.90 (dt, J=18.8, 7.0Hz, 2H), 1.78 (s, 2H), 1.68-1.58 (m, 2H).

[0837] LC-MS, m / z 513 [M+H] +

[0838] Example 44

[0839] 44. tert-Butyl (3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0840]

[0841] The title compound (57 mg, 76%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 5-bromo-2-(trifluoromethyl)pyridine (58 mg, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0842] LC-MS, m / z 437 [M+H] +

[0843] 44.2(3-Fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0844]

[0845] At room temperature, to a solution of tert-butyl 3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-yl)benzylcarbamate (57 mg, 0.13 mmol) in DCM (2 mL) was dropwise added HCl (35 to 37%, 670 μL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with MeOH and evaporated three times to obtain the title compound (49 mg, crude), which was used for the next reaction without separation and purification.

[0846] LC-MS, m / z 337 [M+H] +

[0847] 44.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0848]

[0849] The title compound (60 mg, 83%) was obtained by the same procedure as in Example 27.3 using (3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (49 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (30 mg, 0.13 mmol), T3P (50 wt% solution in EtOAc, 230 μL, 0.39 mmol), DIPEA (100 μL, 0.59 mmol) and DMF (2 mL).

[0850] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.77 (t, J=6.0Hz, 1H), 9.31 (s, 1H), 9.27 (s, 1H) , 8.95 (s, 1H), 8.50 (d, J = 8.6Hz, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.6Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=9.8Hz, 1H), 7.09 (d, J=9.7Hz, 1H), 4.60 (d, J=5.8Hz, 2H), 3.52-3.43 (m, 1H) , 2.05 (d, J=7.8Hz, 2H), 1.90 (dd, J=12.2, 7.4Hz, 2H), 1.78 (s, 2H), 1.68-1.58 (m, 2H).

[0851] LC-MS, m / z 551[M+H] +

[0852] Example 45

[0853] 45. tert-Butyl 1-(3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0854]

[0855] The same procedure as in Example 25.3 was used using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (100 mg, 0.34 mmol), 3-bromophenylmethylsulfone (121 mg, 0.51 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (71 mg, 0.51 mmol) and DMSO (2 mL) to obtain the title compound (104 mg, 68%) as an off-white solid.

[0856] LC-MS, m / z 446[M+H] +

[0857] 45.2(3-Fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0858]

[0859] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate (104 mg, 0.23 mmol), trifluoroacetic acid (0.77 mL) and DCM (2.3 mL) the title compound (350 mg, crude) was obtained.

[0860] LC-MS, m / z 346[M+H] +

[0861] 45.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0862]

[0863] The same procedure as in Example 27.3 was used to obtain the title compound (66 mg, 50% yield in 2 steps) as an off-white foam using 8-cyclopentyl-7H-purine-6-carboxylic acid (54 mg, 0.23 mmol), (3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (107 mg), T3P (50% by weight solution in EtOAc, 223 mg, 0.70 mmol), DIPEA (180 μL, 1.05 mmol) and DMF (2 mL).

[0864] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.79 (t, J=6.4Hz, 1H), 9.27 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.25 (d, J=8.4Hz, 1H), 7.85 (m, 2H), 7.63 (s, 1H), 7.5 3 (d, J=10Hz, 1H), 7.09 (d, J=9.2Hz, 1H), 4.62 (d, J=6.0Hz, 2H), 3.50 (m, 1H), 3.32 ( s, 3H), 2.12-2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0865] LC-MS, m / z 560 [M+H] +

[0866] Example 46

[0867] 46. ​​tert-Butyl (3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0868]

[0869] The same procedure as in Example 25.3 was used using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (100 mg, 0.34 mmol), 1-fluoro-3-iodobenzene (114 mg, 0.51 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (71 mg, 0.51 mmol) and DMSO (2 mL) to obtain the title compound (100 mg, 75%) as an off-white solid.

[0870] LC-MS, m / z 386[M+H] +

[0871] 46.2(3-Fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0872]

[0873] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamate (100 mg, 0.25 mmol), trifluoroacetic acid (0.8 mL) and DCM (2.5 mL) the title compound (100 mg, crude) was obtained.

[0874] LC-MS, m / z 286[M+H] +

[0875] 46.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0876]

[0877] The same procedure as in Example 27.3 was used using 8-cyclopentyl-7H-purine-6-carboxylic acid (59 mg, 0.25 mmol), (3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (100 mg), T3P (50 wt% solution in EtOAc, 59 mg, 0.25 mmol), DIPEA (0.2 mL, 1.15 mmol) and DMF (2 mL) to obtain the title compound as an off-white solid (72 mg, 51.6% yield in 2 steps).

[0878] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.78 (m, 1H), 9.13 (s, 1H), 8.98 (s, 1H), 8.29 (s, 1H), 7.76 (d, J = 9.2Hz, 2H), 7.64-7.53 (m, 2H), 7.48 (d, J = 10.0Hz, 1H) , 7.18 (t, J=8.2Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 4.61 (d, J=6Hz, 2H), 3.50 (m, 1H ), 2.12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0879] LC-MS, m / z 500[M+H]+

[0880] Example 47

[0881] 47. tert-Butyl (3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0882]

[0883] The title compound (32 mg, 48%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 2-fluoro-5-iodopyridine (57 mg, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0884] LC-MS, m / z 387 [M+H] +

[0885] 47.2(3-Fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0886]

[0887] By the same procedure as in Example 44.2, using tert-butyl 3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (32 mg, 0.083 mmol), HCl (35 to 37%, 330 μL) and DCM (1 mL), the title compound (28 mg, crude) was obtained.

[0888] LC-MS, m / z 287 [M+H] +

[0889] 47.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0890]

[0891] The title compound (18 mg, 43%) was obtained by the same method as in Example 1.3 using (3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (28 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (19 mg, 0.83 mmol), T3P (50 wt% solution in EtOAc, 150 μL, 0.25 mmol), DIPEA (63 μL, 0.37 mmol) and DMF (2 mL).

[0892] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.80 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H) , 8.77 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.59 (s, 1H), 7.48 (d, J = 9.9Hz, 1H), 7.42 (d, J=8.7Hz, 1H), 7.10 (d, J=9.2Hz, 1H), 4.62 (d, J=5.6Hz, 2H), 3.48 (d, J=8.2Hz, 1H), 2.07 (s, 2H), 1.93 (d, J=5.9Hz, 2H), 1.80 (s, 2H), 1.66 (s, 2H).

[0893] LC-MS, m / z 501[M+H] +

[0894] Example 48

[0895] 48.1 tert-Butyl (3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0896]

[0897] The title compound (32 mg, 48%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.17 mmol), 2-fluoro-5-iodopyridine (57 mg, 0.26 mmol), CuI (3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (3 mL).

[0898] LC-MS, m / z 495 [M+H] +

[0899] 48.2(3-Fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0900]

[0901] By the same procedure as in Example 44.2, using tert-butyl 3-fluoro-5-(1-(6-iodopyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.041 mmol), HCl (35 to 37%, 333 μL) and DCM (1 mL), the title compound (17 mg, crude) was obtained.

[0902] 48.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0903]

[0904] The title compound (9 mg, 37%) was obtained by the same method as in Example 1.3 using (3-fluoro-5-(1-(6-iodopyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (17 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (19 mg, 0.83 mmol), T3P (50 wt% solution in EtOAc, 150 μL, 0.25 mmol), DIPEA (63 μL, 0.37 mmol) and DMF (2 mL).

[0905] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.77 (s, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.73 (s, 1H), 8.36 (d, J = 10.8Hz, 2H), 7.80 (d, J = 8.6Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=9.8Hz, 1H), 7.08 (d, J=9.2Hz, 1H), 4.60 (d, J=6.1Hz, 2H), 3.49 (s, 1H), 2.06 (s, 2H), 1.93 (s, 2H), 1.80 (s, 2H), 1.66 (s, 2H).

[0906] LC-MS, m / z 609[M+H] +

[0907] Example 49

[0908] 3-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid

[0909]

[0910] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (30 mg, 0.059 mmol) and NaOH (57 mg, 1.42 mmol) were added to EtOH (2 mL) and stirred at 85 ° C for 7 hours. After the reaction was complete, the mixture was diluted with H O, acidified with 1M HCl (pH 4 to 5), extracted three times with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) to obtain the title compound (12.8 mg, 41%).

[0911] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.78 (m, 1H), 9.16 (s, 1H), 8.97 (s, 1H ), 8.43 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.90 (d, J = 8Hz, 1H), 7.7 1-7.44 (m, 3H), 7.07 (d, J = 9.2Hz, 1H), 4.61 (d, J = 6.4Hz, 2H), 3.49 (m, 1H), 2 .12-2.04(m, 2H), 1.97-1.89(m, 2H), 1.86-1.76(m, 2H), 1.71-1.62(m, 2H).

[0912] LC-MS, m / z 526[M+H] +

[0913] Example 50

[0914] 50.1 tert-Butyl (3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)carbamate

[0915]

[0916] The same procedure as in Example 25.3 was used using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 4-iodobenzonitrile (177 mg, 0.77 mmol), CuI (10 mg, 0.051 mmol), L-proline (12 mg, 0.10 mmol), K2CO3 (107 mg, 0.77 mmol) and DMSO (2 mL) to obtain the title compound (152 mg, 75%) as an off-white solid.

[0917] LC-MS, m / z 393[M+H] +

[0918] 50.2 4-(4-(3-(Aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzonitrile, trifluoroacetate

[0919]

[0920] By the same procedure as in Example 25.4, using tert-butyl (3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)carbamate (100 mg, 0.25 mmol), DCM (2.5 mL) and trifluoroacetic acid (0.8 mL), the title compound (154 mg, crude) was obtained.

[0921] LC-MS, m / z 293 [M+H] +

[0922] 50.3 N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0923]

[0924] The title compound (120 mg, 62.5% yield in 2 steps) was obtained as an off-white solid by the same procedure as in Example 27.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (88 mg, 0.38 mmol), 4-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzonitrile, trifluoroacetate (154 mg, crude), T3P (50 wt% solution in EtOAc, 362 mg, 1.14 mmol), DIPEA (0.29 mL, 1.71 mmol) and DMF (2 mL).

[0925] 1H NMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 9.79 (m, 1H), 9.25 (s, 1H), 8.98 (s, 1H), 8.38 (s, 1H), 8.06 (dd, J=23.6, 8.8Hz, 4H), 7.61 (s, 1H), 7.51 (d, J= 10.0Hz, 1H), 7.11 (d, J=10Hz, 1H), 4.62 (d, J=6Hz, 2H), 3.50 (m, 1H), 2.1 2-2.04 (m, 2H), 1.97-1.89 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.62 (m, 2H).

[0926] LC-MS, m / z 507 [M+H] +

[0927] Example 51

[0928] 51.1 tert-Butyl (3-fluoro-5-(1H-pyrazol-3-yl)benzyl)carbamate

[0929]

[0930] The title compound (95 mg, 99%) was obtained by the same method as in Example 4.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (128 mg, 0.66 mmol), 2M K2CO3 aqueous solution (0.6 mL, 1.2 mmol), PdCl2(dppf) (12 mg, 0.017 mmol) and 1,4-dioxane (1.2 mL).

[0931] 1 H NMR (400MHz, DMSO-d6) δ12.99 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.51-7.45 (m , 2H), 6.94 (d, J=9.0Hz, 1H), 6.74 (s, 1H), 4.17 (d, J=6.0Hz, 2H), 1.41 (s, 9H).

[0932] 51.2-tert-Butyl(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)carbamate

[0933]

[0934] The title compound (73 mg, 62%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-3-yl)benzylcarbamate (95 mg, 0.33 mmol), 1-fluoro-4-iodobenzene (110 mg, 0.49 mmol), CuI (6 mg, 0.033 mmol), L-proline (8 mg, 0.066 mmol), K2CO3 (68 mg, 0.49 mmol) and DMSO (2 mL).

[0935] LC-MS, m / z 386[M+H] +

[0936] 51.3 (3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)phenyl)methanamine, hydrochloride

[0937]

[0938] By the same procedure as in Example 44.2, using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzylcarbamate (73 mg, 0.19 mmol), HCl (35 to 37%, 700 μL) and DCM (2 mL), the title compound (61 mg, crude) was obtained.

[0939] 51.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)-7H-purine-6-carboxamide

[0940]

[0941] The title compound (75 mg, 80%) was obtained by the same procedure as in Example 1.3 using (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)phenyl)methanamine hydrochloride (61 mg, crude), 8-cyclopentyl-7H-purine-6-carboxylic acid (44 mg, 0.19 mmol), T3P (50 wt% solution in EtOAc, 340 μL, 0.57 mmol), DIPEA (150 μL, 0.85 mmol) and DMF (2 mL).

[0942] 1H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.85 (s, 1H), 8.97 (s, 1H), 8.57 (d, J=2 .3Hz, 1H), 7.93 (dd, J=9.0, 4.6Hz, 2H), 7.83 (s, 1H), 7.62 (d, J=10.4Hz, 1H), 7 .38 (t, J=8.7Hz, 2H), 7.20 (d, J=8.6Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 4.63 (d, J= 6.2Hz, 2H), 3.48(s, 1H), 2.06(s, 2H), 1.93(s, 2H), 1.80(s, 2H), 1.65(s, 2H).

[0943] LC-MS, m / z 500[M+H] +

[0944] Example 52

[0945] 52.1(tert-Butyl 3-fluoro-5-(1H-pyrrol-3-yl)benzyl)carbamate)

[0946]

[0947] The title compound (95 mg, 99%) was obtained by the same method as in Example 4.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (127 mg, 0.66 mmol), 2M K2CO3 aqueous solution (0.6 mL, 1.2 mmol), PdCl2(dppf) (12 mg, 0.017 mmol) and 1,4-dioxane (1.2 mL).

[0948] 1 H NMR (400MHz, DMSO-d6) δ 11.01 (s, 1H), 7.44 (s, 1H), 7.27-7.14 (m, 3H), 6.82-6.71 (m, J = 32.7Hz, 2H), 6.43 (s, 1H), 4.12 (s, 2H), 1.40 (s, 9H).

[0949] 52.2-tert-Butyl(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)carbamate

[0950]

[0951] The title compound (40 mg, 32%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrrol-3-yl)benzylcarbamate (95 mg, 0.33 mmol), 1-fluoro-4-iodobenzene (110 mg, 0.49 mmol), CuI (6 mg, 0.033 mmol), L-proline (8 mg, 0.066 mmol), K2CO3 (68 mg, 0.49 mmol) and DMSO (2 mL).

[0952] LC-MS, m / z 385[M+H] +

[0953] 52.3 (3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)phenyl)methanamine, hydrochloride

[0954]

[0955] By the same procedure as in Example 44.2, using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzylcarbamate (40 mg, 0.10 mmol), HCl (35 to 37%, 300 μL) and DCM (1 mL), the title compound (33 mg, crude) was obtained.

[0956] 52.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)-7H-purine-6-carboxamide

[0957]

[0958] The title compound (42 mg, 81%) was obtained by the same method as in Example 1.3 using (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)phenyl)methanamine hydrochloride (33 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (24 mg, 0.10 mmol), T3P (50 wt% solution in EtOAc, 190 μL, 0.31 mmol), DIPEA (80 μL, 0.47 mmol) and DMF (2 mL).

[0959] 1H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.77 (s, 1H), 8.97 (s, 1H), 7.94 (s, 1H), 7.69 (dd, J=8.8, 4.7Hz, 2H), 7.51 (s, 1H), 7.43 (s, 1H), 7.35 (d, J=8 .9Hz, 3H), 6.98 (d, J=9.0Hz, 1H), 6.72 (s, 1H), 4.58 (d, J=6.2Hz, 2H), 3. 49 (s, 1H), 2.07 (s, 2H), 1.94 (d, J=7.3Hz, 2H), 1.80 (s, 2H), 1.66 (s, 2H).

[0960] LC-MS, m / z 499[M+H] +

[0961] Example 53

[0962] N-(3-(1-(4-Carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0963]

[0964] N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (30 mg, 0.059 mmol) and NaOH (57 mg, 1.42 mmol) were added to EtOH (1 mL) and stirred at 85 ° C for 2 hours. After the reaction was completed, the reaction mixture was diluted with H O, extracted twice with EtOAc, acidified with 1M HCl (pH 4 to 5), and extracted three times with EtOAc. The organic layer was then dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 20% MeOH in DCM) to obtain the title compound (4.04 mg, 13%).

[0965] 1H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.79 (m, 1H), 9.17 (s, 1H), 8.98 (s, 1H), 8.31 (s, 1H), 8.00 (m, 5H), 7.61 (s, 1H), 7.50 (d, J=9.7Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 10.3Hz, 1H), 4.61 (d, J = 6.1Hz, 2H), 3.50 (m, 1H), 2.1 3-2.03 (m, 2H), 1.98-1.88 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.59 (m, 2H).

[0966] LC-MS, m / z 525 [M+H] +

[0967] Example 54

[0968] 4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid

[0969]

[0970] By the same method as in Example 53, using N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (30 mg, 0.059 mmol), NaOH (57 mg, 1.42 mmol) and EtOH (1 mL) to obtain the title compound (1.91 mg, 6%).

[0971] 1 H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.78 (s, 1H), 8.13 (m, 3H), 7.90 (d, J = 8Hz, 2H), 7.57 (s, 1H), 7.35 (d, J = 8.8Hz, 1H), 7.07 (d, J=10.4Hz, 1H), 4.72 (s, 2H), 3.49 (m, 1H), 2.25-2.15 (m, 2H), 2.09-1.97 (m, 2H), 1.95-1.86 (m, 2H), 1.81-1.72 (m, 2H).

[0972] LC-MS, m / z 526[M+H] +

[0973] Example 55

[0974] 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7-methyl-7H-purine-6-carboxamide

[0975]

[0976] To a mixture of 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide (40 mg, 0.08 mmol) and KCO (13.3 mg, 0.096 mmol) was added DMF (0.8 mL) and stirred at room temperature for 20 minutes. MeI (13.6 mg, 0.096 mmol) was then added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with HO, extracted three times with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (16.7 mg, 40.6% yield).

[0977] 1 H NMR (400MHz, DMSO-d6) δ9.56 (m, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.26 (s, 1H), 7.91 (m, 2H), 7.62 (s, 1H), 7.50 (d, J=10.0Hz, 1H), 7.39 (t, J=8 .8Hz, 2H), 7.16 (d, J=9.6Hz, 1H), 4.64 (d, J=5.6Hz, 2H), 3.82 (s, 3H), 3.55 (m, 1H), 2.14-2.05 (m, 2H), 2.01-1.91 (m, 2H), 1.79-1.59 (m, 4H).

[0978] LC-MS, m / z 514 [M+H] +

[0979] Example 56

[0980] 56.1 tert-Butyl 5-bromo-2-fluorobenzylcarbamate

[0981]

[0982] By the same procedure as in Example 6.1, using (5-bromo-2-fluorophenyl)methanamine (200 mg, 0.98 mmol), Boc2O (430 mg, 2.0 mmol) and DCM (5 mL), the title compound (273 mg, 92%) was obtained as a colorless oil.

[0983] 1H NMR (400MHz, DMSO-d6) δ7.52-7.36 (m, 3H), 7.15 (t, 1H), 4.13 (d, J=6.0Hz, 2H), 1.33 (s, 9H).

[0984] 56.2 tert-Butyl 2-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate

[0985]

[0986] The title compound (190 mg, 60%) was obtained by the same procedure as in Example 4.1 above using tert-butyl 5-bromo-2-fluorobenzylcarbamate (270 mg, 0.90 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (260 mg, 1.3 mmol), 2M aqueous K2CO3 solution (1.6 mL, 3.1 mmol), PdCl2(dppf) (33 mg, 0.045 mmol) and 1,4-dioxane (3.2 mL).

[0987] LC-MS, m / z 292[M+H] +

[0988] 56.3 tert-Butyl 2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0989]

[0990] The title compound (120 mg, 50%) was obtained by the same method as in Example 25.3 using tert-butyl 2-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (190 mg, 0.64 mmol), 1-fluoro-4-iodobenzene (210 mg, 0.96 mmol), CuI (12 mg, 0.064 mmol), L-proline (15 mg, 0.13 mmol), K2CO3 (130 mg, 0.96 mmol) and DMSO (3 mL). LC-MS, m / z 386 [M+H] +

[0991] 56.4(2-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0992]

[0993] By the same procedure as in Example 44.2 using tert-butyl 2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.052 mmol), HCl (35 to 37%, 0.25 mL) and DCM (0.50 mL) to obtain the title compound (17 mg, crude).

[0994] 56.5 8-Cyclopentyl-N-(2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0995]

[0996] The title compound (22 mg, 85%) was obtained by the same procedure as in Example 27.3 using (2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride (17 mg, crude), 8-cyclopentyl-7H-purine-6-carboxylic acid (12 mg, 0.052 mmol), T3P (50 wt% solution in EtOAc, 93 μL, 0.16 mmol), DIPEA (40 μL, 0.23 mmol) and EtOAc (1 mL).

[0997] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.64 (t, J=5.7Hz, 1H), 8.96 (s, 1H), 8.89 (s, 1H), 8 .12 (s, 1H), 7.94-7.83 (m, J=9.0, 4.7Hz, 2H), 7.77 (d, J=7.0Hz, 1H), 7.68-7.62 (m, 1H), 7. 36(t, J=8.8Hz, 2H), 7.30-7.22(m, 1H), 4.66(d, J=6.0Hz, 2H), 3.54-3.44(m, 1H), 2.07(m z, J=7.6Hz, 2H), 1.97-1.87 (m, J=12.6, 6.6Hz, 2H), 1.85-1.74 (m, 2H), 1.70-1.60 (m, 2H).

[0998] LC-MS, m / z 500[M+H] +

[0999] Example 57

[1000] 57.1 tert-Butyl 3-bromobenzylcarbamate

[1001]

[1002] By the same procedure as in Example 6.1, using (3-bromophenyl)methanamine (200 mg, 1.1 mmol), Boc2O (470 mg, 2.2 mmol) and DCM (5 mL), the title compound (300 mg, 96%) was obtained as a colorless oil.

[1003] 1 H NMR (400MHz, DMSO-d6) δ7.49-7.36 (m, 3H), 7.30-7.20 (m, 2H), 4.09 (d, J=6.1Hz, 2H), 1.37 (s, 9H).

[1004] 57.2 tert-Butyl 3-(1H-pyrazol-4-yl)benzylcarbamate

[1005]

[1006] The title compound (57 mg, 20%) was obtained by the same procedure as in Example 4.1 using tert-butyl 3-bromobenzylcarbamate (300 mg, 1.1 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (310 mg, 1.6 mmol), 2M KCO aqueous solution (1.8 mL, 3.7 mmol), PdCl(dppf) (39 mg, 0.053 mmol) and 1,4-dioxane (3.6 mL).

[1007] LC-MS, m / z 274 [M+H] +

[1008] 57.3 tert-Butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[1009]

[1010] The title compound (54 mg, 68%) was obtained by the same procedure as in Example 25.3 using tert-butyl 3-(1H-pyrazol-4-yl)benzylcarbamate (59 mg, 0.22 mmol), 1-fluoro-4-iodobenzene (72 mg, 0.32 mmol), CuI (4 mg, 0.022 mmol), L-proline (5 mg, 0.043 mmol), K2CO3 (45 mg, 0.32 mmol) and DMSO (2 mL).

[1011] LC-MS, m / z 386[M+H] +

[1012] 57.4(3-(1-(4-Fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[1013]

[1014] By the same procedure as in Example 44.2 using tert-butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.054 mmol), HCl (35 to 37%, 0.25 mL) and DCM (0.50 mL) to obtain the title compound (17 mg, crude).

[1015] 57.5 8-Cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1016]

[1017] The title compound (24 mg, 92%) was obtained by the same procedure as in Example 27.3 using (3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride (17 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (13 mg, 0.054 mmol), T3P (50 wt% solution in EtOAc, 97 μL, 0.16 mmol), DIPEA (42 μL, 0.25 mmol) and EtOAc (1 mL).

[1018] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.72 (t, J=5.8Hz, 1H), 8.96 (s, 2H), 8 .18 (s, 1H), 7.97-7.88 (m, 2H), 7.73 (s, 1H), 7.60 (d, J=7.4Hz, 1H), 7.43-7. 32 (m, 3H), 7.27 (d, J = 7.8Hz, 1H), 4.61 (d, J = 6.1Hz, 2H), 3.53-3.44 (m, 1H), 2.13-2.03 (m, 2H), 1.98-1.88 (m, 2H), 1.84-1.75 (m, 2H), 1.71-1.60 (m, 2H).

[1019] LC-MS, m / z 482[M+H] +

[1020] Example 58

[1021] 58.1 tert-Butyl 3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1022]

[1023] The title compound (54 mg, 78%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 1-chloro-4-iodobenzene (62 mg, 0.26 mmol), CuI (3.3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (1 mL).

[1024] LC-MS, m / z 402[M+H] +

[1025] 58.2(3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[1026]

[1027] 3-(1-(4-chlorophenyl)-1H-pyrazole-4-yl)-5-fluorobenzyl tert-butyl carbamate (54mg, 0.13mmol) is dissolved in DCM (1.4mL), trifluoroacetic acid (0.47mL) is added, and the mixture is stirred at room temperature for 1 hour.After completion of the reaction, the reaction mixture is concentrated, adjusted to pH 10 to 11 with the 1M NaOH aqueous solution, and extracted five times with DCM.The organic layer is dried over MgSO4 and concentrated to obtain title compound (20mg, crude product).

[1028] LC-MS, m / z 302[M+H] +

[1029] 58.3 N-(3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1030]

[1031] The same procedure as in Example 27.3 was used using 8-cyclopentyl-7H-purine-6-carboxylic acid (15.7 mg, 0.068 mmol), T3P (50 wt% solution in EtOAc, 65 mg, 0.20 mmol), (3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine (10 mg), DIPEA (52 μL, 0.30 mmol) and EtOAc (1 mL) to obtain the title compound as a white solid (16 mg, 93.5% yield in 2 steps).

[1032] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.79 (t, J=5.9Hz, 1H), 9.10 (s, 1H), 8. 97 (s, 1H), 8.28 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.67-7.55 (m, 3H), 7.48 (d, J = 9.6Hz, 1H), 7.07 (d, J=9.6Hz, 1H), 4.61 (d, J=6.1Hz, 2H), 3.57-3.45 (m, 1H), 2.14-2.01(m, 2H), 2.00-1.88(m, 2H), 1.86-1.74(m, 2H), 1.71-1.59(m, 2H).

[1033] LC-MS, m / z 516 [M+H] +

[1034] Example 59

[1035] 59.1 tert-Butyl 3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1036]

[1037] The title compound (76.5 mg, 96%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (50 mg, 0.17 mmol), 4-bromo-1-fluoro-2-(methylsulfonyl)benzene (65 mg, 0.26 mmol), CuI (3.3 mg, 0.017 mmol), L-proline (4 mg, 0.034 mmol), K2CO3 (36 mg, 0.26 mmol) and DMSO (1 mL).

[1038] LC-MS, m / z 522[MH] -

[1039] 59.2-(3-(1-(4-Bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[1040]

[1041] By the same procedure as in Example 25.4, using tert-butyl 3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (70 mg, 0.15 mmol), DCM (1.5 mL) and trifluoroacetic acid (0.5 mL), the title compound (71 mg, crude) was obtained.

[1042] LC-MS, m / z 293 [M+H] +

[1043] 59.3 N-(3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1044]

[1045] The same procedure as in Example 27.3 was used with 8-cyclopentyl-7H-purine-6-carboxylic acid (35 mg, 0.15 mmol), (3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate (71 mg, crude), T3P (50 wt% solution in EtOAc, 144 mg, 0.453 mmol), DIPEA (0.12 mL, 0.68 mmol) and DMF (2 mL) to obtain the title compound as an off-white solid (33 mg, 39% yield in 2 steps).

[1046] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.78 (t, J=6.0Hz, 1H), 8.97 (s, 1H), 8.65 (s, 1H) , 8.31 (s, 1H), 8.20 (d, J = 2.2Hz, 1H), 8.15 (dd, J = 8.5, 2.3Hz, 1H), 7.68 (d, J = 8.3Hz, 1H ), 7.56 (s, 1H), 7.47 (d, J = 9.4Hz, 1H), 7.07 (d, J = 9.1Hz, 1H), 4.59 (d, J = 5.8Hz, 2H), 3. 48(s, 3H), 2.13-2.00(m, 2H), 1.98-1.86(m, 2H), 1.85-1.74(m, 2H), 1.72-1.59(m, 2H).

[1047] LC-MS, m / z 638[M+H] +

[1048] Example 60

[1049] 60.1 tert-Butyl 3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1050]

[1051] The title compound (19.1 mg, 41%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (33.5 mg, 0.12 mmol), 1,2-difluoro-4-iodobenzene (41.4 mg, 0.17 mmol), CuI (2.2 mg, 0.012 mmol), L-proline (2.6 mg, 0.023 mmol), K2CO3 (24 mg, 0.17 mmol) and DMSO (1.5 mL).

[1052] LC-MS, m / z 404 [M+H] +

[1053] 60.2(3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[1054]

[1055] By the same procedure as in Example 25.4, using tert-butyl 3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (19.1 mg, 0.047 mmol), DCM (0.5 mL) and trifluoroacetic acid (0.16 mL), the title compound (19 mg, crude) was obtained.

[1056] LC-MS, m / z 304 [M+H] +

[1057] 60.3 8-Cyclopentyl-N-(3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[1058]

[1059] 8-Cyclopentyl-7H-purine-6-carboxylic acid (9.2 mg, 0.039 mmol), (3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate (19 mg, crude) and HATU (18 mg, 0.047 mmol) were dissolved in DCM (0.5 mL), DIPEA (10 μL, 0.059 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over MgSO4 and concentrated. The obtained residue was purified by silica gel column chromatography (0 to 4% MeOH in DCM) to obtain the title compound (4.59 mg, 2 steps, 22.5% yield) as a light yellow solid.

[1060] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.64 (s, 1H), 8.07 (s, 1H), 7.81-7.73 (m , 1H), 7.60 (d, J=8.8Hz, 1H), 7.51 (s, 1H), 7.38 (dd, J=18.7, 9.0Hz, 1H), 7.2 9 (d, J=9.5Hz, 1H), 7.04 (d, J=9.1Hz, 1H), 4.70 (s, 2H), 3.52-3.42 (m, 1H), 2 .25-2.12(m,2H), 2.08-1.96(m,2H), 1.95-1.84(m,2H), 1.84-1.68(m,2H).

[1061] LC-MS, m / z 518 [M+H] +

[1062] Example 61

[1063] 61.1 Ethyl 2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidine-4-carboxylate

[1064]

[1065] 2,6-bis-chloro-5-nitropyrimidine-4-carboxylic acid ethyl esters (1.15g, 4.3mmol) are dissolved in THF (20mL), and mixture is cooled to 0 ℃ under nitrogen atmosphere.Add NaHCO (1.09g, 12.9mmol), and in 15 minutes, dropwise add the solution of (2,4-dimethoxyphenyl) methylamine (0.83g, 4.96mmol) in THF (3mL), and mixture is at room temperature stirred.After 1 hour, mixture is diluted with EtOAc, use H o washing, and by organic layer MgSO dry and concentrate.The residue obtained is carried out purifying to obtain the title compound (886mg, 52%) as yellow solid by silica gel column chromatography (20%EtOAc in normal hexane).

[1066] LC-MS, m / z 397 [M+H] +

[1067] 61.2 Ethyl 5-amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate

[1068]

[1069] 2-Chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidine-4-carboxylic acid, ethyl ester (481 mg, 1.21 mmol) was added to EtOH (17 mL), and SnCl (1.16 g, 6.1 mmol) was added, and the mixture was stirred at room temperature. After 3 hours, the reaction mixture was concentrated, and 0° C. H O was added, stirred, and the resulting solid was filtered. The filtered solid was added to EtOH, stirred, filtered, and dried to obtain the title compound (390 mg, 88%) as a yellow solid.

[1070] LC-MS, m / z 367 [M+H] +

[1071] 61.3 5-Amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid

[1072]

[1073] Ethyl 5-amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (1.17 g, 3.19 mmol) was dissolved in THF / EtOH (14 mL / 26 mL), 2.0 M NaOH (9.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was acidified with 3 M HCl at 0° C. (~pH 2), and the resulting solid was filtered to afford the title compound (850 mg, 79%) as a light yellow solid.

[1074] LC-MS, m / z 339[M+H] +

[1075] 61.4 5-amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[1076]

[1077] 5-Amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid (130 mg, 0.39 mmol), (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (110 mg, 0.39 mmol), T3P (50% in EtOAc, 773 mg, 1.20 mmol) and DIPEA (174 μL, 1.02 mmol) were dissolved in EtOAc (8 mL) and stirred at 50° C. After 12 hours, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over Na2SO4 and concentrated. The obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (13 mg, 55%) as a white solid.

[1078] LC-MS, m / z 607 [M+H] +

[1079] 61.5 5,6-Diamino-2-chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[1080]

[1081] 5-Amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (120 mg, 0.20 mmol) was dissolved in CHCl (10 mL) solution, TFA (2 mL) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed, neutralized with aqueous NaOH solution, extracted with EtOAc, and the organic layer was dried over MgSO and concentrated. The obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (85 mg, 93%) as a white solid.

[1082] LC-MS, m / z 456 [M+H] +

[1083] 61.6 2-Chloro-8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1084]

[1085] 5,6-Diamino-2-chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (50 mg, 0.11 mmol), cyclopentanecarboxylic acid (12.5 mg, 0.11 mmol) and T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) were dissolved in dioxane (3 mL). DIPEA (66 μL, 0.39 mmol) was added, and the mixture was stirred at 150° C. using a microwave for 5 hours. After the reaction was complete, ethyl acetate and H2O were added to the reaction mixture, extracted, and the organic layer was dried over Na2SO4 and concentrated. The obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (30 mg, 51%) as a white solid.

[1086] 1 H NMR (400MHz, CD3OD) δ8.61 (s, 1H), 8.08 (s, 1H), 7.81-7.77 (m, 2H), 7.52 (s, 1H), 7.33 (d, J=12Hz, 1H), 7.25-7.2 1 (m, 2H), 7.05 (d, J=8.0Hz, 1H), 4.67 (s, 2H), 3.46 (m, 1H), 2.17 (m, 2H), 2.00 (m, 2H), 1.90 (m, 2H), 1.76 (m, 2H).

[1087] LC-MS, m / z 534 [M+H] +

[1088] Example 62

[1089] 62.1(S)-Benzyl 2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1090]

[1091] 6-Chloropyrimidine-4,5-diamine (484 mg, 3.35 mmol) and (S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylic acid benzyl ester (900 mg, 3.36 mmol) were added to POCl (5 mL) and stirred at 110° C. After 2 hours, the reaction mixture was concentrated and neutralized with a NaHCO aqueous solution. The aqueous layer was extracted twice with CH Cl and the organic layer was dried with Na SO and concentrated. The obtained residue was recrystallized from toluene to obtain the title compound (420 mg, 35%).

[1092] 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 7.36 (m, 3H), 6.96 (t, J=7.5Hz, 1H), 6.81 (d, J= 7.4Hz, 1H), 5.15-4.98 (m, 2H), 3.70 (m, 1H), 3.50 (m, 2H), 2.41 (m, 2H), 1.96 (m, 2H).

[1093] LC-MS, m / z 358 [M+H] +

[1094] 62. Benzyl 2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1095]

[1096] By the same method as in Preparation Example 1.1, using (S)-benzyl 2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate (220 mg, 0.61 mmol), KCN (172 mg, 2.64 mmol) and sodium p-toluenesulfinate (110 mg, 0.62 mmol) to obtain the title compound (160 mg, 75%).

[1097] LC-MS, m / z 349[M+H] +

[1098] 62.3(S)-8-(1-((Benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid methyl ester

[1099]

[1100] By the same method as in Preparation 1.2, using benzyl (S)-2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate (200 mg, 0.57 mmol) and TMSCl (761 μL), the title compound (100 mg, 46%) was obtained.

[1101] LC-MS, m / z 403 [M+Na] +

[1102] 62.4(S)-8-(1-((Benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid

[1103]

[1104] By the same method as in Preparation 1.3, using (S)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid methyl ester (100 mg, 0.26 mmol) and 2M NaOH (834 μL), the title compound (85 mg, 89%) was obtained.

[1105] 1 H NMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 9.02 (s, 1H), 7.36 (m, 3H), 6.91 (t, J=7.5Hz, 1H), 6.78 (d, J=7.5H z, 1H), 5.25 (m, 1H), 5.12-4.93 (m, 2H), 3.70 (m, 2H), 3.54 (m, 2H), 2.47-2.26 (m, 2H), 2.20-1.80 (m, 2H).

[1106] LC-MS, m / z 368[M+H] +

[1107] 62.5(S)-Benzyl 2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1108]

[1109] The title compound (110 mg, 86%) was obtained by the same method as in Example 1.3 using (S)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid (85 mg, 0.23 mmol), (3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (52 mg, 0.25 mmol), T3P (50 wt% solution in EtOAc; 439 mg) and DIPEA (120 μl).

[1110] 1 H NMR (400MHz, DMSO-d6) δ13.38 (s, 1H), 9.81 (s, 1H), 9.00 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.45 (d, J=9.6Hz, 1H), 7.37 (m, 3H), 7.02 (d, J=9.6Hz, 1H), 6.98-6.89 (m, 1H ), 6.83 (t, J=7.5Hz, 1H), 6.75 (d, J=7.4Hz, 1H), 5.30-5.20 (m, 1H), 5.05 (m, 2H), 4.5 9 (d, J=5.5Hz, 2H), 3.86 (s, 3H), 3.70 (m, 2H), 2.45-2.26 (m, 2H), 2.04-1.80 (m, 2H).

[1111] LC-MS m / z 368[M+H] +

[1112] 62.6(S)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[1113]

[1114] (S)-benzyl 2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in dioxane (5 mL), HCl (35% to 37%, 1.82 mL) was added, and the mixture was stirred at 80° C. After 1 hour, the reaction mixture was cooled to room temperature and concentrated, followed by addition of EtOAc and stirring. The solid was filtered and dried to obtain the title compound (60 mg, 73%).

[1115] 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 9.86 (s, 1H), 9.42 (s, 1H), 9.11 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 7.30 (d, J=10.0Hz , 1H), 7.00 (d, J=9.7Hz, 1H), 5.09 (m, 1H), 4.59 (d, J=6.3Hz, 2H), 3.85 (s, 3H), 3.74-3.68 (m, 2H), 3.50-3.46 (m, 2H), 2.20-2.06 (m, 2H).

[1116] LC-MS m / z 421[M+H] +

[1117] Example 63

[1118] (S)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[1119]

[1120] (S)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride (45 mg, 0.11 mmol), paraformaldehyde (15 mg) and NaBH4 (9 mg) were added to trifluoroethanol (3 mL) and refluxed. After 1 hour, the solid was filtered and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (15 mg, 31%).

[1121] 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 9.00 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.31 (d, J=10.3Hz, 1H), 7.00 (d, J=9.6Hz, 1H), 4.57 (d, J=6.3Hz, 2H), 3.85 (s, 3H), 3.15-3.05 (m, 1H), 2.43 (m, 2H), 2.22 (s, 3H), 2.02 (m, 2H), 1.87 (m, 2H).

[1122] LC-MS, m / z 435[M+H] +

[1123] Example 64

[1124] 64. Benzyl 1(R)-2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1125]

[1126] By the same procedure as in Example 62.1, using 6-chloropyrimidine-4,5-diamine (1.16 g, 8.0 mmol) and (R)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (2.14 g, 8.0 mmol), the title compound (960 mg, 34%) was obtained.

[1127] 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 7.36 (m, 3H), 7.09 (m, 1H), 6.85 (s, 1H), 5.07 (d, J=10.3Hz, 2H), 4.81 (m, 1H), 3.70 (m, 2H), 2.41 (m, 2H), 1.98 (m, 2H).

[1128] LC-MS, m / z 358 [M+H] +

[1129] 64. Benzyl 2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1130]

[1131] By the same method as in Preparation 1.1, using benzyl (R)-2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate (250 mg, 0.70 mmol), the title compound (200 mg, 82%) was obtained.

[1132] 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 7.45 (m, 3H), 6.98 (m, 1H), 6.84 (s, 1H), 5.08 (m, 2H), 4.78 (m, H), 3.70 (m, 2H), 2.50 (m, 2H), 2.02 (m, 2H).

[1133] LC-MS, m / z 349[M+H] +

[1134] 64.3(R)-8-(1-((Benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid methyl ester

[1135]

[1136] By the same method as in Preparation 1.2, using benzyl (R)-2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate (300 mg, 0.86 mmol), the title compound (200 mg, 61%) was obtained.

[1137] 1 H NMR (400MHz, CD3OD) δ9.02 (s, 1H), 7.35 (m, 3H), 5.08 (m, 2H), 4.68 (m, 1H), 3.31 (m, 2H), 2.50 (m, 2H), 2.19 (m, 2H).

[1138] LC-MS, m / z 382[M+H] +

[1139] 64.4(R)-8-(1-((Benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid

[1140]

[1141] By the same method as in Preparation 1.3, using (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid methyl ester (200 mg, 0.53 mmol), the title compound (140 mg, 72%) was obtained.

[1142] 1 H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 9.02 (s, 1H), 7.36 (m, 3H), 6.91 (t, J=7.6Hz, 1H), 6.77 ( d, J=7.5Hz, 1H), 5.26 (m, 1H), 5.04 (m, 2H), 3.78-3.63 (m, 2H), 2.40 (m, 2H), 2.18-1.80 (m, 2H).

[1143] LC-MS, m / z 368[M+H] +

[1144] 64.5(R)-Benzyl 2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1145]

[1146] The title compound (170 mg, 81%) was obtained by the same procedure as in Example 1.3 using (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid (140 mg, 0.38 mmol), (3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (86 mg, 0.42 mmol), T3P (50 wt% solution in EtOAc, 724 mg, 1.14 mmol) and DIPEA (198μ, 1.17 mmol).

[1147] 1 H NMR (400MHz, DMSO-d6) δ13.38 (s, 1H), 9.81 (s, 1H), 9.01 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.43 (d, J = 10.7Hz, 1H), 7.36 (m, 3H), 7.00 (d, J = 9.6Hz, 1H), 6.92 ( m,, 1H), 6.82 (t, J=7.3Hz, 1H), 6.74 (d, J=7.5Hz, 1H), 5.25 (m, 1H), 5.04 (m, 2H ), 4.58 (d, J=12.7Hz, 2H), 3.85 (s, 3H), 3.69 (m, 2H), 2.37 (m, 2H), 2.09 (m, 2H).

[1148] LC-MS, m / z 555 [M+H] +

[1149] Example 65

[1150] (R)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[1151]

[1152] The title compound (100 mg, 75%) was obtained by the same procedure as in Example 62.6 using benzyl (R)-2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate (160 mg, 0.29 mmol) and HCl (35% to 37%, 2.9 mL).

[1153] 1H NMR (400MHz, DMSO-d6) δ10.66 (s, 1H), 9.85 (s, 1H), 9.44 (s, 1H), 9.11 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 7.30 (d, J=10.0Hz, 1 H), 7.00 (d, J=9.7Hz, 1H), 5.17-5.03 (m, 1H), 4.59 (d, J=6.3Hz, 2H), 3.85 (s, 3H), 3.74-3.61 (m, 2H), 3.53-3.45 (m, 2H), 2.28-1.97 (m, 2H).

[1154] LC-MS, m / z 421[M+H] +

[1155] Example 66

[1156] (R)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[1157]

[1158] The title compound (22 mg, 50%) was obtained by the same method as in Example 63 using (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride (45 mg, 0.1 mmol), paraformaldehyde (15 mg), NaBH4 (9 mg) and trifluoroethanol (3 mL).

[1159] 1 H NMR (400MHz, DMSO-d6) δ9.74 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H). 7.31 (d, J = 10.4Hz, 1H), 7.00 (d , J=9.6Hz, 1H), 4.57 (d, J=6.4Hz, 2H), 3.85 (s, 3H), 3.10 (m, 1H), 2.48-2.35 (m, 2H), 2.22 (s, 3H), 2.01 (m, 2H), 1.85 (.2H).

[1160] LC-MS, m / z 435[M+H] +

[1161] Example 67

[1162] (S)-N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-isopropylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[1163]

[1164] By the same method as in Example 63, using (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride (20 mg, 0.05 mmol), acetone (30 μL), NaBH4 (3.3 mg) and trifluoroethanol (1 mL) to obtain the title compound (11 mg, 48%).

[1165] 1 H NMR (400MHz, CDCl3) δ9.03 (s, 1H), 8.47 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.25 (s, 1H), 7.12-7.07 (m, 1H), 6.96 (m, 1H) , 4.72 (m, 2H), 4.35 (m, 1H), 3.94 (s, 3H), 3.23 (m, 1H), 2.92-2.63 (m, 2H), 2.43-2.03 (m, 2H), 1.81 (m, 2H), 1.09 (m, 6H).

[1166] LC-MS, m / z: 463 [M+H] +

[1167] Example 68

[1168] 68. Benzyl 1(R)-2-(6-((3-fluorobenzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1169]

[1170] The title compound (155 mg, 93%) was obtained by the same procedure as in Example 1.3 using (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid (130 mg, 0.35 mmol), (3-fluorophenyl)methanamine (41 μL), T3P (50 wt% solution in EtOAc, 687 mg, 1.08 mmol) and DIPEA (156 μL, 0.90 mmol).

[1171] 1H NMR (400MHz, CDCl3) δ11.63 (s, 1H), 9.04 (s, 1H), 8.38 (s, 1H), 7.42-7.34 (m, 5H), 7.17-7.01 ( m, 4H), 5.31 (s, 2H), 5.20 (m, 1H), 4.72 (d, J=12Hz, 2H), 3.55 (m, 2H), 2.25 (m, 2H), 2.11 (m, 2H).

[1172] LC-MS, m / z 475 [M+H] +

[1173] 68.2(R)-N-(3-Fluorobenzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[1174]

[1175] By the same procedure as in Example 62.6, using benzyl (R)-2-(6-((3-fluorobenzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol) and HCl (35% to 37%, 1.85 mL), the title compound (70 mg, 88%) was obtained.

[1176] 1 H NMR (400MHz, DMSO-d6) δ10.57 (s, 1H), 9.91 (s, 1H), 9.43 (s, 1H), 9.11 (s, 1H), 7.39 (m, 1H), 7.2 1 (m, 2H), 7.08 (m, 1H), 5.09 (m, 1H), 4.58 (d, J = 4Hz, 2H), 3.72-3.68 (m, 2H), 2.21-2.08 (m, 4H).

[1177] LC-MS, m / z 341[M+H] +

[1178] 68.3(R)-N-(3-Fluorobenzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[1179]

[1180] By the same method as in Example 63, using (R)-N-(3-fluorobenzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride (70 mg, 0.19 mmol), paraformaldehyde (28 mg), NaBH4 (17 mg) and trifluoroethanol (3 mL) to obtain the title compound (6.7 mg, 10%).

[1181] LC-MS, m / z 355 [M+H] +

[1182] Example 69

[1183] 69.1 Benzyl 4-(6-chloro-7H-purin-8-yl)piperidine-1-carboxylate

[1184]

[1185] The title compound (176 mg, 14%) was obtained by the same procedure as in Example 62.6 using 6-chloropyrimidine-4,5-diamine (500 mg, 3.5 mmol), benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate (974 mg, 3.5 mmol) and POCl3 (5 mL).

[1186] 1 H NMR (400MHz, CD3OD) δ8.64 (s, 1H), 7.35 (dd, J=13.7, 7.0Hz, 5H), 5.15 (s, 2H), 4. 28 (d, J=12.7Hz, 2H), 3.06 (s, 3H), 2.10 (d, J=12.0Hz, 2H), 1.88 (d, J=8.4Hz, 2H).

[1187] LC-MS, m / z 372[M+H] +

[1188] 69.2 Benzyl 4-(6-cyano-7H-purin-8-yl)piperidine-1-carboxylate

[1189]

[1190] By the same method as in Preparation Example 1.1, using benzyl 4-(6-chloro-7H-purin-8-yl)piperidine-1-carboxylate (150 mg, 0.4 mmol), KCN (105 mg, 1.6 mmol), sodium p-toluenesulfinate (72 mg, 0.4 mmol) and cyclopentane (3 mL) to obtain the title compound (69 mg, 35%).

[1191] 1 H NMR (400MHz, DMSO-d6) δ14.02 (s, 1H), 8.99 (s, 1H), 7.40-7.32 (m, 5H), 5.11 (s, 2H), 4.10 (d, J=13.1Hz, 2H), 3.07 (s, 3H), 2.08 (d, J=10.2Hz, 2H), 1.77 (d, J=8.2Hz, 2H).

[1192] LC-MS, m / z 363[M+H] +

[1193] 69.3 Methyl 8-(1-((Benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylate

[1194]

[1195] By the same method as in Preparation 1.2, benzyl 4-(6-cyano-7H-purin-8-yl)piperidine-1-carboxylate (190 mg, 0.52 mmol) and TMSCl (680 μL, 5.4 mmol) were used to obtain the title compound (104 mg, 50%).

[1196] 1 H NMR (400MHz, DMSO-d6) δ13.07 (s, 1H), 9.00 (s, 1H), 7.37 (t, J=11.0Hz, 5H), 5.12 (s, 2H) , 4.13 (d, J=12.7Hz, 2H), 4.00 (s, 3H), 3.02 (s, 3H), 2.03 (d, J=13.9Hz, 2H), 1.82 (s, 2H).

[1197] 69.4 8-(1-((Benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylic acid

[1198]

[1199] By the same procedure as in Preparation 1.3, using methyl 8-(1-((benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylate (100 mg, 0.25 mmol) and 2M NaOH (750 μL, 1.5 mmol), the title compound (95 mg, crude) was obtained.

[1200] LC-MS, m / z 382[M+H] +

[1201] 69.5 Benzyl 4-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)piperidine-1-carboxylate

[1202]

[1203] The title compound (50 mg, 42%) was obtained by the same procedure as in Example 1.3 using 8-(1-((benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylic acid (80 mg, crude), (3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (52 mg, 0.25 mmol), T3P (50 wt% solution in EtOAc, 187 μL, 0.63 mmol) and DIPEA (71 μL, 0.42 mmol).

[1204] 1 H NMR (400MHz, DMSO-d6) δ13.24 (s, 1H), 9.76 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.42-7.29 (m, 7H), 6.99 (d, J=9.4Hz , 1H), 5.11 (s, 2H), 4.57 (d, J=6.2Hz, 2H), 4.11 (d, J=13.2Hz, 2H), 3.85 (s, 3H), 3.00 (s, 3H), 1.99 (s, 2H), 1.81 (d, J=8.9Hz, 2H).

[1205] LC-MS, m / z 569[M+H] +

[1206] Example 70

[1207] N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(piperidin-4-yl)-7H-purine-6-carboxamide hydrochloride

[1208]

[1209] 4-(6-((3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)piperidine-1-carboxylate (40 mg, 0.070 mmol) was dissolved in dioxane (4 mL), HCl (35% to 37%, 728 μL) was added, and the mixture was heated and stirred at 80° C. After 1 hour, the reaction mixture was concentrated, co-evaporated with toluene three times, and then dried under vacuum to obtain the title compound (32 mg, 99%).

[1210] 1H NMR (400MHz, CD3OD) δ9.03 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.42 (s, 1H), 7.20 (d, J = 10.2Hz, 1H), 7.00 (d, J = 9.8Hz, 1H) , 4.69 (s, 2H), 3.92 (d, J = 10.2Hz, 3H), 3.57 (d, J = 12.8Hz, 2H), 3.48 (m, 1H), 3.25-3.18 (m, 2H), 2.35 (m, 2H), 2.21 (m, 2H).

[1211] LC-MS, m / z 435[M+H] +

[1212] Example 71

[1213] N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpiperidin-4-yl)-7H-purine-6-carboxamide

[1214]

[1215] The title compound (8 mg, 23%) was obtained by the same method as in Example 63 using N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(piperidin-4-yl)-7H-purine-6-carboxamide hydrochloride (35 mg, 0.074 mmol), paraformaldehyde (10 mg), NaBH4 (6 mg, 0.15 mmol) and trifluoroethanol (2 mL).

[1216] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.74 (s, 1H), 8.98 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 7.30 (d, J=10.4Hz, 1H), 6.99 (d, J=9.3Hz, 1H), 4.57 (d, J=5.9Hz, 2H), 3.85 (s, 3H), 3.04 (s, 1H), 2.91 (d, J=14.3Hz, 2H), 2.24 (s, 3H), 2.09-1.88 (m, 6H).

[1217] LC-MS, m / z 449[M+H] +

[1218] Example 72

[1219] 72.1 Ethyl 5-amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate

[1220]

[1221] Ethyl 5-amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (270 mg, 0.74 mmol) was dissolved in THF / EtOH (9 mL / 9 mL), ammonium formate (464 mg, 7.36 mmol) and 10% palladium on carbon (Pd / C; 100 mg) were added, and the mixture was stirred at 60° C. After 30 minutes, the solids of the reaction mixture were removed by filtration, and the filtrate was concentrated to obtain the title compound (163 mg, 67%).

[1222] LC-MS, m / z 333[M+H] +

[1223] 72.2 5-Amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid

[1224]

[1225] 5-Amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid ethyl ester (130 mg, 0.39 mmol) was dissolved in THF / EtOH (1.6 mL / 3 mL), 2.0 M NaOH (1.02 mL) was added, and the mixture was stirred at room temperature. After 1 hour, the reaction mixture was cooled to 0° C., acidified to pH 5 with 3 M HCl, and the resulting solid was filtered to obtain the title compound (88 mg, 74%).

[1226] LC-MS, m / z 305 [M+H] +

[1227] 72.3 5-amino-6-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[1228]

[1229] (3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (65 mg, 0.31 mmol), T3P (50 wt% solution in EtOAc) (512 mg, 0.80 mmol) and DIPEA (116 μL, 0.68 mmol) were added to a solution of 5-amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid (80 mg, 0.26 mmol) and DMF (5 mL), and the mixture was stirred at 50° C. After stirring overnight, H2O was added to the reaction mixture and extracted three times with EtOAc. The organic layer was dried over MgSO4 and concentrated, and the obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (46 mg, 36%).

[1230] LC-MS, m / z 492[M+H] +

[1231] 72.4 5,6-Diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[1232]

[1233] 5-Amino-6-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (230 mg, 0.47 mmol) was dissolved in CH Cl (5 mL) solution, TFA (2 mL) was added, and the mixture was stirred at room temperature. After 12 hours, the reaction mixture was concentrated, neutralized with aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over MgSO and concentrated, and the obtained residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (130 mg, 81%).

[1234] LC-MS, m / z 342[M+H] +

[1235] 72.5-Benzyl((6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)methyl)carbamate

[1236]

[1237] To a solution of 5,6-diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (160 mg, 0.46 mmol) in DMF (10 mL) was added ((benzyloxy)carbonyl)glycine (96 mg, 0.46 mmol), T3P (50 wt% solution in EtOAc, 927 mg, 1.45 mmol) and DIPEA (234 μL, 1.37 mmol), and the mixture was stirred at 150° C. using a microwave. After 1 hour, the reaction mixture was concentrated, diluted with CH2Cl2, and washed with H2O. The organic layer was dried over MgSO4 and concentrated, and the residue was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (65 mg, 27%).

[1238] 1 H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 7.34-7.31 (m, 4H), 7 .19 (d, J=12Hz, 1H), 6.98 (t, J=8.0Hz, 2H), 5.10 (s, 2H), 4.67 (s, 2H), 4.66 (s, 2H), 3.88 (s, 3H).

[1239] LC-MS, m / z 515 [M+H] +

[1240] Example 73

[1241] 8-(Aminomethyl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1242]

[1243] Benzyl ((6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)methyl)carbamate (60 mg, 0.12 mmol) was dissolved in dioxane (2.5 mL) and HCl (35% to 37%, 1.2 mL) was added. The mixture was heated at 80 ° C and stirred for 1 hour. The reaction mixture was concentrated and recrystallized from toluene, and the resulting solid was filtered. The solid was dried to obtain the title compound (45 mg, 90%).

[1244] 1H NMR (400MHz, CD3OD) δ9.10 (s, 1H), 8.23 ​​(s, 1H), 8.13 (s, 1H), 7.46 (s, 1H), 7.26 (d, J=12Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 4.70 (s, 2H), 4.60 (s, 2H), 3.99 (s, 3H).

[1245] LC-MS, m / z [M+H] +

[1246] Example 74

[1247] 74.1 7H-purine-6-carboxylic acid methyl ester

[1248]

[1249] By the same method as in Preparation 1.2, using 7H-purine-6-carbonitrile (80 mg, 0.55 mmol) and TMSCl (760 μL), the title compound (63 mg, 64%) was obtained.

[1250] LC-MS, m / z 247 [M+H] +

[1251] 74.2 7H-Purine-6-carboxylic acid

[1252]

[1253] By the same method as in Preparation 1.3, using methyl 7H-purine-6-carboxylate (60 mg, 0.34 mmol) and 2M NaOH (850 μL), the title compound (45 mg, 81%) was obtained.

[1254] LC-MS, m / z 165 [M+H] +

[1255] 74.3 N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1256]

[1257] The title compound (17 mg, 28%) was obtained by the same procedure as in Example 1.3 using 7H-purine-6-carboxylic acid (40 mg, 0.17 mmol), (3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine (55 mg, 0.21 mmol), T3P (50 wt% solution in EtOAc, 335 mg, 1.06 mmol) and DIPEA (76 μL, 0.44 mmol).

[1258] 1 H NMR (400MHz, DMSO-d6) δ13.45(s, 1H), 9.78(s, 1H), 9.05(s, 1H), 8.73(s, 1H), 8.14(s, 1H), 7.86(s , 1H), 7.40 (s, 1H), 7.30 (d, J=12Hz, 1H), 6.99 (d, J=12Hz, 1H), 4.57 (d, J=8.0Hz, 2H), 3.83 (s, 3H).

[1259] LC-MS, m / z 352[M+H] +

[1260] Example 75

[1261] Benzyl 3-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[1262]

[1263] The title compound (45 mg, 54%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (50 mg, 0.15 mmol), 1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (37 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[1264] 1 H NMR (400MHz, CD3OD) δ8.98 (s, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.35-7.31 (m, 5H), 7.20 (d, J=12Hz, 1H ), 7.00 (d, J=12Hz, 1H), 5.13 (d, J=8.0Hz, 2H), 4.67 (s, 2H), 3.89 (s, 3H), 3.71 (m, 1H), 3.56 (m, 4H), 2.44 (m, 2H).

[1265] LC-MS m / z 555[M+H] +

[1266] Example 76

[1267] N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-3-yl)-7H-purine-6-carboxamide hydrochloride

[1268]

[1269] The title compound (15 mg, 57%) was obtained by the same procedure as in Example 73 using benzyl 3-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate (Example 108) (30 mg, 0.058 mmol) and HCl (35% to 37%, 540 μL).

[1270] 1 H NMR (400MHz, CD3OD) δ8.82 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.43 (s, 1H), 7.20 (d, J=8.0Hz, 1H), 7.02 (d, J= 8.0Hz, 1H), 4.69 (s, 2H), 3.90 (s, 3H), 3.81 (m, 1H), 3.53-3.45 (m, 2H), 3.19-3.15 (m, 2H), 2.41-2.31 (m, 2H).

[1271] LC-MS, m / z 421[M+H] +

[1272] Example 77

[1273] 8-(6,6-difluorobicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1274]

[1275] The title compound (7 mg, 10%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (50 mg, 0.15 mmol), 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (37 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[1276] 1H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.20 (d, J=8Hz, 1 H), 7.00 (d, J=12Hz, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.63 (m, 1H), 2.24 (m, 4H), 2.06 (m, 2H).

[1277] LC-MS, m / z 468[M+H] +

[1278] Example 78

[1279] 8-(Bicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1280]

[1281] The title compound (3.3 mg, 5%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (50 mg, 0.15 mmol), bicyclo[3.1.0]hexane-3-carboxylic acid (19 mg, 0.15 mmol), T3P (50 wt% solution in EtOAc, 305 mg, 0.48 mmol) and DIPEA (66 μL, 0.39 mmol).

[1282] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.40 (s, 1H), 7.19 (d, J=8Hz, 1H), 6.99 (d, J=8Hz, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.17 (m, 1H), 2.27 (m, 4H), 1.47 (m, 2H), 0.47-0.40 (m, 2H).

[1283] LC-MS m / z 432[M+H] +

[1284] Example 79

[1285] N-(3-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-3-yl)-7H-purine-6-carboxamide

[1286]

[1287] By the same method as in Example 63, using N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-3-yl)-7H-purine-6-carboxamide hydrochloride (15 mg, 0.036 mmol), paraformaldehyde (5 mg), NaBH4 (3 mg, 0.075 mmol) and trifluoroethanol (1 mL) to obtain the title compound (7 mg, 45%).

[1288] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.42 (s, 1H), 7.21 (d, J = 12Hz, 1H), 7.00 (d, J = 8.0Hz, 1H) , 4.71 (s, 2H), 4.07 (m, 1H), 3.90 (s, 3H), 3.65-3.57 (m, 2H), 3.38-3.34 (m, 2H), 2.85 (s, 3H), 2.63 (m, 1H), 2.40 (m, 1H).

[1289] LC-MS, m / z 435[M+H] +

[1290] Example 80

[1291] 80.1 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid

[1292]

[1293] By the same method as in Preparation Example 1, the title compound (260 mg, 78%) was obtained as a white solid.

[1294] 1 H NMR (400MHz, CD3OD) δ9.02 (s, 1H), 3.81 (m, 1H), 2.88-2.62 (m, 2H), 2.40-2.34 (m, 2H), 2.28-2.24 (m, 2H).

[1295] LC-MS, m / z 269[M+H] +

[1296] 80.2 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1297]

[1298] The title compound (115 mg, 57%) was obtained by the same procedure as in Example 1.3 using 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (100 mg, 0.37 mmol), (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine (106 mg), T3P (50 wt% solution in EtOAc, 356 mg, 1.12 mmol) and DIPEA (217 mg, 1.68 mmol).

[1299] 1 H NMR (400MHz, CD3OD) δ8.99 (s, 1H), 8.61 (s, 1H), 8.08 (s, 1H), 7.83-7.75 (m, 2H), 7.53 (s, 1H), 7.32 (d, J=10Hz, 1H), 7.24 (t, J =8.4Hz, 2H), 7.05 (d, J = 9.2Hz, 1H), 4.71 (s, 2H), 3.84-3.73 (m, 1H), 2.71-2.60 (m, 2H), 2.4-2.33 (m, 2H), 2.30-2.18 (m, 2H).

[1300] LC-MS, m / z 536[M+H] +

[1301] Example 81

[1302] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1303]

[1304] The title compound (18 mg, 43%) was obtained by the same procedure as in Example 1.3 using 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (10 mg, 0.037 mmol), (3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (12 mg), T3P (50 wt% solution in EtOAc, 67 μL, 0.11 mmol) and DIPEA (29 μL, 0.17 mmol).

[1305] 1H NMR (400MHz, DMSO-d6) δ13.34(s, 1H), 9.82(s, 1H), 9.13(s, 1H), 9.01(s, 1H) , 8.29 (s, 1H), 7.76 (d, J=8.9Hz, 2H), 7.62-7.54 (m, J=10.1Hz, 2H), 7.49 (d, J =9.9Hz, 1H), 7.19 (t, J = 7.8Hz, 1H), 7.09 (d, J = 9.1Hz, 1H), 4.62 (d, J = 6.3Hz, 2H), 3.80(mzz, 1H), 2.69-2.58(m, 2H), 2.37-2.27(m, 2H), 2.23-2.09(m, 2H).

[1306] LC-MS, m / z 536[M+H] +

[1307] Example 82

[1308] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1309]

[1310] The title compound (11 mg, 54%) was obtained by the same procedure as in Example 1.3 using 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (10 mg, 0.037 mmol), (3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (12 mg), T3P (50 wt% solution in EtOAc, 67 μL, 0.11 mmol) and DIPEA (29 μL, 0.17 mmol).

[1311] 1 H NMR (400MHz, DMSO-d6) δ13.34(s, 1H), 9.83(s, 1H), 9.12(s, 1H), 9.01(s, 1H), 8.77 (s, 1H), 8.46 (t, J=6.5Hz, 1H), 8.33 (s, 1H), 7.59 (s, 1H), 7.48 (d, J=10.0H z, 1H), 7.41 (dd, J=8.9, 2.8Hz, 1H), 7.10 (d, J=8.9Hz, 1H), 4.62 (d, J=6.2Hz, 2H ), 3.85-3.76 (m, 1H), 2.68-2.59 (m, 2H), 2.37-2.27 (m, 2H), 2.23-2.09 (m, 2H).

[1312] LC-MS, m / z 537 [M+H] +

[1313] Example 83

[1314] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1315]

[1316] The title compound (31 mg, 75%) was obtained by the same procedure as in Example 1.3 using 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (21 mg, 0.079 mmol), (3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (24 mg), T3P (50 wt% solution in EtOAc, 140 μL, 0.24 mmol) and DIPEA (60 μL, 0.36 mmol).

[1317] 1 H NMR (400MHz, DMSO-d6) δ13.33 (s, 1H), 9.80 (t, J=5.7Hz, 1H), 9.17 (s, 2H), 9.02(s, 1H), 8.58(s, 1H), 8.34(s, 1H), 8.30(d, J=8.0Hz, 1H), 7.68-7.56(m , 2H), 7.50 (d, J=9.5Hz, 1H), 7.10 (d, J=9.5Hz, 1H), 4.62 (d, J=6.0Hz, 2H), 3 .86-3.77(m, 1H), 2.70-2.58(m, 2H), 2.39-2.27(m, 2H), 2.24-2.08(m, 2H).

[1318] LC-MS, m / z 519 [M+H] +

[1319] Example 84

[1320] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide (E1, E2)

[1321]

[1322] 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide (100 mg) obtained in Example 80 above was separated by SFC (column: Daicel Chiralpak AD, 250×50 mm ID 10 μm, mobile phase: A is CO2 and B is 2-propanol (0.1% NH3H2O), gradient: B% = 45% isocratic elution mode), and the fractions containing each enantiomer were concentrated and lyophilized to obtain the title compounds E1 (36 mg) and E2 (36 mg).

[1323] E1 (retention time: 2.04 minutes, column: Daicel Chiralpak AD-3, 50×4.6 mm id., 3 μm, mobile phase: A is CO 2 and B is 2-propanol (0.1% isopropylamine, v / v), mobile phase: B% from 5% to 50% in 2 minutes).

[1324] 1 H NMR (400MHz, DMSO-d6) δ13.33 (s, 1H), 9.80 (s, 1H), 9.03 (s, 1H), 9.01 (s, 1H), 8.24 (s, 1H), 7.94-7.86 (m, 2H), 7.58 (s, 1H), 7.47 (d, J=10.1Hz, 1H) , 7.39 (t, J=8.8Hz, 2H), 7.07 (d, J=9.5Hz, 1H), 4.61 (d, J=6.2Hz, 2H), 3.8 8-3.74 (m, 1H), 2.73-2.55 (m, 2H), 2.41-2.26 (m, 2H), 2.25-2.07 (m, 2H).

[1325] LC-MS, m / z 536[M+H] +

[1326] E2 (retention time: 2.29 minutes, column: Daicel Chiralpak AD-3, 50×4.6 mm id., 3 μm, mobile phase: A is CO 2 and B is 2-propanol (0.1% isopropylamine, v / v), mobile phase: B% from 5% to 50% in 2 minutes).

[1327] 1H NMR (400MHz, DMSO-d6) δ13.33 (s, 1H), 9.80 (s, 1H), 9.03 (s, 1H), 9.01 (s, 1H), 8.24 (s, 1H), 7.94-7.86 (m, 2H), 7.58 (s, 1H), 7.47 (d, J=10.2Hz, 1H) , 7.39 (t, J=8.8Hz, 2H), 7.07 (d, J=9.3Hz, 1H), 4.61 (d, J=6.2Hz, 2H), 3.8 7-3.71 (m, 1H), 2.73-2.55 (m, 2H), 2.40-2.25 (m, 2H), 2.24-2.07 (m, 2H).

[1328] LC-MS, m / z 536[M+H] +

[1329] Example 85

[1330] (R)-N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-2-yl)-7H-purine-6-carboxamide

[1331]

[1332] The title compound (12 mg, 24%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (42 mg, 0.10 mmol), (R)-tetrahydrofuran-2-carboxylic acid (12 mg, 0.10 mmol), T3P (50 wt% solution in EtOAc, 203 mg, 0.32 mmol) and DIPEA (66 μL, 0.26 mmol).

[1333] 1 H NMR (400MHz, CD3OD) δ8.99 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.79-7.75 (m, 2H), 7.51 (s, 1H), 7.33 (d, J=12Hz, 1H), 7.22 (t, J=8.0Hz , 2H), 7.04 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 4.69 (s, 2H), 4.16-4.06 (m, 2H), 2.51-2.46 (m, 1H), 2.28-2.23 (m, 1H), 2.09-2.02 (m, 2H).

[1334] LC-MS, m / z 502[M+H] +

[1335] Example 86

[1336] (R)-N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide

[1337]

[1338] The title compound (2.02 mg, 5.5%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (30 mg, 0.071 mmol), (R)-3-oxocyclopentanecarboxylic acid (9.1 mg, 0.071 mmol), T3P (50 wt% solution in EtOAc) (113 mg, 0.355 mmol) and DIPEA (24 μL, 0.14 mmol).

[1339] 1 H NMR (400MHz, CD3OD) δ9.01 (s, 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.81-7.78 (m, 2H), 7.53 (s, 1H), 7.32 (d, J=9.8Hz, 1H), 7.23 (t, J=8. 6Hz, 2H), 7.05 (d, J = 8.9Hz, 1H), 4.71 (s, 2H), 3.75-3.61 (m, 1H), 2.50-2.38 (m, 1H), 2.27 (m, 2H), 2.17-2.05 (m, 2H), 2.01 (m, 1H).

[1340] LCMS, m / z 514 [M+H] +

[1341] Example 87

[1342] 87.1 tert-Butyl 3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1343]

[1344] The same procedure as in Example 25.3 was used using tert-butyl 3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (53 mg, 0.18 mmol), 2-chloro-1-fluoro-4-iodobenzene (70 mg, 0.27 mmol), CuI (3.5 mg, 0.018 mmol), L-proline (4.2 mg, 0.037 mmol), K2CO3 (38 mg, 0.27 mmol) and DMSO (2 mL) to obtain the title compound (57 mg, 74%) as a light brown solid.

[1345] LCMS, m / z 420 [M+H] +

[1346] 87.2(3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[1347]

[1348] The title compound (58 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (57 mg, 0.14 mmol), trifluoroacetic acid (0.45 mL) and DCM (1.4 mL).

[1349] LCMS, m / z 320 [M+H] +

[1350] 87.3 N-(3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1351]

[1352] 8-Cyclopentyl-7H-purine-6-carboxylic acid (26 mg, 0.11 mmol), (3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate (58 mg, crude) and HOBt (18 mg, 0.14 mmol) were dissolved in ethyl acetate (2 mL), DIPEA (29 μL) and EDC (26 mg, 0.14 mmol) were added, and the mixture was stirred at room temperature overnight. Ethyl acetate and H O were added to the reaction mixture, extracted, and the organic layer was dried over MgSO and concentrated. The obtained residue was purified by silica gel column chromatography (0 to 2% MeOH in DCM) to give the title compound (34 mg, 2 steps, 56% yield) as an off-white solid.

[1353] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.77 (s, 1H), 9.12 (s, 1H), 8.97 (s, 1H), 8. 29 (s, 1H), 8.13 (dd, J=6.4, 2.4Hz, 1H), 7.95-7.87 (m, 1H), 7.68-7.56 (m, 2H), 7.4 7 (d, J=10.0Hz, 1H), 7.09 (d, J=9.3Hz, 1H), 4.61 (d, J=6.4Hz, 2H), 3.54-3.44 (m, 1H), 2.12-2.03(m, 2H), 1.99-1.88(m, 2H), 1.85-1.76(m, 2H), 1.71-1.61(m, 2H).

[1354] LCMS, m / z 534 [M+H] +

[1355] Example 88

[1356] (S)-N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide

[1357]

[1358] The title compound (30 mg, 49%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (50 mg, 0.12 mmol), (S)-3-oxocyclopentanecarboxylic acid (15 mg, 0.12 mmol), T3P (50 wt% solution in EtOAc, 203 mg, 0.32 mmol) and DIPEA (66 μL, 0.26 mmol).

[1359] 1 H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.83-7.75 (m, 2H), 7.51 (s, 1H), 7.30 (d, J =8Hz, 1H), 7.21 (t, 2H), 7.04 (d, J = 8Hz, ]H), 4.69 (s, 2H), 3.91 (m, 1H), 2.75 (m, 2H), 2.57-2.27 (m, 4H).

[1360] LCMS, m / z 514 [M+H]+

[1361] Example 89

[1362] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-3-yl)-7H-purine-6-carboxamide

[1363]

[1364] The title compound (0.83 mg, 5%) was obtained by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (13.9 mg, 0.033 mmol), tetrahydrofuran-3-carboxylic acid (3.8 mg, 0.033 mmol), T3P (50 wt% solution in EtOAc) (53 mg, 0.17 mmol) and DIPEA (11.2 μL, 0.66 mmol).

[1365] 1 H NMR (400MHz, CD3OD) δ9.00 (s, 1H), 8.63 (s, 1H), 8.09 (s, 1H), 7.80 (dd, J=9.0, 4.6Hz, 2H), 7.55 (s, 1H), 7.33 (d, J=10.5Hz, 1H), 7.24 ( t, J=8.7Hz, 2H), 7.06 (d, J=8.7Hz, 1H), 4.72 (s, 2H), 4.22 (t, J=8.0Hz, 1H), 4.14-4.04 (m, 2H), 4.00-3.84 (m, 2H), 2.51-2.40 (m, 2H).

[1366] LCMS, m / z 502 [M+H] +

[1367] Example 90

[1368] 90.1(R)-tert-Butyl (1-(3-bromophenyl)ethyl)carbamate

[1369]

[1370] The title compound (140 mg, 95%) was obtained by the same procedure as in Example 6.1 using (R)-1-(3-bromophenyl)ethanamine (200 mg, 1.1 mmol), Boc2O (470 mg, 2.2 mmol) and DCM (5 mL) solution.

[1371] 1H NMR (400MHz, DMSO-d6) δ7.53-7.37 (m, 6H), 7.31-7.24 (m, 4H), 4.64-4.54 (m, 2H), 1.36 (s, 17H), 1.28 (d, J=7.0Hz, 6H).

[1372] 90.2(R)-tert-Butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[1373]

[1374] The title compound (49 mg, 74%) was obtained by the same procedure as in Example 4.1 using tert-butyl (R)-(1-(3-bromophenyl)ethyl)carbamate (52 mg, 0.17 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (54 mg, 0.26 mmol), 2M aqueous K2CO3 solution (0.31 mL, 0.61 mmol), PdCl2(dppf) (6.3 mg, 0.087 mmol) and 1,4-dioxane (0.62 mL).

[1375] LCMS, m / z 382 [M+H] +

[1376] 90.3(R)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[1377]

[1378] To a solution of (R)-tert-butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (49 mg, 0.13 mmol) in DCM (1.3 mL) was slowly added 4M HCl in dioxane (400 μL), and the mixture was stirred at room temperature. After 90 minutes, MeOH was added to the reaction mixture, which was then concentrated. This process was repeated three times to afford the title compound (24 mg, crude) as a white solid.

[1379] LCMS, m / z 282 [M+H] +

[1380] 90.4(R)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[1381]

[1382] The same procedure as in Example 87.3 was used using (R)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride (41 mg), 8-cyclopentyl-7H-purine-6-carboxylic acid (25 mg, 0.11 mmol), EDC (25 mg, 0.13 mmol), HOBt (17 mg, 0.13 mmol), DIPEA (54 μL, 0.32 mmol) and DCM (2 mL) to obtain the title compound (38 mg, 72%) as a light brown solid.

[1383] 1 H NMR (400MHz, DMSO-d6) δ13.12 (s, 1H), 9.40 (d, J=5.8Hz, 1H), 8.94 (s, 2H), 8.18 (s, 1H), 7.90 (dd, J=8.9, 4.7Hz, 2H), 7.81 (s, 1H), 7.57 (s , 1H), 7.42-7.26 (m, 4H), 5.29-5.19 (m, 1H), 3.51-3.40 (m, 1H), 2.12-1.97 (m, 2H), 1.95-1.83 (m, 2H), 1.76 (s, 2H), 1.61 (d, J=6.8Hz, 5H).

[1384] LCMS, m / z 496 [M+H] +

[1385] Example 91

[1386] 91.1(S)-tert-Butyl (1-(3-bromophenyl)ethyl)carbamate

[1387]

[1388] By the same procedure as in Example 6.1, using (S)-1-(3-bromophenyl)ethanamine (100 mg, 0.50 mmol), Boc2O (220 mg, 1.0 mmol) and DCM (3 mL), the title compound (140 mg, 91%) was obtained.

[1389] 1 H NMR (400MHz, DMSO-d6) δ7.55-7.37 (m, 3H), 7.28 (d, J=6.5Hz, 2H), 4.64-4.55 (m, 1H), 1.36 (s, 8H), 1.28 (d, J=7.0Hz, 3H).

[1390] 91.2(S)-tert-Butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[1391]

[1392] The title compound (49 mg, 74%) was obtained by the same procedure as in Example 4.1 above using (S)-tert-butyl(1-(3-bromophenyl)ethyl)carbamate (47 mg, 0.16 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (49 mg, 0.24 mmol), PdCl2(dppf) (6.0 mg, 0.0077 mmol), 2M K2CO3 aqueous solution (0.28 mL, 0.55 mmol) and 1,4-dioxane (0.55 mL).

[1393] LCMS, m / z 382 [M+H] +

[1394] 91.3(S)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[1395]

[1396] By the same procedure as in Example 90.3 using (S)-tert-butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (60 mg, 0.16 mmol), 4M HCl in dioxane (800 μL) and DCM (1.6 mL) the title compound (50 mg, crude) was obtained.

[1397] LCMS, m / z 282 [M+H] +

[1398] 91.4(S)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[1399]

[1400] The same procedure as in Example 87.3 was used using (S)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride (50 mg, 0.16 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (30 mg, 0.13 mmol), EDC (30 mg, 0.16 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (68 μL, 0.39 mmol) and DCM (2 mL) to obtain the title compound (37 mg, 57%) as a light brown solid.

[1401] 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 9.43 (d, J=7.8Hz, 1H), 8.97 (s, 2H), 8.20 (s, 1H), 7.92 (dd, J=9.0, 4.7Hz, 2H), 7.83 (s, 1H), 7.59 (s , 1H), 7.47-7.30(m, 4H), 5.31-5.21(m, 1H), 3.51-3.43(m, 1H), 2.13-2.00(m, 2H), 1.98-1.85(m, 2H), 1.79(s, 2H), 1.64(d, J=6.9Hz, 5H).

[1402] LCMS, m / z 496 [M+H] +

[1403] Example 92

[1404] 8-(3,3-difluorocyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1405]

[1406] The title compound (14.9 mg, 30%) was obtained as an off-white solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (40 mg, 0.095 mmol), 3,3-difluorocyclobutanecarboxylic acid (12.9 mg, 0.095 mmol), T3P (50 wt% solution in EtOAc) (151 mg, 0.475 mmol), DIPEA (32 μL, 0.19 mmol) and 1,4-dioxane (1 mL).

[1407] 1 H NMR (400MHz, DMSO-d6) δ13.40 (s, 1H), 9.81 (s, 1H), 9.03 (s, 2H), 8.24 (s, 1H), 7.91 (dd, J=9.1, 4.7Hz, 2H), 7.58 (s, 1H), 7.47 (d, J=10.3Hz, 1H), 7.39 (t, J=8.8Hz, 2H), 7.07 (d, J=9.5Hz, 1H), 4.61 (d, J=6.2Hz, 2H), 3.87-3.74 (m, 1H), 3.18-2.99 (m, 4H).

[1408] LCMS, m / z 522 [M+H]+

[1409] Example 93

[1410] 2-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[1411]

[1412] The title compound (23 mg, 51%) was obtained by the same procedure as in Example 27.3 using (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (36 mg, 0.11 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (22 mg, 0.09 mmol), T3P (50 wt% solution in EtOAc, 168 mg, 0.53 mmol), DIPEA (38 μL, 0.22 mmol) and DMF (3 mL).

[1413] 1 H NMR (400MHz, CD3OD) δ8.57 (s, 1H), 8.37 (d, J=4Hz, 1H), 8.05 (s, 1H), 7.78-7.75 (m, 2H), 7.69 (s, 1H), 7.51 (s, 1H), 7.30 (d, J= 12Hz, 1H), 7.21 (t, 2H), 7.04 (d, J = 12Hz, 1H), 4.69 (s, 2H), 3.44 (m, 1H), 2.06 (m, 2H), 1.96 (m, 2H), 1.88 (m, 2H), 1.73 (m, 2H).

[1414] LCMS, m / z 499[M+H]+

[1415] Example 94

[1416] 94.1 tert-Butyl 3-bromophenethylcarbamate

[1417]

[1418] By the same procedure as in Example 6.1, using 2-(3-bromophenyl)ethanamine (200 mg, 1.0 mmol), Boc2O (440 mg, 2.0 mmol) and DCM (3 mL), the title compound (290 mg, 96%) was obtained.

[1419] 1H NMR (400MHz, DMSO-d6) δ7.39 (d, J=6.3Hz, 2H), 7.28-7.18 (m, 2H), 6.88 (s, 1H), 3.18-3.10 (m, 2H), 2.69 (t, J=7.0Hz, 2H), 1.35 (s, 9H).

[1420] 94.2 tert-Butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethylcarbamate

[1421]

[1422] The title compound (38 mg, 55%) was obtained by the same procedure as in Example 4.1 using tert-butyl 3-bromophenethylcarbamate (54 mg, 0.18 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (56 mg, 0.27 mmol), PdCl2(dppf) (6.6 mg, 0.0090 mmol), 2M K2CO3 aqueous solution (0.31 mL, 0.63 mmol) and 1,4-dioxane (0.62 mL).

[1423] LCMS, m / z 382 [M+H] +

[1424] 94.3 2-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[1425]

[1426] By the same procedure as in Example 90.3 using tert-butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethylcarbamate (38 mg, 0.10 mmol), 4M HCl in dioxane (500 μL) and DCM (1 mL) the title compound (50 mg, crude) was obtained.

[1427] LCMS, m / z 282 [M+H] +

[1428] 94.4 8-Cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethyl)-7H-purine-6-carboxamide

[1429]

[1430] The title compound (33 mg, 80%) was obtained by the same procedure as in Example 87.3 using 2-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride (32 mg, 0.10 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (19 mg, 0.083 mmol), EDC (19 mg, 0.10 mmol), HOBt (13 mg, 0.10 mmol), DIPEA (42 μL, 0.25 mmol) and DCM (2 mL).

[1431] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.23 (s, 1H), 8.94 (d, J=7.3Hz, 2H), 8.17 ( s, 1H), 7.97-7.85 (m, 2H), 7.62 (s, 1H), 7.56 (d, J=7.6Hz, 1H), 7.43-7.31 (m, 3H) , 7.16 (d, J=7.6Hz, 1H), 3.74-3.65 (m, 2H), 3.55-3.46 (m, 1H), 2.98 (t, J=7.3Hz, 2H), 2.14-2.02(m, 2H), 1.98-1.87(m, 2H), 1.86-1.75(m, 2H), 1.72-1.60(m, 2H).

[1432] LCMS, m / z 496 [M+H] +

[1433] Example 95

[1434] 95.1 tert-Butyl 3-bromo-2-fluorobenzylcarbamate

[1435]

[1436] By the same procedure as in Example 6.1, using (3-bromo-2-fluorophenyl)methanamine (200 mg, 0.98 mmol), Boc2O (430 mg, 2.0 mmol) and DCM (3 mL), the title compound (290 mg, 97%) was obtained.

[1437] 1 H NMR (400MHz, DMSO-d6) δ7.58 (t, J=7.1Hz, 1H), 7.47 (t, J=5.4Hz, 1H), 7.30 (t, J=6.9Hz, 1H), 7.14 (t, J=7.8Hz, 1H), 4.19 (d, J=5.8Hz, 2H), 1.56-1.21 (m, 9H).

[1438] 95.2 tert-Butyl 2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[1439]

[1440] The title compound (50 mg, 73%) was obtained by the same procedure as in Example 4.1 using tert-butyl 3-bromo-2-fluorobenzylcarbamate (54 mg, 0.18 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (55 mg, 0.27 mmol), PdCl2(dppf) (6.4 mg, 0.0088 mmol), 2M K2CO3 aqueous solution (0.31 mL, 0.62 mmol) and 1,4-dioxane (0.62 mL).

[1441] LCMS, m / z 386 [M+H] +

[1442] 95.3 2-Fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride

[1443]

[1444] By the same procedure as in Example 90.3 using tert-butyl 2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.13 mmol), 4M HCl in dioxane (700 μL) and DCM (1.3 mL) the title compound (42 mg, crude) was obtained.

[1445] LCMS, m / z 286 [M+H] +

[1446] 95.4 8-Cyclopentyl-N-(2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1447]

[1448] The title compound (35 mg, 65%) was obtained by the same procedure as in Example 87.3 using (2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (42 mg, 0.13 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (25 mg, 0.11 mmol), EDC (25 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol), DIPEA (66 μL, 0.39 mmol) and DCM (2 mL).

[1449] 1 H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 9.72 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.2 2 (s, 1H), 7.96 (dd, J=9.0, 4.8Hz, 2H), 7.74 (t, J=7.3Hz, 1H), 7.39 (t, J=8.8Hz, 2H) , 7.33 (t, J = 7.0Hz, 1H), 7.22 (t, J = 7.7Hz, 1H), 4.70 (d, J = 6.1Hz, 2H), 3.53-3.46 (m , 1H), 2.13-2.03(m, 2H), 1.98-1.88(m, 2H), 1.86-1.75(m, 2H), 1.72-1.61(m, 2H).

[1450] LCMS, m / z 500 [M+H] +

[1451] Example 96

[1452] 96.1 tert-Butyl 4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[1453]

[1454] The title compound (37 mg, 66%) was obtained by the same procedure as in Example 4.1 using tert-butyl 3-bromo-4-fluorobenzylcarbamate (44 mg, 0.14 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (45 mg, 0.22 mmol), PdCl2(dppf) (5.3 mg, 0.0073 mmol), 2M K2CO3 aqueous solution (0.26 mL, 0.52 mmol) and 1,4-dioxane (0.52 mL).

[1455] LCMS, m / z 386 [M+H] +

[1456] 96.2(4-Fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride

[1457]

[1458] By the same procedure as in Example 90.3 using tert-butyl 4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (37 mg, 0.096 mmol), 4M HCl in dioxane (500 μL) and DCM (1 mL) the title compound (31 mg, crude) was obtained.

[1459] LCMS, m / z 2856 [M+H] +

[1460] 96.3 8-Cyclopentyl-N-(4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1461]

[1462] The title compound (26 mg, 64%) was obtained by the same procedure as in Example 87.3 using (4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride (31 mg, 0.096 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (19 mg, 0.080 mmol), EDC (18 mg, 0.096 mmol), HOBt (13 mg, 0.096 mmol), DIPEA (41 μL, 0.24 mmol) and DCM (2 mL).

[1463] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.74 (s, 1H), 8.96 (s, 1H), 8.87 (s, 1H), 8.17 (s, 1H), 7.95 (dd, J=9.0, 4.7Hz, 2H), 7.84 (d, J=6.0Hz, 1H), 7.38 ( t, J=8.8Hz, 2H), 7.34-7.23 (m, 2H), 4.59 (d, J=6.1Hz, 2H), 3.55-3.44 (m, 1 H), 2.13-2.02(m, 2H), 1.99-1.88(m, 2H), 1.80(s, 2H), 1.71-1.60(m, 2H).

[1464] LCMS, m / z 500 [M+H] +

[1465] Example 97

[1466] 8-(3,3-Dimethylcyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1467]

[1468] The title compound (9.25 mg, 34.5%) was obtained as a yellow solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (22 mg, 0.052 mmol), 3,3-dimethylcyclobutanecarboxylic acid (7 mg, 0.052 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 155 μL, 0.26 mmol) and DIPEA (18 μL, 0.10 mmol).

[1469] 1 H NMR (400MHz, DMSO-d6) δ13.10 (s, 1H), 9.76 (s, 1H), 9.03 (s, 1H), 8.98 (s, 1H), 8.2 5 (d, J=7.3Hz, 1H), 7.91 (dd, J=9.0, 4.7Hz, 2H), 7.58 (s, 1H), 7.47 (d, J=9.5Hz, 1H ), 7.39 (t, J=8.8Hz, 2H), 7.07 (d, J=9.3Hz, 1H), 4.61 (d, J=6.1Hz, 2H), 3.94-3.81 (m, 1H), 2.28 (t, J=10.2Hz, 2H), 2.15 (t, J=10.2Hz, 2H), 1.24 (s, 3H), 1.15 (s, 3H).

[1470] LC-MS, m / z 514 [M+H] +

[1471] Example 98

[1472] 8-(6,6-difluorospiro[3.3]heptane-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1473]

[1474] The title compound (5 mg, 18%) was obtained as a light yellow solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (19.8 mg, 0.047 mmol), 6,6-difluorospiro[3.3]heptane-2-carboxylic acid (8.3 mg, 0.047 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 140 μL, 0.24 mmol) and DIPEA (16 μL, 0.094 mmol).

[1475] 1 H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.82-7.74 (m, 2H), 7.51 (s, 1H), 7.30 (d, J=9. 8Hz, 1H), 7.22 (t, J=8.7Hz, 2H), 7.03 (d, J=9.4Hz, 1H), 4.69 (s, 2H), 3.90-3.79 (m, 1H), 2.81-2.52 (m, 8H).

[1476] LC-MS, m / z 562[M+H] +

[1477] Example 99

[1478] 8-(Bicyclo[1.1.1]pentan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1479]

[1480] The title compound (14.15 mg, 59.9%) was obtained as a yellow solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), bicyclo[1.1.1]pentane-1-carboxylic acid (5.3 mg, 0.048 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol) and DIPEA (16 μL, 0.095 mmol).

[1481] 1H NMR (400MHz, DMSO-d6) δ13.36 (s, 1H), 9.77 (s, 1H), 9.10-8.94 (m, 2H), 8.24 (s, 1H), 7.97-7.82 (m, 2H), 7.58 (s, 1 H), 7.47 (d, J=9.7Hz, 1H), 7.43-7.33 (m, 2H), 7.07 (d, J=9.9Hz, 1H), 4.61 (s, 2H), 2.61-2.55 (m, 1H), 2.31 (s, 6H).

[1482] LC-MS, m / z 498[M+H] +

[1483] Example 100

[1484] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[3.3]heptan-2-yl)-7H-purine-6-carboxamide

[1485]

[1486] The title compound (14.15 mg, 59.9%) was obtained as a light yellow solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), spiro[3.3]heptane-2-carboxylic acid (7 mg, 0.048 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol) and DIPEA (16 μL, 0.095 mmol).

[1487] 1 H NMR (400MHz, CD3OD) δ8.94 (s, 1H), 8.57 (s, 1H), 8.04 (s, 1H), 7.81-7.72 (m, 2H), 7.50 (s, 1H), 7.28 (d, J=9.8Hz, 1H), 7.21 (t, J=8.7Hz, 2H), 7 .02 (d, J=9.2Hz, 1H), 4.68 (s, 2H), 3.78-3.66 (m, 1H), 2.55-2.43 (m, 4H), 2.24-2.12 (m, 2H), 2.02-1.99 (d, J=7.6Hz, 2H), 1.90-1.82 (m, 2H).

[1488] LC-MS, m / z 526[M+H] +

[1489] Example 101

[1490] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7H-purine-6-carboxamide

[1491]

[1492] The title compound (8.43 mg, 34.4%) was obtained as an off-white solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (6.2 mg, 0.048 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol) and DIPEA (16 μL, 0.095 mmol).

[1493] 1 H NMR (400MHz, CD3OD) δ8.99 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.83-7.73 (m, 2H), 7.51 (s, 1H), 7.29 (d, J=9.8Hz, 1H), 7.22 (t, J=8.7Hz, 2H), 7.03 (d, J=9.4Hz, 1H), 4.70 (s, 2H), 2.64 (d, J=2.2Hz, 6H).

[1494] LC-MS, m / z 516 [M+H] +

[1495] Example 102

[1496] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclobutyl)-7H-purine-6-carboxamide

[1497]

[1498] The title compounds were prepared as diastereomers A (3.18 mg, 13.3%) and B (5.29 mg, 22%), respectively, by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), 3-fluorocyclobutanecarboxylic acid (5.6 mg, 0.048 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol) and DIPEA (16 μL, 0.095 mmol).

[1499] Diastereomer A (retention time: 2.363 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B% from 30% to 100% for 4 minutes) / TLC, R f = 0.6 (4% MeOH in DCM), eluted 4 times)

[1500] 1 H NMR (400MHz, CD3OD) δ8.98 (s, 1H), 8.60 (s, 1H), 8.07 (s, 1H), 7.79 (dd, J=9.0, 4.6Hz, 2H), 7.52 (s, 1H), 7.31 (d, J=9.9 Hz, 1H), 7.23 (t, J=8.7Hz, 2H), 7.04 (d, J=9.4Hz, 1H), 5.53-5.29 (m, 1H), 4.70 (s, 2H), 3.96 (s, 1H), 2.93-2.69 (m, 4H).

[1501] LC-MS, m / z 504 [M+H] +

[1502] Diastereomer B (retention time: 2.309 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B% from 30% to 100% for 4 minutes) / TLC, R f = 0.55 (4% ​​MeOH in DCM, eluted 4 times)

[1503] 1H NMR (400MHz, CD3OD) δ8.98 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.78 (dd, J=8.7, 4.5Hz, 2H), 7.51 (s, 1H), 7.30 (d, J=9.8Hz, 1H), 7 .22 (t, J=8.5Hz, 2H), 7.03 (d, J=9.1Hz, 1H), 5.21-4.98 (m, 1H), 4.70 (s, 2H), 3.47-3.36 (m, 1H), 2.88 (s, 2H), 2.78-2.64 (m, 2H).

[1504] LC-MS, m / z 504 [M+H] +

[1505] Example 103

[1506] Methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate

[1507]

[1508] The title compound was prepared as diastereomers A (4.05 mg, 15.7%) and B (4.05 mg, 15.7%), respectively, by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), 3-(methoxycarbonyl)cyclobutanecarboxylic acid (7.5 mg, 0.048 mmol), 1,4-dioxane (1 mL), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol) and DIPEA (16 μL, 0.095 mmol).

[1509] Diastereomer A (retention time: 2.308 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B from 30% to 100% for 4 minutes) / TLC, R f = 0.51 (4% MeOH in DCM), eluted 4 times)

[1510] 1H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.77 (dd, J=8.6, 4.6Hz, 2H), 7.51 (s, 1H), 7.29 (d, J=9.4Hz, 1H), 7.22 (t, J=8.5Hz, 2H), 7.03 (d, J=9.3Hz, 1H), 4.69 (s, 2H), 4.06-3.95 (m, 1H), 3.80-3.66 (m, 3H), 3.46-3.35 (m, 1H), 2.82-2.68 (m, 4H).

[1511] LC-MS, m / z 544[M+H] +

[1512] Diastereomer B (retention time: 2.274 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B% from 30% to 100% for 4 minutes) / TLC, R f = 0.47 (4% MeOH in DCM, eluted 4 times)

[1513] 1 H NMR (400MHz, CD3OD) δ8.97 (s, 1H), 8.60 (s, 1H), 8.06 (s, 1H), 7.78 (dd, J=8.7, 4.7Hz, 2H), 7.52 (s, 1H), 7.31 (d, J=9.5Hz, 1H), 7.23 (t, J=8.6Hz, 2H), 7.03 (d, J=9.0Hz, 1H), 4.70 (s, 2H), 3.94-3.80 (m, 1H), 3.77-3.63 (m, 3H), 3.35-3.33 (m, 1H), 2.87-2.63 (m, 4H).

[1514] LC-MS, m / z 544[M+H] +

[1515] Example 104

[1516] 104.1 tert-Butyl 3-bromo-5-chlorobenzylcarbamate

[1517]

[1518] By the same procedure as in Example 6.1 using (3-bromo-5-chlorophenyl)methanamine (226.6 mg, 1.03 mmol), (Boc)2O (30% in THF, 1.6 mL, 2.06 mmol) and DCM (3.4 mL), the title compound (329 mg, 99%) was obtained as a colorless clear oil.

[1519] 1 H NMR (400MHz, CDCl3) δ7.41 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 1.47 (s, 9H).

[1520] 104.2 tert-Butyl 3-chloro-5-(1H-pyrazol-4-yl)benzylcarbamate

[1521]

[1522] The title compound (197 mg, 62.3%) was obtained as a colorless clear oil by the same procedure as in Example 25.2 using tert-butyl 3-bromo-5-chlorobenzylcarbamate (329 mg, 1.03 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (299 mg, 1.54 mmol), Na2CO3 (381.24 mg, 3.60 mmol), Pd(PPh3)4 (59.4 g, 0.051 mmol), DMF (4.9 mL) and H2O (2 mL).

[1523] LC-MS, m / z 308 [M+H] +

[1524] 104.3 tert-Butyl 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[1525]

[1526] The title compound (25 mg, 56%) was obtained as an off-white solid by the same procedure as in Example 25.3 using tert-butyl 3-chloro-5-(1H-pyrazol-4-yl)benzylcarbamate (34.29 mg, 0.11 mmol), 1-fluoro-4-iodobenzene (37 mg, 0.17 mmol), CuI (2.1 mg, 0.011 mmol), L-proline (3 mg, 0.022 mmol), K2CO3 (23 mg, 0.17 mmol) and DMSO (1 mL).

[1527] LC-MS, m / z 402[M+H] +

[1528] 104.4(3-Chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[1529]

[1530] By the same procedure as in Example 25.4 using tert-butyl 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (25 mg, 0.14 mmol), TFA (0.4 mL) and DCM (1.2 mL), the title compound (25.6 mg, crude) was obtained.

[1531] LC-MS, m / z 302[M+H] +

[1532] 104.5 N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1533]

[1534] The title compound (15.0 mg, 47%) was obtained as a light yellow solid by the same procedure as in Example 87.3 using (3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (25.6 mg, 0.062 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (14.5 mg, 0.062 mmol), EDC (14.3 mg, 0.075 mmol), HOBt (10 mg, 0.075 mmol), DIPEA (42 μL, 0.25 mmol) and THF (1.5 mL).

[1535] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.80 (s, 1H), 9.07 (s, 1H), 8.97 (s, 1H), 8.26 (s, 1H), 7.91 (dd, J=9.0, 4.7Hz, 2H), 7.71 (d, J=6.6Hz, 2H), 7.39 ( t, J=8.8Hz, 2H), 7.31 (s, 1H), 4.60 (d, J=6.2Hz, 2H), 3.56-3.43 (m, 1H), 2. 13-2.03 (m, 2H), 2.00-1.88 (m, 2H), 1.88-1.73 (m, 2H), 1.72-1.59 (m, 2H).

[1536] LC-MS, m / z 516 [M+H]+

[1537] Example 105

[1538] 105.1 tert-Butyl (3-bromo-5-fluorophenyl)carbamate

[1539]

[1540] To a solution of 3-bromo-5-fluoroaniline (200mg, 1.1mmol) in DCM (5mL) was added (Boc) O (200mg, 0.93mmol) and TEA (220 μL, 1.6mmol). The mixture was stirred at 50°C overnight. After the reaction was complete, the reaction mixture was concentrated, and the residue obtained was purified by silica gel column chromatography (0 to 10% EtOAc, in hexane) to obtain title compound (170mg, 54%).

[1541] LC-MS, m / z 291[M+H] +

[1542] 105. tert-Butyl 2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)carbamate

[1543]

[1544] The title compound (160 mg, 77%) was obtained as a white solid by the same procedure as in Example 4.1 using tert-butyl (3-bromo-5-fluorophenyl)carbamate (170 mg, 0.57 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (180 mg, 0.86 mmol), PdCl2(dppf) (21 mg, 0.029 mmol), 2M aqueous K2CO3 solution (1 mL) and 1,4-dioxane (2 mL).

[1545] LC-MS, m / z 372[M+H] +

[1546] 105.3 3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)aniline

[1547]

[1548] By the same procedure as in Example 58.2 using tert-butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)carbamate (80 mg, 0.22 mmol), 4M HCl in dioxane (1 mL) and DCM (2 mL), the title compound was obtained as a light yellow solid (58 mg, crude).

[1549] LC-MS, m / z 272 [M+H] +

[1550] 105.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-7H-purine-6-carboxamide

[1551]

[1552] The title compound (4 mg, 4%) was obtained as a light yellow solid by the same procedure as in Example 87.3 using 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)aniline (58 mg, 0.22 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (50 mg, 0.22 mmol), EDC (49 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), DIPEA (110 μL, 0.65 mmol) and THF (2 mL).

[1553] 1 H NMR (400MHz, DMSO-d6) δ13.36 (s, 1H), 11.13 (s, 1H), 9.09-8.99 (m, 2H), 8.20 (s, 1H), 8.13 (s, 1H), 7.93 (dd, J=9.1, 4.7Hz, 2H), 7.84 (d .

[1554] LC-MS, m / z 486 [M+H] +

[1555] Example 106

[1556] 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylic acid

[1557]

[1558] 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)benzyl)carbamoyl)-7H-purine-8-yl)cyclobutanecarboxylic acid methyl ester (18.69mg, 0.034mmol) is dissolved in MeOH (1mL), the 0.1M NaOH aqueous solution (2mL) is added, and the mixture is at room temperature stirred. After 3 hours, by reaction mixture H o dilution, acidification (pH 4 to 5), and with EtOAc extraction. By organic layer MgSO dried and concentrated. The residue obtained is purified by silica gel column chromatography (0 to 10%MeOH in DCM) to obtain title compound, it is prepared into the diastereomer (4.68mg, productive rate 25.7%, diastereomer mixture) as light brown solid.

[1559] 1 H NMR (400 MH, CD3OD + CDCl3, mixture of diastereomers) δ 8.97 (s, 1H), 8.94 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.80-7.70 (m, 4H), 7.51 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 9.8 Hz, 1H), 7.26-7.13 (m, 5H), 7. 04 (d, J=9.5Hz, 1H), 6.95 (d, J=9.1Hz, 1H), 4.74 (s, 2H), 4.71 (s, 2H), 4.06-3.95 (m, 1H), 3.90-3.80 (m, 1H), 3.30-3.24(m, 1H), 3.25-3.16(m, 1H), 2.98-2.81(m, 2H), 2.77(t, J=7.8Hz, 4H), 2.71-2.59(m, 2H).

[1560] LC-MS, m / z 530 [M+H] +

[1561] Example 107

[1562] 107.1 2-Chloro-3-nitroisonicotinic acid

[1563]

[1564] Methyl 2-chloro-3-nitroisonicotinate (100 mg, 0.46 mmol) was dissolved in MeOH (9 mL), 0.1 M NaOH aqueous solution (17 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was acidified (pH 4 to 5) with 1 M HCl aqueous solution, extracted with EtOAc, and the organic layer was dried over MgSO4. The organic layer was concentrated to obtain the title compound (88.24 mg, 94.4%) as a white solid.

[1565] LC-MS.m / z 201[MH] -

[1566] 107.2 2-Chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide

[1567]

[1568] 2-Chloro-3-nitroisonicotinic acid (88.24 mg, 0.44 mmol), (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine (124.3 mg, 0.44 mmol), DIPEA (96 μL, 0.57 mmol) and HATU (199 mg, 0.52 mmol) were dissolved in THF (4 mL) and stirred at room temperature overnight. The reaction mixture was diluted with H O and extracted with EtOAc. The organic layer was dried over MgSO and concentrated to give the title compound (189 mg, crude) as an off-white solid.

[1569] LC-MS, m / z 470 [M+H] +

[1570] 107.3 2-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide

[1571]

[1572] 2-Chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide (189 mg, 0.40 mmol), (2,4-dimethoxyphenyl)methanamine (81 mg, 0.48 mmol) and CsCO (170 mg, 0.52 mmol) were dissolved in 1,4-dioxane (6 mL) and stirred at room temperature overnight. The reaction mixture was diluted with H O and extracted with EtOAc. The organic layer was dried over MgSO and concentrated to afford the title compound (196.4 mg, crude) as a yellow solid.

[1573] LC-MS, m / z 601[M+H] +

[1574] 107.4 3-Amino-N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-2-((2,4-dimethoxybenzyl)amino)isonicotinamide

[1575]

[1576] The title compound (51 mg, 54.7%) was obtained by the same procedure as in Example 61.2 using a mixture of 2-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide (196.4 mg, 0.33 mmol), SnCl2 (310 mg, 1.64 mmol) and EtOH (10 mL).

[1577] LC-MS, m / z 571[M+H] +

[1578] 107.5 2,3-Diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)isonicotinamide

[1579]

[1580] By the same procedure as in Example 61.5, using 3-amino-N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-2-((2,4-dimethoxybenzyl)amino)isonicotinamide (46 mg, 0.087 mmol), TFA (0.54 mL) and DCM (1.6 mL), the title compound (20.54 mg, 60.6%) was obtained.

[1581] LC-MS, m / z 421 [M+H] +

[1582] 107.6 2-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide

[1583]

[1584] The title compound (2.13 mg, 8.7%) was obtained by the same procedure as in Example 72.5 using 2,3-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)isonicotinamide (20.54 mg, 0.049 mmol), cyclopentanecarboxylic acid (6 mg, 0.049 mmol), T3P (50 wt% solution in EtOAc, 146 μL, 0.24 mmol), DIPEA (17 μL, 0.098 mmol) and 1,4-dioxane (1.5 mL).

[1585] 1 H NMR (400MHz, CDCl3+CD3OD) δ9.42-8.34 (m, 2H).8.01 (s, 1H), 7.84 (d, J=5.1Hz, 1H), 7.73 (dd, J=8.9, 4.4Hz, 2H), 7.49 (s, 1H), 7.30-7.18 ( m, 3H), 7.10 (d, J = 8.9Hz, 1H), 4.81 (s, 2H), 3.42-3.35 (m, 1H), 2.21-2.09 (m, 2H), 2.06-1.92 (m, 2H), 1.87-1.75 (m, 2H), 1.75-1.64 (m, 2H).

[1586] LC-MS, m / z 499[M+H] +

[1587] Example 108

[1588] 108.1 tert-Butyl 4-bromobenzylcarbamate

[1589]

[1590] By the same procedure as in Example 6.1 using (4-bromophenyl)methanamine (100 mg, 0.54 mmol), (Boc)2O (30% in THF, 421 μL, 0.55 mmol), TEA (113 μL, 0.81 mmol) and DCM (1 mL), the title compound was obtained as a white solid (149 mg, 96.9%).

[1591] 1H NMR (400MHz, CDCl3) δ7.45 (d, J=8.3Hz, 2H), 7.16 (d, J=8.2Hz, 2H), 4.85 (broad peak, 1H), 4.26 (d, J=5.4Hz, 2H), 1.46 (s, 9H).

[1592] 108.2 tert-Butyl 4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[1593]

[1594] The title compound (131 mg, 70.9%) was obtained as a white solid by the same procedure as in Example 4.1 using tert-butyl 4-bromobenzylcarbamate (144 mg, 0.50 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (156 mg, 0.76 mmol), PdCl2(dpPf) (7.2 mg, 0.0099 mmol), 2MK2CO3 (0.9 mL, 1.76 mmol) and 1,4-dioxane (3.5 mL).

[1595] LC-MS, m / z 368[M+H] +

[1596] 108.3(4-(1-(4-Fluorophenyl)-1H-pyrazol-4-yl)phenyl)methylamine trifluoroacetate

[1597]

[1598] The title compound (63 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (50.38 mg, 0.14 mmol), TFA (0.5 mL) and DCM (1.4 mL).

[1599] LC-MS, m / z 268[M+H] +

[1600] 108.4 8-Cyclopentyl-N-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1601]

[1602] The title compound (36.25 mg, 54.95%) was obtained as a light yellow solid by the same procedure as in Example 87.3 using (4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (52 mg, 0.14 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (31.8 mg, 0.14 mmol), EDC (31.5 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (70 μL, 0.41 mmol) and THF (1.4 mL).

[1603] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.72 (t, J = 6.2Hz, 1H). 8.95 (d, J = 9.3Hz, 2H), 8.18 (s, 1H), 7.90 (dd, J = 9.0, 4.8Hz, 2H), 7.66 (d, J = 8.0Hz , 2H), 7.46-7.32 (m, 4H), 4.56 (d, J=6.2Hz, 2H), 3.57-3.44 (m, 1H), 2.15 -2.03 (m, 2H), 2.10-1.86 (m, 2H), 1.85-1.74 (m, 2H), 1.73-1.59 (m, 2H).

[1604] LC-MS, m / z 482[M+H] +

[1605] Example 109

[1606] 109.1 3-Fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzonitrile

[1607]

[1608] By the same procedure as in Example 4.1, using 4-bromo-3-fluorobenzonitrile (100 mg, 0.50 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (155 mg, 0.75 mmol), PdCl2(dppf) (18.3 mg, 0.025 mmol), 2MK2CO3 (0.9 mL, 1.76 mmol) and 1,4-dioxane (3.5 mL) to obtain the title compound (116 mg, 82.6%) as a white solid.

[1609] 1H NMR (400MHz, CDCl3) δ 8.33 (d, J = 1.8Hz, 1H), 8.11 (s, 1H), 7.77-7.67 (m, 3H), 7.54-7.43 (m, 2H), 7.24-7.15 (m, 2H).

[1610] LC-MS, m / z 282 [M+H] +

[1611] 109.2(3-Fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine

[1612]

[1613] By the same procedure as in Example 7.2 using 3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzonitrile (46.2 mg, 0.16 mmol), LAH (2M in THF, 0.16 mL, 0.36 mmol) and THF (2 mL), the title compound was obtained as a yellow solid (20.34 mg, 40%).

[1614] LC-MS, m / z 286[M+H] +

[1615] 109.3 8-Cyclopentyl-N-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1616]

[1617] The same procedure as in Example 87.3 was used using (3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine (20.34 mg, 0.071 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (16.6 mg, 0.071 mmol), EDC (16.4 mg, 0.086 mmol), HOBt (12 mg, 0.086 mmol), DIPEA (37 μL, 0.21 mmol) and THF (1.4 mL) to obtain the title compound (14.1 mg, 39.6%) as a light yellow solid.

[1618] 1H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.78 (t, J=6.2Hz, 1H), 8.97 (s, 1H), 8.8 6 (s, 1H), 8.16 (s, 1H), 7.93 (dd, J=9.0, 4.8Hz, 2H), 7.78 (t, J=8.0Hz, 1H), 7.3 7(t, J=8.8Hz, 2H), 7.33-7.25(m, 2H), 4.58(d, J=6.3Hz, 2H), 3.56-3.44(m, 1H ), 2.14-2.02(m, 2H), 2.00-1.88(m, 2H), 1.86-1.75(m, 2H), 1.72-1.60(m, 2H).

[1619] LC-MS, m / z 500[M+H] +

[1620] Example 110

[1621] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclopentyl)-7H-purine-6-carboxamide

[1622]

[1623] The title compound was prepared as diastereomers A (1.2 mg, 4.9%) and B (1.2 mg, 4.9%), respectively, by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), 3-fluorocyclopentanecarboxylic acid (6.3 mg, 0.048 mmol), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol), DIPEA (16 μL, 0.095 mmol) and 1,4-dioxane (1 mL).

[1624] Diastereomer A (retention time: 2.44 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B from 30% to 100% for 4 minutes) / TLC, R f = 0.49 (2% MeOH in DCM), eluted 4 times)

[1625] 1H NMR (400MHz, CDCl3) δ10.63 (s, 1H), 9.05 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.68 (dd, J=9.0, 4.6Hz, 2H), 7.33 (s, 1H), 7.22-7.13 (m, 3H), 7.00 (d, J=9.4Hz, 1H), 5.47-5.27 (m, 1H), 4.74 (d, J=6.1Hz, 2H), 3.80-3.67 (m, 1H), 2.64-1.98 (m, 6H).

[1626] LC-MS, m / z 518 [M+H] +

[1627] Diastereomer B (retention time: 2.36 minutes, column: XSELECT CSH C18 3.0×50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v) and B is acetonitrile (0.01% formic acid v / v), gradient: B% from 30% to 100%, 4 minutes) / TLC, R f = 0.47 (2% MeOH in DCM, eluted 4 times)

[1628] 1 H NMR (400MHz, CDCl3) δ10.59 (s, 1H), 9.05 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.73-7.64 (m, 2H), 7.33 (s, 1H) ), 7.22-7.14 (m, 3H), 7.00 (d, J=8.6Hz, 1H), 5.50-5.27 (m, 1H), 4.74 (d, J=6.3Hz, 2H), 3.83 (m, 1H), 2.59-1.94 (m, 6H).

[1629] LC-MS, m / z 518 [M+H] +

[1630] Example 111

[1631] N-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[2.3]hexan-5-yl)-7H-purine-6-carboxamide

[1632]

[1633] The same procedure as in Example 72.5 was used using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), spiro[2.3]hexane-5-carboxylic acid (6 mg, 0.048 mmol), T3P (50 wt% solution in EtOAc, 142 μL, 0.24 mmol), DIPEA (16 μL, 0.095 mmol) and 1,4-dioxane (2 mL) to obtain the title compound (1.6 mg, 4.8%) as an off-white solid.

[1634] 1 H NMR (400MHz, CD3OD) δ8.98 (s, 1H), 8.62 (s, 1H), 8.08 (s, 1H), 7.80 (dd, J=7.7, 5.0Hz, 2H), 7.55 (s, 1H), 7.33 (d, J=9.2Hz, 1H), 7.24 (t, J=7.8Hz, 2H), 7.05 (d, J=9.8Hz, 1H), 4.72 (s, 2H), 4.17-4.03 (m, 1H), 2.90-2.75 (m, 2H), 2.57-2.44 (m, 2H), 0.67-0.43 (m, 4H).

[1635] LC-MS, m / z 512 [M+H] +

[1636] Example 112

[1637] 112.1 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl(methyl)carbamate

[1638]

[1639] 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazole-4-yl)benzyl tert-butyl carbamate (100mg, 0.26mmol) is dissolved in THF (2.5mL), and NaH (60% suspension in mineral oil) (7mg, 0.29mmol) is slowly added at 0 DEG C. Reaction temperature is warmed to room temperature, and the mixture is stirred for 20 minutes.MeI (19 μ L, 0.31mmol) is added, and the mixture is stirred at 45 DEG C and spends the night.By reaction mixture H o is quenched, extracted with EtOAc, and by organic layer MgSO dry.Concentrated residue is carried out to purifying to obtain title compound (18.89mg, 18%) by silica gel column chromatography (0 to 15% EtOAc in hexane).

[1640] LC-MS, m / z 400 [M+H] +

[1641] 112.2 1-(3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-N-methylmethanamine trifluoroacetate

[1642]

[1643] The title compound (8.27 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl(methyl)carbamate (8 mg, 0.02 mmol), TFA (0.3 mL) and DCM (1 mL).

[1644] LC-MS, m / z 300 [M+H] +

[1645] 112.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-N-methyl-7H-purine-6-carboxamide

[1646]

[1647] The title compound (8.48 mg, 82.6%, mixture of rotamers) was obtained as a white solid by the same procedure as in Example 87.3 using 1-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-N-methylmethanamine trifluoroacetate (8.27 mg, 0.02 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (5 mg, 0.02 mmol), EDC (5 mg, 0.024 mmol), HOBt (3.24 mg, 0.024 mmol), DIPEA (11 μL, 0.06 mmol) and THF (2 mL).

[1648] 1H NMR (400 MHz, DMSO-d6. rotamer mixture 50 / 50) δ 13.41 (s, 1H), 9.07 (s, 0.5H), 8.98 (s, 0.5H), 8.87 (d, J = 10.8 Hz, 1H), 8.32 (s, 0.5H), 8.20 (s, 0.5H), 7.99-7.86 (m, 2H), 7.60 (s, 0.5H), 7.54(d, J=9.6Hz, 0.5H), 7.50-7.33(m, 3H), 7.19(s, 0.5H), 7.08(s, 0.5H), 4.85(s, 1H), 4.62-4.33 (m, 1H), 3.47-3.25 (m.1H), 3.04 (s, 1.5H), 2.87 (s, 1.5H), 2.15-1.54 (m, 8H).

[1649] LC-MS, m / z 514 [M+H] +

[1650] Example 113

[1651] 8-(Bicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1652]

[1653] The title compound (2.4 mg, 6.6%) was obtained as an off-white solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (30 mg, 0.071 mmol), bicyclo[3.1.0]hexane-3-carboxylic acid (9 mg, 0.071 mmol), T3P (50 wt% solution in EtOAc, 212 μL, 0.36 mmol), DIPEA (24 μL, 0.14 mmol) and 1,4-dioxane (2 mL).

[1654] 1H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.62 (s, 1H), 8.08 (s, 1H), 7.79 (dd, J=8. 9, 4.7Hz, 2H), 7.53 (s, 1H), 7.32 (d, J = 10.3Hz, 1H), 7.24 (1, J = 8.7Hz, 2H), 7. 04(d, J=9.1Hz, 1H), 4.70(s, 2H), 3.23-3.11(m, 1H), 2.26(d, J=8.9Hz, 2H), 2.07-1.87(m, 2H), 1.36-1.27(m, 2H), 0.50-0.43(m, 1H), 0.42-0.11(m, 1H).

[1655] LC-MS, m / z 512 [M+H] +

[1656] Example 114

[1657] 8-(Bicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1658]

[1659] The title compound (3.16 mg, 12.7%) was obtained as an off-white solid by the same procedure as in Example 72.5 using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (20 mg, 0.048 mmol), bicyclo[2.2.1]heptane-2-carboxylic acid (7 mg, 0.048 mmol), T3P (50 wt% solution in EtOAc, 141 μL, 0.24 mmol), DIPEA (16 μL, 0.095 mmol) and 1,4-dioxane (1.5 mL).

[1660] 1 H NMR (400MHz, CD3OD) δ9.01-8.91 (m, J=6.8Hz.1H), 8.61 (s, 1H), 7.79 (dd, J=9.0, 4.6Hz, 2H), 7.53 (s, 1H), 7.32 (d, J=9.9Hz, 1H), 7.23 (t , J=8.7Hz, 2H), 7.05 (d, J=9.4Hz, 1H), 4.71 (s, 2H), 3.21-3.10 (m, 1H), 2.56 (s, 1H), 2.41 (s, 1H), 2.26-2.16 (m, 1H), 1.86-1.17 (m, 8H).

[1661] LC-MS, m / z 526 [M+H] +

[1662] Example 115

[1663] 8-(Bicyclo[2.1.1]hexan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1664]

[1665] The same procedure as in Example 72.5 was used, using 5,6-diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide (30 mg, 0.071 mmol), bicyclo[2.1.1]hexane-1-carboxylic acid (9 mg, 0.071 mmol), T3P (50 wt% solution in EtOAc, 212 μL, 0.36 mmol), DIPEA (24 μL, 0.14 mmol) and 1,4-dioxane (2 mL) to obtain the title compound (1.1 mg, 3%) as an off-white solid.

[1666] 1 H NMR (400MHz, CD3OD) δ8.99 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.81 (dd, J=9.0, 4.6Hz, 2H), 7.55 (s, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.25 (t, J=8.7Hz, 2H), 7.07 (d, J=9.9Hz, 1H), 4.72 (s, 2H), 2.63 (s, 1H), 2.21-1.89 (m, 7H), 1.71-1.55 (m, 2H).

[1667] LC-MS, m / z 512 [M+H] +

[1668] Example 116

[1669] 116.1 tert-Butyl 3-azido-5-fluorobenzylcarbamate

[1670]

[1671] By tert-butyl 3-bromo-5-fluorobenzylcarbamate (300mg, 0.99mmol), NaN (128mg, 1.97mmol), CuI (38mg, 0.20mmol), trans-N, N' dimethylcyclohexane-1,2-diamine (47 μ L, 0.30mmol) and sodium ascorbate (20mg, 0.099mmol) are dissolved in EtOH (7mL) / H in O (3mL), and the mixture is stirred at 100 ℃ and spends the night.The reaction mixture is diluted with H O, extracted with EtOAc, and the organic layer is dried with Na SO.The organic layer is concentrated to obtain title compound (263mg, 99%).

[1672] 116.2 tert-Butyl 3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzylcarbamate

[1673]

[1674] By tert-butyl 3-azido-5-fluorobenzylcarbamate (263mg, 0.99mmol), 1-ethynyl-4-fluorobenzylcarbamate (119mg, 0.99mmol), CuSO 5H 10% aqueous solution of O (767 μ L, 0.30mmol) and sodium ascorbate (59mg, 0.30mmol) are dissolved in t-BuOH (5mL) / H In O (5mL), and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with H O, extracted with EtOAc, and the organic layer is dried with MgSO . The organic layer is concentrated, and the residue obtained is purified by silica gel column chromatography (0 to 20% EtOAc in hexane) to obtain title compound (222.7mg, 57.6%).

[1675] 1 H NMR (400MHz, CDCl3) δ8.14 (s, 1H), 7.92-7.85 (m, 2H), 7.54 (s, 1H), 7.46 (d, J=8.3Hz, 1H), 7. 17 (t, J=8.5Hz, 2H), 7.11 (d, J=8.8Hz, 1H), 5.05 (s, 1H), 4.42 (d, J=5.9Hz, 2H), 1.48 (s, 9H).

[1676] 116.3(3-Fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine trifluoroacetate

[1677]

[1678] By the same procedure as in Example 25.4, using tert-butyl 3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzylcarbamate (33.32 mg, 0.086 mmol), TFA (0.3 mL) and DCM (1 mL), the title compound (34.4 mg, crude) was obtained.

[1679] LC-MS, m / z 287 [M+H] +

[1680] 116.4 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7H-purine-6-carboxamide

[1681]

[1682] The same procedure as in Example 87.3 was used using (3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine trifluoroacetate (34.4 mg, 0.086 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (20 mg, 0.086 mmol), EDC (20 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), DIPEA (44 μL, 0.26 mmol) and THF (2 mL) to obtain the title compound (29.57 mg, 68.7%) as a light yellow solid.

[1683] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.90 (s, 1H), 9.32 (s, 1H), 8.98 (s, 1H), 7.95 (dd, J=8.6, 5.6Hz, 2H), 7.90 (s, 1H), 7.75 (d, J=9.5Hz, 1H ), 7.42-7.30 (m, 3H), 4.68 (d, J = 6.2Hz, 2H), 3.55-3.43 (m, 1H), 2.13-2.02 (m, 2H), 1.99-1.86 (m, 2H), 1.85-1.74 (m, 2H), 1.70-1.59 (m, 2H).

[1684] LC-MS, m / z 501[M+H] +

[1685] Example 117

[1686] 117.1 tert-Butyl 3-fluoro-5-(1-(thien-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1687]

[1688] The title compound (186.19 mg, 72.3%) was obtained as a yellow solid by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (201.53 mg, 0.69 mmol), 3-iodothiophene (218.4 mg, 1.04 mmol), CuI (13 mg, 0.069 mmol), L-proline (16 mg, 0.14 mmol), K2CO3 (144 mg, 1.04 mmol) and DMSO (6 mL).

[1689] LC-MS, m / z 374 [M+H] +

[1690] 117.2(3-Fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[1691]

[1692] The title compound (150 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (144.45 mg, 0.39 mmol), TFA (1.3 mL) and DCM (4 mL).

[1693] LC-MS, m / z 274 [M+H] +

[1694] 117.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(thien-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1695]

[1696] The title compound (137.3 mg, 72.8%) was obtained as a yellow solid by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (150 mg, 0.39 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (89.8 mg, 0.39 mmol), EDC (89 mg, 0.46 mmol), HOBt (63 mg, 0.46 mmol), DIPEA (197 μL, 1.16 mmol) and THF (4 mL).

[1697] 1H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.78 (t, J=6.4Hz, 1H), 8.97 (s, 1H), 8 .91(s, 1H), 8.18(s, 1H), 7.76-7.69(m, 2H), 7.61-7.53(m, 2H), 7.44(d, J=10 .0Hz, 1H), 7.06 (d, J=9.3Hz, 1H), 4.60 (d, J=6.1Hz, 2H), 3.55-3.43 (m, 1H), 2.15-2.02(m, 2H), 1.98-1.87(m, 2H), 1.86-1.72(m, 2H), 1.75-1.57(m, 2H).

[1698] LC-MS, m / z 488[M+H] +

[1699] Example 118

[1700] 118.1 3-Fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzonitrile

[1701]

[1702] The title compound (0.364 g, 33.7%) was obtained as a yellow solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (1 g, 5.00 mmol), 1-methyl-1H-pyrazol-3-amine (434 μL, 5.00 mmol), Pd2(dba)3 (91.6 mg, 0.100 mmol), Xantphos (145 mg, 0.250 mmol), K2CO3 (2.07 g, 15.0 mmol) and dioxane (31 mL).

[1703] 1 H NMR (400MHz, CDCl3) δ7.28 (d, J=2.0Hz, 1H), 7.22-7.13 (m, 2H), 6.78 (d, J=7.9Hz, 1H), 6.12 (s, 1H), 5.91 (d, J=2.2Hz, 1H), 3.84 (s, 3H).

[1704] LC-MS, m / z 217 [M+H] +

[1705] 118.2N-(3-(Aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-3-amine

[1706]

[1707] 3-Fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzonitrile (0.36 g, 1.66 mmol) was dissolved in THF (17 mL), LAH solution (2.0 M in THF; 1.7 mL) was added at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, cooled to 0°C, quenched by the addition of MeOH, and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to afford the title compound (321 mg, 87.5%) as a yellow oil.

[1708] 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.16 (d, J = 12.3Hz , 1H), 6.85 (s, 1H), 6.46 (d, J=9.9Hz, 1H), 5.75 (d, J=2.2Hz, 2H), 3.72 (s, 3H).

[1709] LC-MS, m / z 221[M+H] +

[1710] 118.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzyl)-7H-purine-6-carboxamide

[1711]

[1712] The title compound (0.155 g, 25.6%) was obtained as a yellow solid by the same procedure as in Example 87.3 using N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-3-amine (0.306 g, 1.39 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (0.323 g, 1.39 mmol), HOBt (0.320 g, 1.67 mmol), EDC (0.320 g, 1.67 mmol) and THF (32 mL).

[1713] 1H NMR (400MHz, DMSO-d6) δ13.15 (bs, 1H), 9.67 (t, J=5.0Hz, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 7.45 (d, J=2.0Hz, 1H), 7.21 (d, J=12.3Hz, 1H), 6.92 (s, 1H), 6.48 (d, J=8.9Hz, 1H), 5.70 (d, J=2.2Hz, 1H), 4.46 (d, J=6.1Hz, 2H), 3.64 ( s, 3H), 2.05 (s, 2H), 1, 93 (d, J=7.9Hz, 2H), 1.79 (s, 2H), 1.68-1.62 (m, 2H).

[1714] LC-MS, m / z 435[M+H] +

[1715] Example 119

[1716] 119.1 tert-Butyl 3-fluoro-5-((trimethylsilyl)ethynyl)benzylcarbamate

[1717]

[1718] By tert-butyl 3-bromo-5-fluorobenzylcarbamate (100mg, 0.33mmol), TMSA (52mg, 0.53mmol), CuI (3mg, 0.016mmol), Pd(PPh ) (19mg, 0.016mmol) and Et The mixture of N (3mL) was stirred at 110 ℃ and spent the night.Reactant mixture H o was diluted, extracted with DCM, and by organic layer MgSO dry.Concentrated residue was purified by silica gel column chromatography (0 to 20% EtOAc in hexane) to obtain the title compound (42.8mg, 40.5%) as yellow oil.

[1719] 1 H NMR (400MHz, CDCl3) δ7.16 (s, 1H), 7.05 (d, J=8.4Hz, 2H), 6.96 (d, J=9.0Hz, 2H), 4.86 (broad peak, 1H), 4.28 (d, J=5.4Hz, 2H), 1.46 (s, 9H), 0.24 (s, 9H).

[1720] 119.2 tert-Butyl 3-ethynyl-5-fluorobenzylcarbamate

[1721]

[1722] tert-Butyl 3-fluoro-5-((trimethylsilyl)ethynyl)benzylcarbamate (40 mg, 0.12 mmol) was dissolved in THF (2 mL) and then TBAF (1 M in THF, 0.19 mL, 0.19 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane) to obtain the title compound (31 mg, 99%).

[1723] 119.3 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzylcarbamate

[1724]

[1725] By tert-butyl 3-ethynyl-5-fluorobenzylcarbamate (31mg, 0.12mmol), 1-azido-4-fluorobenzene (17mg, 0.12mmol), CuSO 5H 10% aqueous solution (192 μ L, 0.074mmol), sodium ascorbate (14.8mg, 0.074mmol) and t-BuOH (2mL) / H The mixture of O (2mL) was stirred at room temperature overnight. By reaction mixture H O was diluted, extracted with EtOAc, and by organic layer MgSO Drying. Concentrated gained residue was carried out to purifying to obtain title compound (15mg, 31.2%) by silica gel column chromatography (0 to 2%MeOH in DCM).

[1726] LC-MS, m / z 387 [M+H] +

[1727] 119.4(3-Fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)methanamine trifluoroacetate

[1728]

[1729] The title compound (14.4 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzylcarbamate (14 mg, 0.036 mmol), TFA (0.6 mL) and DCM (2 mL).

[1730] LC-MS, m / z 287 [M+H] +

[1731] 119.5 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1732]

[1733] The title compound (14.27 mg, 79.2%) was obtained as a yellow solid by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)methanamine trifluoroacetate (14.4 mg, 0.036 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (8.4 mg, 0.036 mmol), EDC (8.3 mg, 0.043 mmol), HOBt (6 mg, 0.043 mmol), DIPEA (18 μL, 0.11 mmol) and THF (2 mL).

[1734] 1 H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.92 (s, 1H), 7.91 (dd, J=8.9.4.7Hz, 2H), 7.80 (s, 1H), 7.56 (d, J=9.7Hz, 1H), 7.34 (t, J=8.6Hz, 2H ), 7.18 (d, J = 9.2Hz, 1H), 4.75 (s, 2H), 3.55-3.42 (m, 1H), 2.27-2.12 (m, 2H), 2.10-1.98 (m, 2H), 1.96-1.84 (m, 2H), 1.84-1.70 (m, 2H).

[1735] LC-MS, m / z 501[M+H] +

[1736] Example 120

[1737] 120.1 tert-Butyl (3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)carbamate

[1738]

[1739] The title compound (10.5 mg, 21%) was obtained as an off-white solid by the same procedure as in Example 10.1 using tert-butyl (3-bromo-5-fluorobenzyl)carbamate (50 mg, 0.164 mmol), tert-butyl 3-amino-1H-pyrazole-1-carboxylate (30 mg, 0.164 mmol), Pd2(dba)3 (2.9 mg, 0.0032 mmol), Xantphos (5.02 mg, 0.0084 mmol), K2CO3 (53 mg, 0.38 mmol) and dioxane (1.05 mL).

[1740] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J=2.3Hz, 1H), 6.88 (d, J=11.2Hz, 1H), 6.78 (s, 1H), 6.47 (d, J=8. 8Hz, 1H), 6.30 (s, 1H), 6.06 (d, J=2.4Hz, 1H), 4.87 (s, 1H), 4.24 (d, J=6.0Hz, 2H), 1.46 (s, 9H).

[1741] LC-MS, m / z 307 [M+H] +

[1742] 120.2N-(3-(Aminomethyl)-5-fluorophenyl)-1H-pyrazol-3-amine trifluoroacetate

[1743]

[1744] By the same procedure as in Example 25.4 using tert-butyl (3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)carbamate (10 mg, 0.033 mmol), trifluoroacetic acid (0.06 mL) and DCM (0.33 mL), the title compound was obtained as a yellow solid (17 mg, crude).

[1745] LC-MS, m / z 207 [M+H] +

[1746] 120.3N-(3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1747]

[1748] The title compound (5 mg, 36%) was obtained as a yellow solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (7.95 mg, 0.034 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-3-amine trifluoroacetate (17 mg, 0.033 mmol), T3P (propylphosphonic anhydride, 50 wt% solution in DMF, 16 mg) and DMF (0.65 mL).

[1749] 1H NMR (400MHz, DMSO-d6) δ13.18(s, 1H), 12.03(s, 1H), 9.70(s, 1H), 8.96(s, 1H), 8.69 (s, 1H), 7.55 (s, 1H), 7.26 (d, J = 12.3Hz, 1H), 6.93 (s, 1H), 6.49 ( d, J=9.6Hz, 1H), 5.79 (s, 1H), 4.47 (d, J=6.3Hz, 2H), 3.55-3.42 (m, 1H), 2. 14-2.01 (m, 2H), 1.98-1.86 (m, 2H), 1.86-1.73 (m, 2H), 1.73-1.59 (m, 2H).

[1750] LC-MS, m / z 421[M+H] +

[1751] Example 121

[1752] 121.1 3-Fluoro-5-(iso (3-oxazol-3-ylamino)benzonitrile

[1753]

[1754] 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (30 mg, 0.121 mmol), isocyanate Oxazole-3-amine (20mg, 0.243mmol), Cu (OAc) 2(22mg, 0.121mmol) and TEA (34 μ L, 0.243mmol) are dissolved in ACN / EtOH (115 μ L / 6 μ L) and stirred for 1 hour at 80 ℃.Reactant mixture is filtered through diatomaceous earth pad and washed several times with EtOAc.Filtrate is concentrated, and the residue obtained is purified by silica gel column chromatography (0 to 25% EtOAc in hexane) to obtain the title compound (11mg, 41.8%) as white solid.

[1755] 1 H NMR (400MHz, DMSO-d6) δ 9.92 (s, 1H), 8.70 (d, J = 1.7Hz, 1H), 7.60 (d, J = 1.7Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 7.8Hz, 1H), 6.29 (d, J = 1.7Hz, 1H).

[1756] LC-MS, m / z 202 [MH] -

[1757] 121.2N-(3-(Aminomethyl)-5-fluorophenyl)iso Azol-3-amine

[1758]

[1759] 3-Fluoro-5-(iso (4-(2-oxazol-3-ylamino)benzonitrile (11 mg, 0.054 mmol) was dissolved in THF (0.53 mL), LAH solution (2.0 M in THF; 53 μL) was added at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C again, quenched by adding H2O, and stirred for 30 minutes. The resulting solid was filtered and dried in vacuo to afford the title compound (9.6 mg, 87.2%) as a yellow solid.

[1760] LC-MS, m / z 206[MH] -

[1761] 121.3 8-Cyclopentyl-N-(3-fluoro-5-(iso (oxazol-3-ylamino)benzyl)-7H-purine-6-carboxamide

[1762]

[1763] By the same method as in Example 1.3, N-(3-(aminomethyl)-5-fluorophenyl)isothiazolinone was used. To the reaction mixture of oxazol-3-amine (9.6 mg, 0.046 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (10.8 mg, 0.046 mmol), T3P (50 wt% solution in DMF, 81 μL, 0.139 mmol), DIPEA (32 μL, 0.185 mmol) and DMF (0.28 mL) was obtained the title compound (3.8 mg, 18.4%) as a yellow solid.

[1764] 1 H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.32 (d, J = 1.7Hz, 1H), 7.23 (d, J = 11.1Hz, 1H), 7.16 (s, 1H), 6.68 (d, J = 9.2Hz, 1H), 6.10 (d, J = 1.7H z, 1H), 4.65 (s, 2H), 3.53-3.45 (m, 1H), 2.20 (d, J=4.9Hz, 2H), 2.05-2.00 (m, 2H), 1.91 (d, J=8.5Hz, 2H), 1.77 (dd, J=6.9, 4.5Hz, 2H).

[1765] LC-MS, m / z 422[M+H] +

[1766] Example 122

[1767] 122.1 tert-Butyl (3-((4-cyanophenyl)amino)-5-fluorobenzyl)carbamate

[1768]

[1769] The title compound (0.364 g, 33.7%) was obtained as a yellow solid by the same procedure as in Example 10.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5 g, 1.64 mmol), 4-aminobenzonitrile (0.194 g, 1.64 mmol), Pd2(dba)3 (30.1 mg, 0.033 mmol), Xantphos (47.6 mg, 0.082 mmol), K2CO3 (0.523 g, 3.78 mmol) and dioxane (10.3 mL).

[1770] 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.60 (d, J = 8.7Hz, 2H), 7.42 (t, J = 6.2Hz, 1H), 7.12 (d, J = 8.8Hz, 2H), 6.87 (s, 1H), 6.80 (d, J=10.9Hz, 1H), 6.63 (d, J=9.7Hz, 1H), 4.08 (d, J=6.1Hz, 2H), 1.37 (s, 9H).

[1771] 122.2 4-((3-(Aminomethyl)-5-fluorophenyl)amino)benzonitrile trifluoroacetate

[1772]

[1773] By the same procedure as in Example 25.4 using tert-butyl (3-((4-cyanophenyl)amino)-5-fluorobenzyl)carbamate (0.154 g, 0.451 mmol), TFA (1.5 mL) and DCM (4.5 mL) the title compound was obtained as a yellow oil (0.123 mg, 78.4%, crude).

[1774] 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.02 (bs, 2H), 7.64 (d, J = 8.8Hz, 2H), 7.18 (d, J = 8.8Hz, 2H), 7.12 (s, 1H), 6.91 (d, J = 10.4Hz, 2H), 4.00 (s, 2H).

[1775] 122.3N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1776]

[1777] [0.128 g, 79.5%) was obtained by the same procedure as in Example 87.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (82 mg, 0.354 mmol), 4-((3-(aminomethyl)-5-fluorophenyl)amino)benzonitrile trifluoroacetate (0.120 g, 0.354 mmol), HOBt (57.3 mg, 0.424 mmol), EDC (81.4 mg, 0.424 mmol), DIPEA (180 μL, 1.06 mmol) and THF (8.2 mL) to obtain the title compound as a yellow solid (0.128 g, 79.5%).

[1778] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.94 (s, 1H), 7.56 (d, J = 8.6Hz, 2H), 7.10 (d, J = 8.8Hz, 2H) , 6.98 (s, 1H), 6.86-6.76 (m, 2H), 4.51 (d, J=6.4Hz, 2H), 3.47 (s, 1H), 2.05 (s, 2H), 1.91 (s, 2H), 1.79 (s, 2H), 1.64 (s, 2H).

[1779] LC-MS, m / z 456 [M+H] +

[1780] Example 123

[1781] 123.1 tert-Butyl 3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1782]

[1783] The same procedure as in Example 25.3 was used using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (30 mg, 0.103 mmol), 1-(4-iodophenyl)ethanone (38 mg, 0.15 mmol), CuI (2 mg, 0.010 mmol), L-proline (2.4 mg, 0.021 mmol), K2CO3 (21.3 mg, 0.15 mmol) and DMSO (1 mL) to obtain the title compound (30.89 mg, 73%) as an off-white solid.

[1784] LC-MS, m / z 410 [M+H] +

[1785] 123.2 1-(4-(4-(3-(Aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)phenyl)ethanone trifluoroacetate

[1786]

[1787] The title compound (28 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (27.19 mg, 0.066 mmol), TFA (0.3 mL) and DCM (1 mL).

[1788] LC-MS, m / z 310 [M+H] +

[1789] 123.3N-(3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1790]

[1791] The same method as in Example 87.3 was used using 1-(4-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)phenyl)ethanone, trifluoroacetate (28 mg, 0.066 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (15.3 mg, 0.066 mmol), EDC (15.2 mg, 0.079 mmol), HOBt (10.7 mg, 0.079 mmol), DIPEA (34 x L, 0.20 mmol) and THF (2 mL) to obtain the title compound (24.7 mg, 71.5%) as a yellow solid.

[1792] 1H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.79 (tJ=6.4Hz, 1H), 9.22 (s, 1H), 8.97 (s, 1H ), 8.34 (s, 1H), 8.12 (d, J = 8.7Hz, 2H), 8.03 (d, J = 8.5Hz, 2H), 7.62 (s, 1H), 7.52 (d, J =9.8Hz, 1H), 7.09 (d, J = 8.7Hz, 1H), 4.61 (d, J = 6.2Hz, 2H), 3.57-3.43 (m, 1H), 2.61 ( s, 3H), 2.14-2.01 (m, 2H), 2.00-1.86 (m, 2H), 1.86-1.72 (m, 2H), 1.72-1.57 (m, 2H).

[1793] LC-MS, m / z 524 [M+H] +

[1794] Example 124

[1795] 124.1 tert-Butyl 3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1796]

[1797] By the same procedure as in Example 25.3, using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (100 mg, 0.34 mmol), 3-bromofuran (75.5 mg, 0.51 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (70 mg, 0.51 mmol) and DMSO (3 mL), the title compound (32.29 mg, 26.3%) was obtained as a colorless clear oil.

[1798] LC-MS, m / z 358 [M+H] +

[1799] 124.2(3-Fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[1800]

[1801] The title compound (33 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (32.29 mg, 0.066 mmol), TFA (0.3 mL) and DCM (1 mL).

[1802] LC-MS, m / z 258 [M+H] +

[1803] 124.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1804]

[1805] The title compound (27.15 mg, 63.98%) was obtained by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (33 mg, 0.09 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (20.9 mg, 0.09 mmol), EDC (20.7 mg, 0.11 mmol), HOBt (14.6 mg, 0.11 mmol), DIPEA (46 μL, 0.27 mmol) and THF (2 mL) to obtain the title compound as an off-white solid.

[1806] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.77 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.17 (s, 2H), 7.79 (s, 1H), 7.54 (s, 1H), 7.42 (d, J=10.3Hz, 1H ), 7.11-6.99 (m, 2H), 4.59 (d, J=6.3Hz, 2H), 3.59-3.42 (m, 1H), 2.16-2.01 (m, 2H), 1.98-1.85 (m, 2H), 1.86-1.74 (m, 2H), 1.72-1.58 (m, 2H).

[1807] LC-MS, m / z 472[M+H] +

[1808] Example 125

[1809] 125.1 tert-Butyl 3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzylcarbamate

[1810]

[1811] The title compound (25.92 mg, 16.9%) was obtained as a light yellow solid by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (100 mg, 0.34 mmol), 1-benzyl-4-bromo-1H-pyrazole (122 mg, 0.52 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (71.2 mg, 0.51 mmol) and DMSO (3 mL).

[1812] LC-MS, m / z 448 [M+H] +

[1813] 125.2(3-(1'-Benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorophenyl)methanamine trifluoroacetate

[1814]

[1815] The title compound (25 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzylcarbamate (24 mg, 0.054 mmol), TFA (0.3 mL) and DCM (1 mL).

[1816] LC-MS, m / z 348 [M+H] +

[1817] 125.3N-(3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1818]

[1819] The same procedure as in Example 87.3 was used using (3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorophenyl)methanamine trifluoroacetate (25 mg, 0.054 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (12.54 mg, 0.054 mmol), EDC (12.4 mg, 0.065 mmol), HOBt (9 mg, 0.065 mmol), DIPEA (28 μL, 0.16 mmol) and THF (2 mL) to obtain the title compound (18.08 mg, 59.6%) as an off-white solid.

[1820] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.49 (s, 1H), 7.41-7.23 (m, 6H), 7.03 (d, J=9 .6Hz, 1H), 5.36(s, 2H), 4.69(s, 2H), 3.55-3.41(m, 1H), 2.27-2.13(m, 2H), 2.08-1.97(m, 2H), 1.97-1.83(m, 2H), 1.83-1.68(m, 2H).

[1821] LC-MS, m / z 562[M+H] +

[1822] Example 126

[1823] N-(3-((4-Carbamoylphenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1824]

[1825] N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (50 mg, 0.110 mmol) and KCO (30.3 mg, 0.220 mmol) were dissolved in DMSO (0.46 mL) at 0° C., and H0 (35% in H0, 0.16 mL) was added. After stirring at room temperature for 2 hours, H0 was added to the reaction mixture and stirred at room temperature for another hour. The resulting solid was filtered to obtain the title compound (40 mg, 77.0%) as a white solid.

[1826] 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 2H), 8.92 (s, 1H), 8.76-8.69 (m, 1H), 7.74-7.70 (m, 2H), 7.05 (d, J = 8.7Hz, 2H), 6.94 (s, 1H), 6.76 (d, J = 11.0H z, 1H), 6.68 (d, J=8.4Hz, 1H), 4.49 (d, J=6.2Hz, 2H), 3.46 (s, 1H), 2.04 (s, 2H), 1.91 (dd, J=11.1, 7.1Hz, 2H), 1.78 (s, 2H), 1.67-1.60 (m, 2H).

[1827] LC-MS, m / z 474 [M+H] +

[1828] Example 127

[1829] 127.1 Ethyl 4-((3-(((tert-Butoxycarbonyl)amino)methyl)-5-fluorophenyl)amino)benzoate

[1830]

[1831] The title compound (0.212 g, 32.3%) was obtained as a yellow solid by the same procedure as in Example 10.1 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5 g, 1.64 mmol), ethyl 4-aminobenzoate (0.271 g, 1.64 mmol), Pd2(dba)3 (30.1 mg, 0.033 mmol), Xantphos (47.6 mg, 0.082 mmol), K2CO3 (0.523 g, 3.78 mmol) and dioxane (10.3 mL).

[1832] 1 H NMR (400MHz, CD3OD) δ7.87 (d, J=8.8Hz, 2H), 7.09 (d, J=8.8Hz, 2H), 6.92 (s, 1H), 6.74 (d, J=10.5Hz, 1H), 6.58 (d, J=9.2Hz, 1H), 4.30 (q, J=7.1Hz, 2H), 4.18 (s, 2H), 1.44 (s, 9H), 1.36 (d, J=7.1Hz, 3H).

[1833] 127.2 Ethyl 4-((3-(Aminomethyl)-5-fluorophenyl)amino)benzoate trifluoroacetate

[1834]

[1835] By the same procedure as in Example 25,4, using tert-butyl 3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzylcarbamate (0.2 g, 0.451 mmol), TFA (1.7 mL) and DCM (5.1 mL) to obtain the title compound (0.138 g, 69.4%).

[1836] 127.3 Ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate

[1837]

[1838] The title compound (86.2 mg, 48.4%) was obtained as a yellow solid by the same procedure as in Example 87.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (82.4 mg, 0.355 mmol), ethyl 4-((3-(aminomethyl)-5-fluorophenyl)amino)benzoate trifluoroacetate (0.137 g, 0.355 mmol), HOBt (57.5 mg, 0.426 mmol), EDC (81.5 mg, 0.426 mmol), DIPEA (181 μL, 1.06 mmol) and THF (8.2 mL).

[1839] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 7.81 (d, J=8.8Hz, 2H), 7.10-7.03 (m, 3H), 6.78 (d, J=10.9Hz, 1H), 6.73 (d, J=9.5Hz, 1H), 4.63 (s, 2H), 4.3 0 (q, J=7.1Hz, 2H), 3.53-3.43 (m, 1H), 2.20 (d, J=7.9Hz, 2H), 2.06-1.99 (m, 2H), 1.94-1.88 (m, 2H), 1.80-1.72 (m, 2H), 1.35 (t, J=7.1Hz, 3H).

[1840] LC-MS, m / z 503 [M+H] +

[1841] Example 128

[1842] 128.1 tert-Butyl 3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzylcarbamate

[1843]

[1844] By the same procedure as in Example 25.3, using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (100 mg, 0.34 mmol), 4-iodo-1-methyl-1H-pyrazole (107 mg, 0.51 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (71.2 mg, 0.51 mmol) and DMSO (3 mL), the title compound (87.14 mg, 68%) was obtained as a colorless clear oil.

[1845] LC-MS, m / z 372[M+H] +

[1846] 128.2(3-Fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)phenyl)methanamine trifluoroacetate

[1847]

[1848] The title compound (41 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzylcarbamate (40 mg, 0.22 mmol), TFA (0.35 mL) and DCM (1 mL).

[1849] LC-MS, m / z 272 [M+H] +

[1850] 128.3 8-Cyclopentyl-N-(3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzyl)-7H-purine-6-carboxamide

[1851]

[1852] The same procedure as in Example 87.3 was used using (3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)phenyl)methanamine trifluoroacetate (41 mg, 0.11 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (25 mg, 0.11 mmol), EDC (25 mg, 0.13 mmol), HOBt (17.5 mg, 0.13 mmol), DIPEA (55.3 μL, 0.32 mmol) and THF (2 mL) to obtain the title compound (15.15 mg, 29%) as an off-white solid.

[1853] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.77 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H) , 8.13 (d, J = 12.4Hz, 2H), 7.82 (s, 1H), 7.52 (s, 1H), 7.40 (d, J = 10.2Hz, 1H), 7 .04(d, J=9.5Hz, 1H), 4.59(d, J=5.5Hz, 2H), 3.88(s, 3H), 3.54-3.43(m, 1H), 2.14-1.02(m, 2H), 2.00-1.86(m, 2H), 1.86-1.73(m, 2H), 1.71-1.62(m, 2H).

[1854] LC-MS, m / z 486[M+H]+

[1855] Example 129

[1856] 129.1 3-Fluoro-5-((1-methylpiperidin-4-yl)amino)benzonitrile

[1857]

[1858] By the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (100 mg, 0.50 mmol), 1-methylpiperidin-4-amine (68 mg, 0.60 mmol), BINAP (10 mg, 0.016 mmol), Pd2(dba)3 (8.0 mg, 0.009 mmol), sodium tert-butoxide (58 mg, 0.60 mmol) and toluene (1 mL) and stirring at 120°C to obtain the title compound (39 mg, 33%) as a white solid.

[1859] 1 H NMR (400MHz, CD3OD) δ6.70 (s, 1H), 6.61-6.57 (m, 2H), 2.86 (d, J=8Hz, 2H), 2.30 (s, 3H), 2.26-2.20 (m, 2H), 2.01 (d, J=8Hz, 2H), 1.52-1.49 (m, 2H).

[1860] LC-MS, m / z 234 [M+H] +

[1861] 129.2N-(3-(Aminomethyl)-5-fluorophenyl)-1-methylpiperidin-4-amine

[1862]

[1863] By the same procedure as in Example 1.2, using 3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzonitrile (35 mg, 0.15 mmol) and LAH solution (2.0 M in THF; 0.15 mL), the title compound (30 mg, 84%) was obtained as a yellow syrup.

[1864] LC-MS, m / z 238 [M+H] +

[1865] 129.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[1866]

[1867] The title compound (14 mg, 27%) was obtained as a white solid by the same procedure as in Example 87.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (26 mg, 0.11 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-1-methylpiperidin-4-amine (30 mg, 0.13 mmol), HOBt (23 mg, 0.17 mmol), EDC (26 mg, 0.14 mmol), DIPEA (52 μL, 0.30 mmol) and THF (1 mL).

[1868] 1 H NMR (400MHz, CD3OD) δ8.94 (s, 1H), 6.44 (s, 1H), 6.34 (d, J = 12Hz, 1H), 6.24 (d, J = 12Hz, 1H), 4.54 (s, 2H). 3.50-3.45 (m, 1H), 2.98 -2.95 (m, 2H), 2.44-2.35 (m, 6H), 2.18-2.14 (m, 2H), 2.04-2.01 (m, 4H), 1.97-1.91 (m, 2H), 1.78-1.75 (m, 2H), 1.56-1.50 (m, 2H).

[1869] LC-MS, m / z 452[M+H] +

[1870] Example 130

[1871] 130.1 3-Fluoro-5-(thiophen-3-ylamino)benzonitrile

[1872]

[1873] By the same procedure as in Example 10.1, using 3-bromo-5-fluorobenzonitrile (100 mg, 0.50 mmol), thiophene-3-amine oxalate (113 mg, 0.60 mm), Cs2CO3 (489 mg, 1.5 mmol), BINAP (10 mg, 0.016 mmol), Pd2(dba)3 (8.0 mg, 0.009 mmol) and dioxane (2 mL) and reacting at 100°C to obtain the title compound (70 mg, 64%) as a yellow solid.

[1874] 1 H NMR (400MHz, CD3OD) δ7.41-7.39 (t, J=4Hz, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 6.94-6.90 (m, 2H), 6.79 (d, J=8Hz, 1H).

[1875] LC-MS, m / z 219[M+H]+

[1876] 130.2N-(3-(Aminomethyl)-5-fluorophenyl)thiophene-3-amine

[1877]

[1878] By the same procedure as in Example 1.2, using 3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzonitrile (70 mg, 0.32 mmol) and LAH solution (2.0 M in THF; 0.32 mL), the title compound (50 mg, 70%) was obtained as a yellow syrup.

[1879] LC-MS, m / z 223[M+H]+

[1880] 130.3 8-Cyclopentyl-N-(3-fluoro-5-(thien-3-ylamino)benzyl)-7H-purine-6-carboxamide

[1881]

[1882] The title compound (24 mg, 27%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (47 mg, 0.20 mmol), N-(3-(aminomethyl)-5-fluorophenyl)thiophene-3-amine (50 mg, 0.22 mmol), T3P (50 wt% solution in EtOAc, 393 mg) and DIPEA (138 μL).

[1883] 1 H NMR (400MHz, dmso-d6) δ13.19 (s, 1H), 9.74-9.72 (m, 1H), 8.97 (s, 1H), 8.58 (s, 1H), 7.44-7.42 (m, 1H), 6.91-6.83 (m, 3H).6.63 (d, J=12Hz, 1 H), 6.55 (d, J=8Hz, 1H), 4.50 (d, J=8Hz, 2H), 3.53-3.49 (m, 1H), 2.10-2.05 (m, 2H), 1.96-1.89 (m, 2H), 1.84-1.78 (m, 2H), 1.70-1.65 (m, 2H).

[1884] LC-MS, m / z 437[M+H]+

[1885] Example 131

[1886] 131.1 (3-Fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)methanamine

[1887]

[1888] The same method as in Example 8.1 was used, using 1-(4-fluorophenyl)piperazine (150 mg, 0.83 mmol), tert-butyl (3-bromo-5-fluorobenzyl)carbamate (241 mg, 0.79 mmol), Pd2(dba)3 (16.8 mg, 0.018 mmol), BINAP (20.7 mg, 0.033 mmol), NaO t Bu (160 mg, 1.66 mmol) and toluene (1.5 mL) to obtain the title compound (35 mg, 11%) as a brown viscous syrup.

[1889] 1 H NMR (400MHz, CDCl3) δ7.00-6.90 (m, 4H), 6.71 (s, 1H), 6.57-6.48 (m, 2H), 3.84 (s, 2H), 3.37-3.26 (m, 4H), 3.25-3.19 (m, 4H), 2.37 (br s, NH2, 2H).

[1890] LC-MS, m / z 304 [M+H] +

[1891] 131.2 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)benzyl)-7H-purine-6-carboxamide

[1892]

[1893] The title compound (5 mg, 9%) was obtained as an off-white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (27.3 mg, 0.12 mmol), (3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)methanamine (34 mg, 0.11 mmol), T3P (propylphosphonic anhydride, 50 wt% solution in DMF, 23 mg), DIPEA (N,N-diisopropylethylamine, 76 μL) and DMF (2.3 mL).

[1894] 1H NMR (400MHz, CDCl3) δ10.37 (s, 1H), 9.02 (s, 1H), 8.47-8.29 (m, 1H), 7.03-6.87 (m, 4H), 6.71 (s, 1H), 6.58 (d, J = 10.4Hz, 2H), 4.64 (d, J = 6.2Hz, 2H) , 3.48-3.38(m, 1H), 3.38-3.29(m, 4H), 3.27-3.18(m, 4H), 2.30-2.17(m, 2H), 2.05 (td, J=15.6, 7.8Hz, 2H), 1.97-1.85 (m, 2H), 1.83-1.72 (m, 2H).

[1895] LC-MS, m / z 518 [M+H] +

[1896] Example 132

[1897] 132.1 tert-Butyl (3-fluoro-5-(1H-tetrazol-5-yl)benzyl)carbamate

[1898]

[1899] By (3-cyano group-5-fluorobenzyl) t-butyl carbamate (80mg, 0.32mmol), NaN (42mg, 0.64mmol) and NH Cl (34mg, 0.64mmol) is dissolved among the DMF (3mL) and stirs at 140 ℃ and spends the night.After reaction is complete, by a small amount of H with mixture o dilution, with 1N HCl acidifying (pH 5), and extracts three times with EA.With organic layer MgSO dry and concentrate to obtain the title compound (100mg, rough thing) as light brown solid.

[1900] LC-MS, m / z 294 [M+H] +

[1901] 132.2(3-Fluoro-5-(5-(4-fluorophenyl)-1,3,4- tert-Butyl)oxadiazol-2-yl)benzyl)carbamate

[1902]

[1903] By (3-fluoro-5-(1H-tetrazol-5-yl) benzyl) t-butyl carbamate (86mg, 0.29mmol), 4-fluorobenzoic acid (97mg, 0.35mmol), 1M DCC (in DCM) (350 μ L, 0.35mmol) and 1, the mixture of 2-ethylene dichloride (3mL) was stirred 24 hours at 100 ℃.After reaction is complete, by mixture with a small amount of H o dilution and extract three times with EA.With organic layer MgSO dry and concentrate, and the residue obtained is carried out purifying to obtain the title compound (74mg, 65%) as white solid by silica gel column chromatography (0 to 20%EtOAc in hexane).

[1904] LC-MS, m / z 388[M+H] +

[1905] 132.3(3-Fluoro-5-(5-(4-fluorophenyl)-1,3,4- oxadiazol-2-yl)phenyl)methylamine trifluoroacetate

[1906]

[1907] By the same method as in Example 25.4, using (3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-

[0149] tert-Butyl)oxadiazol-2-yl)benzyl)carbamate (74 mg, 0.19 mmol), trifluoroacetic acid (1 mL) and DCM (2 ml) were added to afford the title compound (98 mg, crude) as a light brown oil.

[1908] LC-MS, m / z 288 [M+H] +

[1909] 132.4 8-Cyclopentyl-N-(3-fluoro-5-(5-(4-fluorophenyl)-1,3,4- oxadiazole-2-yl)benzyl)-7H-purine-6-carboxamide

[1910]

[1911] By the same method as in Example 87.3, using (3-fluoro-5-(5-(4-fluorophenyl)-1,3,4- To the mixture of oxadiazole-2-yl)phenyl)methanamine trifluoroacetate (98 mg, 0.24 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (47 mg, 0.20 mmol), EDC (47 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol), DIPEA (170 μL, 1.0 mmol) and THF (2 mL) was added to afford the title compound (38 mg, 37%) as an off-white solid.

[1912] 1 H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 9.93 (t, J=6.1Hz, 1H), 8.99 (s, 1H), 8.21 (dd, J=8.7, 5.3Hz, 2H), 8.05 (s, 1H), 7.87 (d, J=8.5Hz, 1H) , 7.57-7.42 (m, 3H), 4.68 (d, J=6.0Hz, 2H), 3.54-3.46 (m, 1H), 2.13-2.03 (m, 2H), 1.99-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.72-1.60 (m, 2H).

[1913] LC-MS, m / z 502[M+H] +

[1914] Example 133

[1915] 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoic acid

[1916]

[1917] Ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate (35 mg, 0.070 mmol) was dissolved in MeOH / THF (141 μL / 1.4 mL) and LiOH (8.3 mg) dissolved in HO (141 μL) was added and stirred at room temperature overnight. The reaction mixture was acidified with 1 M HCl, extracted with EtOAc, and the organic layer was dried over NaSO. The concentrated residue was purified by silica gel column chromatography MPLC (5% to 15% MeOH in DCM) to obtain the title compound (16.2 mg, 49.0%) as a yellow solid.

[1918] 1H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 7.83 (d, J = 8.8Hz, 2H), 7.08 (d, J = 8.8Hz, 2H), 7.04 (s, 1H), 6.78 (d, J = 11.0Hz, 1H), 6.72 (d, J=9.4Hz, 1H), 4.64 (s, 2H), 3.52-3.45 (m, 1H), 2.19 (s, 2H), 2.03 (s, 2H), 1.92 (s, 2H), 1.77 (s, 2H).

[1919] LC-MS, m / z 475 [M+H] +

[1920] Example 134

[1921] 134.1 3-((1,3,4- oxadiazol-2-yl)amino)-5-fluorobenzonitrile

[1922]

[1923] 3-Cyano-5-fluorophenylboronic acid (0.2 g, 1.21 mmol) was dissolved in DCM (4.9 mL) and 1,3,4- To 4-diazole-2-amine (0.206g, 2.43mmol), Cu (OAc) 2 (0.220g, 1.21mmol) and TEA (338 μ L, 2.43mmol). After stirring at room temperature for 8 hours under air condition, reaction mixture was filtered through diatomaceous earth pad and washed several times with EtOAc. Filtrate was concentrated, and the residue obtained was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the title compound (59.1mg, 23.9%) as white solid.

[1924] 1 H NMR (400MHz, CD3OD) δ 8.56 (s, 1H), 8.23 ​​(s, 1H), 7.79-7.73 (m, 1H), 7.71 (s, 1H), 7.19 (d, J = 7.1Hz, 1H).

[1925] LC-MS, m / z 205 [M+H] +

[1926] 134.2N-(3-(Aminomethyl)-5-fluorophenyl)-1,3,4- 2-Diazole

[1927]

[1928] 3-((1,3,4- oxadiazole-2-yl)amino)-5-fluorobenzonitrile (59 mg, 0.289 mmol) was dissolved in THF (2.9 mL), LAH solution (2.0 M in THF; 0.29 mL) was added at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, quenched by the addition of H2O, filtered through a pad of celite and washed several times with EtOAc. The filtrate was washed with H2O, and the organic layer was dried over Na2SO4 and concentrated. The title compound (31.4 mg, 87.5%) was obtained as a yellow solid and used in the next reaction without purification.

[1929] LC-MS, m / z 209 [M+H] +

[1930] 134.3N-(3-((1,3,4- (oxadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1931]

[1932] By the same method as in Example 87.3, using 8-cyclopentyl-7H-purine-6-carboxylic acid (34.6 mg, 0.149 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-1,3,4- Oxadiazole-2-amine (31 mg, 0.149 mmol), HOBt (24.1 mg, 0.179 mmol), EDC (81.5 mg, 0.179 mmol), DIPEA (76 μL, 0.447 mmol) and THF (3.5 mL) were added to afford the title compound (1.4 mg, 2.2%) as a yellow solid.

[1933] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 8.48 (s, 1H), 7.36 (d, J = 10.3Hz, 1H), 7.31 (s, 1H), 6.83 (d, J = 9.6Hz, 1H), 4.67 (s , 2H), 3.51-3.46 (m, 1H), 2.21-2.17 (m, 2H), 2.06-2.01 (m, 2H), 1.91 (d, J=5.8Hz, 2H), 1.77 (dd, J=6.7, 4.9Hz, 2H).

[1934] LC-MS, m / z 423 [M+H] +

[1935] Example 135

[1936] 8-Cyclopentyl-N-(3-(cyclopentylamino)-5-fluorobenzyl)-7H-purine-6-carboxamide

[1937]

[1938] By the same method as in Example 1.3, 8-cyclopentyl-7H-purine-6-carboxylic acid (19 mg, 0.082 mmol), 3-(aminomethyl)-N-cyclopentyl-5-fluoroaniline (19 mg, 0.091 mmol), T3P (50 wt% solution in EtOAc, 159 mg) and DIPEA (56 μL) were used to obtain

[1939] The title compound (13 mg, 38%) was obtained as a white solid.

[1940] 1 H NMR (400MHz, CDCl3) δ8.94 (s, 1H), 6.42 (s, 1H), 6.31 (d, J = 12Hz, 1H), 6.20 (d, J = 12Hz, 1H), 4.54 (s, 2H), 3.71 -3.68(m, 1H), 3.50-3.46(m, 1H), 2.20-2.18(m, 2H), 2.04-1.91(m, 6H), 1.78-1.65(m, 4H), 1.50-1.42(m, 4H).

[1941] LC-MS, m / z 423[M+H]+

[1942] Example 136

[1943] 136.1 3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzonitrile

[1944]

[1945] The title compound (10 mg, 38%) was obtained as a white solid by the same procedure as in Example 121.1 using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (30 mg, 0.12 mmol), 1,3,4-thiadiazol-2-amine (25 mg, 0.24 mmol), Cu(OAc)2 (22 mg, 0.12 mmol), TEA (34 μL, 0.52 mmol) acetonitrile (115 μL) / ethanol (6 μL).

[1946] 1H NMR (400MHz, CD3OD) δ 8.11 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 12Hz, 1H), 7.30 (d, J = 8Hz, 1H).

[1947] LC-MS, m / z 221[M+H]+

[1948] 136.2 N-(3-(Aminomethyl)-5-fluorophenyl)-1,3,4-thiadiazol-2-amine

[1949]

[1950] By the same procedure as in Example 1.2, using 3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzonitrile (10 mg, 0.045 mmol) and LAH solution (2.0 M in THF; 0.05 mL), the title compound (7 mg, 69%) was obtained as a yellow syrup.

[1951] LC-MS, m / z 225[M+H]+

[1952] 136.3 N-(3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1953]

[1954] The title compound (1.7 mg, 13%) was obtained as a white solid by the same procedure as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (7 mg, 0.037 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-1,3,4-thiadiazol-2-amine (7 mg, 0.03 mmol), T3P (50 wt% solution in EtOAc, 64 mg) and DIPEA (20 μL).

[1955] 1 H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.78 (s, 1H), 7.53 (d, J = 12Hz, 1H), 7.33 (s, 1H), 6.83 (d, J = 8Hz, 1H), 4. 67(s, 2H), 3.51-3.47(m, 1H), 2.25-2.17(m, 2H), 2.06-1.99(m, 2H), 1.94-1.88(m, 2H), 1.80-1.74(m, 2H).

[1956] LC-MS, m / z 439[M+H]+

[1957] Example 137

[1958] 137.1 tert-Butyl (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)benzyl)carbamate

[1959]

[1960] The same method as in Example 8.1 was used, using 1-(4-fluorophenyl)-1,4-diazepane (42 mg, 0.22 mmol), tert-butyl (3-bromo-5-fluorobenzyl)carbamate (62.6 mg, 0.21 mmol), Pd2(dba)3 (4.2 mg, 0.0045 mmol), BINAP (5.2 mg, 0.0.0082 mmol), NaO t Bu (39.6 mg, 0.412 mmol) and toluene (1.03 mL) were added to obtain the title compound (16 mg, 19%) as a yellow solid.

[1961] 1 H NMR (400MHz, CDCl3) δ6.94 (t, J=8.7Hz, 2H), 6.64 (dd, J=9.0, 4.2Hz, 2H), 6.39 (s, 1H), 6.29 (d, J=9.7Hz, 2H), 4.82 ( s, 1H), 4.22 (d, J=5.5Hz, 2H), 3.67-3.54 (m, 4H), 3.40 (dd, J=11.3, 5.8Hz, 4H), 2.09 (p, J=6.3Hz, 2H), 1.47 (s, 9H).

[1962] LC-MS, m / z 418 [M+H] +

[1963] 137.2(3-Fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)phenyl)methanamine trifluoroacetate

[1964]

[1965] By the same procedure as in Example 25.4 using tert-butyl (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)benzyl)carbamate (15.5 mg, 0.037 mmol), trifluoroacetic acid (57 μL) and DCM (0.74 mL), the title compound was obtained as a yellow solid (21.8 mg, crude).

[1966] LC-MS, m / z 318 [M+H] +

[1967] 137.3 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)benzyl)-7H-purine-6-carboxamide

[1968]

[1969] The title compound (3.1 mg, 16%) was obtained as an off-white solid by the same method as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (9.1 mg, 0.039 mmol), (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)phenyl)methanamine trifluoroacetate (21.8 mg, crude, 0.037 mmol), T3P (propylphosphonic anhydride, 50 wt% solution in DMF, 16 mg), DIPEA (N,N-diisopropylethylamine, 32 μL) and DMF (0.74 mL).

[1970] 1 H NMR (400MHz, CDCl3) δ10.42 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 6.93 (t, J=8.7Hz, 2H), 6.70-6.57 (m, 2H), 6.45 (s, 1H), 6.36 (dd, J=21.1, 10.4Hz , 2H), 4.61 (d, J=6.1Hz, 2H), 3.67-3.57 (m, 4H), 3.46-3.35 (m, 5H), 2.30 -2.18(m, 2H), 2.13-1.98(m, 4H), 1.97-1.85(m, 2H), 1.83-1.71(m, 2H).

[1971] LC-MS, m / z 532[M+H] +

[1972] Example 138

[1973] 138.1 tert-Butyl 3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1974]

[1975] By the same procedure as in Example 4.1, using tert-butyl 3-bromo-5-fluorobenzylcarbamate (101.5 mg, 0.33 mmol), 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131.2 mg, 0.50 mmol), PdCl2(dppf) (12.2 mg, 0.017 mmol), 2M K2CO3 (0.6 mL, 1.17 mmol) and 1,4-dioxane (2 mL), the title compound (77.94 mg, 65%) was obtained as a colorless clear oil.

[1976] LC-MS, m / z 360 [M+H] +

[1977] 138.2(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorophenyl)methylamine trifluoroacetate

[1978]

[1979] The title compound (81 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (77.94 mg, 0.22 mmol), TFA (0.7 mL) and DCM (2 mL).

[1980] LC-MS, m / z 260 [M+H] +

[1981] 138.3 8-Cyclopentyl-N-(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[1982]

[1983] The title compound (54.52 mg, 53%) was obtained by the same procedure as in Example 87.3 using (3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine trifluoroacetate (81 mg, 0.22 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (50.3 mg, 0.22 mmol), EDC (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), DIPEA (111 μL, 0.65 mmol) and THF (2 mL) to obtain the title compound as a light yellow solid (54.52 mg, 53%).

[1984] 1H NMR (400MHz,, DMSO-d6) δ13.17 (s, 1H), 9.74 (s, 1H), 8.96 (s, 1H), 8.26 (s, 1H), 7.88 (s, 1H), 7.45 (s, 1H), 7.33 (d, J=10.1Hz, 1H), 6.98 (d, J=9.4Hz, 1H ), 4.68 (dt, J=13.8, 6.9Hz, 1H), 4.56 (d, J=6.2Hz, 2H), 3.56-3.41 (m, 1H), 2 .16-2.01(m, 4H), 2.00-1.98(m, 4H), 1.86-1.73(m, 4H), 1.73-1.57(m, 4H).

[1985] LC-MS, m / z 474 [M+H] +

[1986] Example 139

[1987] 139.1 tert-Butyl 3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1988]

[1989] By the same procedure as in Example 4.1, using tert-butyl 3-bromo-5-fluorobenzylcarbamate (101.73 mg, 0.33 mmol), 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (138.6 mg, 0.50 mmol), PdCl2(dppf) (12.2 mg, 0.017 mmol), 2M K2CO3 (0.6 mL, 1.17 mmol) and 1,4-dioxane (2 mL), the title compound (107.22 mg, 85.8%) was obtained as a yellow oil.

[1990] LC-MS, m / z 374 [M+H] +

[1991] 139.2(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorophenyl)methylamine trifluoroacetate

[1992]

[1993] The title compound (56 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (53.6 mg, 0.14 mmol), TFA (0.7 mL) and DCM (2 mL).

[1994] LC-MS, m / z 274 [M+H] +

[1995] 139.3 N-(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1996]

[1997] The title compound (39.38 mg, 56.3%) was obtained as a yellow solid by the same procedure as in Example 87.3 using (3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine trifluoroacetate (56 mg, 0.14 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (33.3 mg, 0.14 mmol), EDC (33 mg, 0.17 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (74 μL, 0.43 mmol) and THF (2 mL).

[1998] 1 H NMR(400MHz,,DMSO-d6)δ13.17(s,1H),9.74(s,1H),8.96(s,1H),8.25(s,1H),7.8 7 (s, 1H), 7.44 (s, 1H), 7.32 (d, J = 9.8Hz, 1H), 6.98 (d, J = 9.6Hz, 1H), 4.56 (d, J = 6.4 Hz, 2H), 4.12 (t, J=11.4Hz, 1H), 3.57-3.42 (m, 1H), 2.15-1.99 (m, 4H), 1.99-1.87 ( m, 2H), 1.86-1.76 (m, 4H), 1.75-1.57 (m, 4H), 1.49-1.29 (m, 2H), 1.28-1.12 (m, 2H).

[1999] LC-MS, m / z 488[M+H] +

[2000] Example 140

[2001] 140.1 tert-Butyl 3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[2002]

[2003] By the same procedure as in Example 4.1, using tert-butyl 3-bromo-5-fluorobenzylcarbamate (40 mg, 0.13 mmol), 1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52 mg, 0.20 mmol), PdCl2(dppf) (4.8 mg, 0.0066 mmol), 2M K1CO3 (0.23 mL, 0.46 mmol) and 1,4-dioxane (1.5 mL) to obtain the title compound (14.82 mg, 31%) as a colorless clear oil.

[2004] LC-MS, m / z 362[M+H] +

[2005] 140.2(3-Fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[2006]

[2007] The title compound (15 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (14.82 mg, 0.041 mmol), TFA (0.6 mL) and DCM (2 mL).

[2008] LC-MS, m / z 262[M+H] +

[2009] 140.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2010]

[2011]

[0266] The title compound (11.82 mg, 60.6%) was obtained by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (14.82 mg, 0.041 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (9.5 mg, 0.041 mmol), EDC (9.5 mg, 0.049 mmol), HOBt (7 mg, 0.049 mmol), DIPEA (21 μL, 0.12 mmol) and THF (2 mL).

[2012] 1H NMR (400MHz, CD3OD) δ8.96 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.44 (s, 1H), 7.22 (d, J = 9.5Hz, 1H), 7.00 (d, J=9.6Hz, 1H), 5.10-4.98 (m, 1H), 4.68 (s, 2H), 4.12 (dd, J=15.3, 7.8Hz, 1H), 4. 04 (d, J=4.7Hz, 2H), 3.91 (dd, J=14.2, 8.4Hz, 1H), 3.58-3.41 (m, 1H), 2.60-2.41 (m, 1H), 2.4 1-2.28(m, 1H), 2.26-2.13(m, 2H), 2.09-1.98(m, 2H), 1.98-1.85(m, 2H), 1.85-1.67(m, 2H).

[2013] LC-MS, m / z 476[M+H] +

[2014] Example 141

[2015] 141.1 tert-Butyl 3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzylcarbamate

[2016]

[2017] The title compound (58 mg, 44%) was obtained as a light yellow solid by the same procedure as in Example 25.3 using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (101.95 mg, 0.35 mmol), 4-bromothiazole (86.1 mg, 0.52 mmol), CuI (6.7 mg, 0.035 mmol), L-proline (8 mg, 0.069 mmol), K2CO3 (72.5 mg, 0.52 mmol) and DMSO (3 mL).

[2018] LC-MS, m / z 375 [M+H] +

[2019] 141.2(3-Fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[2020]

[2021] The title compound (57.3 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzylcarbamate (55.22 mg, 0.15 mmol), TFA (0.5 mL) and DCM (1.5 mL).

[2022] LC-MS, m / z 275 [M+H] +

[2023] 141.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2024]

[2025] The title compound (57.46 mg, 79.7%) was obtained by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (57.3 mg, 0.15 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (34.3 mg, 0.15 mmol), EDC (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), DIPEA (75 μL, 0.44 mmol) and THF (2 mL) to obtain the title compound as a light yellow solid (57.46 mg, 79.7%).

[2026] 1 H NMR (400MHz, DMSO-d6) δ13.18 (s, 1H), 9.77 (t, J = 6.6Hz, 1H), 9.22 (d, J = 2.0Hz, 1 H), 8.97 (s, 1H), 8.91 (s, 1H), 8.28 (s, 1H), 7.77 (d, J=2.1Hz, 1H), 7.65 (s, 1H), 7. 54 (d, J=9.7Hz, 1H), 7.06 (d, J=9.3Hz, 1H), 4.60 (d, J=6.0Hz, 2H), 3.57-3.43 (m, 1H), 2.16-2.03(m, 2H), 1.99-1.87(m, 2H), 1.87-1.74(m, 2H), 1.73-1.57(m, 2H).

[2027] LC-MS, m / z 489[M+H] +

[2028] Example 142

[2029] 142.1 tert-Butyl (3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)carbamate

[2030]

[2031] The title compound (53.3 mg, 18.9%) was obtained as a yellow solid by the same procedure as in Example 87.3 using tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.268 g, 0.881 mmol), 1-methyl-1H-pyrrol-3-amine hydrochloride (0.129 g, 0.881 mmol), (±)BINAP (54.9 mg, 0.088 mmol), Pd2(dba)3 (80.8 mg, 0.088 mmol), sodium tert-butoxide (0.212 g, 2.20 mmol) and toluene (4.9 mL).

[2032] 1 H NMR (400MHz, DMSO-d6) δ7.59 (s, 1H), 7.30 (t, J = 5.4Hz, 1H), 6.57 (d, J = 10.9Hz, 2H), 6.45 (s, 1H), 6.30 (d, J = 11.4Hz, 1 H), 6.15 (d, J=9.0Hz, 1H), 5.81 (s, 1H), 4.08 (dd, J=10.6, 5.4Hz, 1H), 3.95 (d, J=6.2Hz, 2H), 3.55 (s, 3H), 1.37 (s, 9H).

[2033] LC-MS, m / z 320 [M+H] +

[2034] 142.2 N-(3-(Aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrrol-3-amine hydrochloride

[2035]

[2036] By the same method as in Example 90.3 using tert-butyl (3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)carbamate (20 mg, 0.063 mmol) and 4M HCl in dioxane (0.31 mL) to obtain the title compound (12 mg, 74.9%) as a brown solid, which was used in the next reaction without isolation and purification.

[2037] 1 H NMR (400MHz, DMSO-d6) δ 8.16 (s, 2H), 6.62 (d, J = 5.8Hz, 3H), 6.45 (d, J = 10.2Hz, 2H), 5.85 (s, 1H), 3.86 (d, J = 5.8Hz, 2H), 3.55 (d, J = 5.3Hz, 3H).

[2038] LC-MS, m / z 220 [M+H] +

[2039] 142.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)-7H-purine-6-carboxamide

[2040]

[2041] The title compound (2.6 mg, 12.8%) was obtained as a yellow solid by the same procedure as in Example 87.3 using N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrrol-3-amine hydrochloride (12 mg, 0.047 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (10.9 mg, 0.047 mmol), HOBt (7.6 mg, 0.056 mmol), EDC (10.8 mg, 0.056 mmol), DIPEA (170 μL, 0.141 mmol) and THF (1.1 mL).

[2042] 1 H NMR (400MHz, CD3OD) δ8.95 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H), 6.34 (t, J = 11.5Hz, 3H), 5.86 (d, J = 2.8Hz, 1H), 4.54 (s, 2H), 3.55 (s, 3H), 3.52-3.47 (m, 1H), 2.20 (d, J=8.0Hz, 2H), 2.05-2.00 (m, 2H), 1.94-1.90 (m, 2H), 1.80-1.75 (m, 2H).

[2043] LC-MS, m / z 434 [M+H] +

[2044] Example 143

[2045] 143.1 3-Iodothiophene 1-oxide

[2046]

[2047] 3-Iodothiophene (500 mg, 2.38 mmol) was dissolved in DCE (12 mL), 3-chloroperbenzoic acid (1.3 g, 5.95 mmol) was added, and stirred at 90 ° C for 2 hours. The reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane) to obtain the title compound (116 mg, 23%) as a red oil.

[2048] 143.2 tert-Butyl 3-fluoro-5-(1-(1-oxothiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[2049]

[2050] The same procedure as in Example 25.3 was used using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (99 mg, 0.34 mmol), 3-iodothiophene 1-oxide (115 mg, 0.51 mmol), CuI (6.5 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K2CO3 (70 mg, 0.51 mmol) and DMSO (3.5 mL) to obtain the title compound (29.0 mg, 23%) as a brown solid.

[2051] LC-MS, m / z 390 [M+H] +

[2052] 143.3 3-(4-(3-(Aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)thiophene 1-oxide trifluoroacetate

[2053]

[2054] The title compound (29 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(1-oxothiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (28.08 mg, 0.072 mmol), TFA (0.3 mL) and DCM (1 mL).

[2055] LC-MS, m / z 290 [M+H] +

[2056] 143.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(1-oxothiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2057]

[2058] The title compound (9.7 mg, 27%) was obtained as a white solid by the same procedure as in Example 87.3 using 3-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)thiophene 1-oxide trifluoroacetate (29 mg, 0.072 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (16.7 mg, 0.072 mmol), EDC (16.6 mg, 0.087 mmol), HOBt (11.7 mg, 0.087 mmol), DIPEA (37 μL, 0.22 mmol) and THF (2 mL).

[2059] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.77 (s, 1H), 8.96 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.48 (s, 1H), 7.38 (d, J=11.0Hz, 1H), 7.04 (d, J=9.1Hz, 1H), 5.75 (s, 1H), 5 .50(d, J=13.4Hz, 1H), 5.28(d, J=13.2Hz, 1H), 4.58(d, J=5.9Hz, 2H), 3.50-3.44(m , 1H), 2.14-2.02(m, 2H), 2.02-1.87(m, 2H), 1.86-1.74(m, 2H), 1.72-1.61(m, 2H).

[2060] LC-MS, m / z 504 [M+H] +

[2061] Example 144

[2062] 144.1 3-Fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile

[2063]

[2064] The title compound (0.545 g, 50.4%) was obtained as a white solid by the same procedure as in Example 10.1 using 3-bromo-5-fluorobenzonitrile (1 g, 5.00 mmol), 1-methyl-1H-pyrazol-4-amine (426 μL, 5.00 mm), followed by Pd2(dba)3 (91.6 mg, 0.100 mmol), Xantphos (145 mg, 0.250 mmol), K2CO3 (1.59 g, 11.5 mmol) and dioxane (31 mL).

[2065] 1H NMR (400MHz, DMSO-d6) δ 8.24 (s, 1H), 7.77 (s, 1H), 7.35 (s, 1H), 6.92 (d, J = 7.4Hz, 1H), 6.84 (s, 1H), 6.74 (d, J = 11.8Hz, 1H), 3.80 (s, 3H).

[2066] LC-MS, m / z 217 [M+H] +

[2067] 144.2 N-(3-(Aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine

[2068]

[2069] The title compound (0.518 g, 94.1%) was obtained as a brown solid by the same procedure as in Example 7.2 above using 3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile (0.541 g, 2.50 mmol), LAH solution (2.0 M in THF; 2.5 mL) and THF (25 mL).

[2070] 1 H NMR (400MHz, DMSO-d6) δ7.70 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.51 (s, 1H), 6.37 (d, J = 9.3Hz, 1H), 6.28 (d, J = 11.8Hz, 1H), 3.78 (s, 3H), 3.56 (s, 2H).

[2071] LC-MS, m / z 221[M+H] +

[2072] 144.3 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[2073]

[2074] The title compound (29 mg, 27.6%) was obtained as a yellow solid by the same procedure as in Example 87.3 using N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine (49.3 mg, 0.224 mmol), 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (60 mg, 0.224 mmol), EDC (51.5 mg, 0.268 mmol), HOBt (36.3 mg, 0.268 mmol) and THF (5.2 mL).

[2075] 1 H NMR (400MHz, DMSO-d6) δ13.34(s, 1H), 9.71(s, 1H), 9.01(s, 1H), 7.80(s, 1H ), 7.63 (s, 1H), 7.29 (d, J = 0.5Hz, 1H), 6.59 (s, 1H), 6.42 (d, J = 9.4Hz, 1H), 6 .34 (dt, J=11.8, 2.2Hz, 1H), 4.44 (d, J=6.3Hz, 2H), 3.81 (dd, J=8.7, 5.9Hz, 1H), 3.77(s, 3H), 2.70-2.59(m, 2H), 2.36-2.27(m, 2H), 2.26-2.09(m, 2H).

[2076] LC-MS, m / z 471[M+H] +

[2077] Example 145

[2078] 145.1 tert-Butyl 3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzylcarbamate

[2079]

[2080] The same procedure as in Example 25.3 was used using tert-butyl 3-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate (30 mg, 0.103 mmol), bromobenzene-d5 (25 mg, 0.15 mmol), CuI (2 mg, 0.010 mmol), L-proline (2.5 mg, 0.021 mmol), K2CO3 (21.3 mg, 0.15 mmol) and DMSO (2 mL) to obtain the title compound (7.27 mg, 18.95%) as a colorless clear oil.

[2081] LC-MS, m / z 373 [M+H] +

[2082] 145.2(3-Fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)phenyl)methylamine trifluoroacetate

[2083]

[2084] The title compound (8 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzylcarbamate (7.27 mg, 0.02 mmol), TFA (0.2 mL) and DCM (0.6 mL).

[2085] LC-MS, m / z 275 [M+H] +

[2086] 145.3 8-Cyclopentyl-N-(3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2087]

[2088] The title compound (7.24 mg, 76.3%) was obtained as an off-white solid by the same procedure as in Example 87.3 using (3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate (8 mg, 0.02 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (4.5 mg, 0.02 mmol), EDC (4.5 mg, 0.023 mmol), HOBt (3.2 mg, 0.023 mmol), DIPEA (10 μL, 0.059 mmol) and THF (2 mL).

[2089] 1 H NMR (400MHz, DMSO-d6) δ13.17 (s, 1H), 9.77 (t, J = 5.6Hz, 1H), 9.06 (s, 1H), 8.97 (s, 1H), 8.24 (s, 1H), 7.61 (s, 1H), 7.49 (d, J = 9.9Hz, 1H), 7. 07 (d, J=9.3Hz, 1H), 4.61 (d, J=6.4Hz, 2H), 3.58-3.43 (m, 1H), 2.15-2.01 (m, 2H), 2.02-1.87 (m, 2H), 1.97-1.75 (s, 2H), 1.73-1.61 (s, 2H).

[2090] LC-MS, m / z 487 [M+H] +

[2091] Example 146

[2092] 146.1 tert-Butyl 3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)benzylcarbamate

[2093]

[2094] The same procedure as in Example 25.2 was used using tert-butyl 3-bromo-5-fluorobenzylcarbamate (244.75 mg, 0.8 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (251 mg, 1.21 mmol), Na2CO3 (298.5 mg, 2.82 mmol), Pd(PPh3)4 (46.3 mg, 0.04 mmol) and DMF (4 mL) / H2O (1.7 mL) to obtain the title compound (191.97 mg, 78%) as a colorless clear oil.

[2095] LC-MS, m / z 306 [M+H] +

[2096] 146.2 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzylcarbamate

[2097]

[2098] By the same method as in Example 25.3, using tert-butyl 3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)benzylcarbamate (28.39 mg, 0.093 mmol), 1-fluoro-4-iodobenzene (31 mg, 0.14 mmol), CuI (1.8 mg, 0.0093 mmol), L-proline (2 mg, 0.019 mmol), K2CO3 (19.2 mg, 0.14 mmol) and DMSO (2 mL), the title compound (18.41 mg, 49.6%) was obtained as a colorless clear oil. (TLC, R f =0.32, elution condition Hex:EA=8:2).

[2099] LC-MS, m / z 400 [M+H] +

[2100] 146.3(3-Fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[2101]

[2102] The title compound (17 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzylcarbamate (16.41 mg, 0.041 mmol), TFA (0.6 mL) and DCM (1.8 mL).

[2103] LC-MS, m / z 275 [M+H] +

[2104] 146.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2105]

[2106] The title compound (10.1 mg, 48%) was obtained as a yellow solid by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (17 mg, 0.041 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (9.5 mg, 0.041 mmol), EDC (9.4 mg, 0.049 mmol), HOBt (6.65 mg, 0.049 mmol), DIPEA (21 μL, 0.12 mmol) and THF (2 mL).

[2107] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.80 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 7.91-7.81 (m, 2H), 7.43 (s, 1H), 7.35 (t, J=8.8Hz, 2H), 7.29 (d, J=10.1Hz, 1H) , 7.12 (d, J = 9.2Hz, 1H), 4.61 (d, J = 5.9Hz, 2H), 3.55-3.45 (m, 1H), 2.39 (s, 3H) , 2.15-2.01(m, 2H), 1.01-1.87(m, 2H), 1.86-1.75(m, 2H), 1.71-1.61(m, 2H).

[2108] LC-MS, m / z 514 [M+H] +

[2109] Example 147

[2110] 147.1 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzylcarbamate

[2111]

[2112] The title compound (18.64 mg, 11.2%) was obtained by the same method as in Example 25.3 using tert-butyl 3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)benzylcarbamate (127.25 mg, 0.42 mmol), 1-fluoro-4-iodobenzene (139 mg, 0.63 mmol), CuI (8 mg, 0.042 mmol), L-proline (10 mg, 0.083 mmol), K2CO3 (87 mg, 0.63 mmol) and DMSO (4 mL). (TLC, R f =0.22, elution condition Hex:EA=8:2)

[2113] LC-MS, m / z 400 [M+H] +

[2114] 147.2 3-Fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzylcarbamate trifluoroacetate

[2115]

[2116] The title compound (18 mg, crude) was obtained by the same procedure as in Example 25.4 using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzylcarbamate (16.64 mg, 0.042 mmol), TFA (0.5 mL) and DCM (1.5 mL).

[2117] LC-MS, m / z 300 [M+H] +

[2118] 147.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2119]

[2120] The title compound (10.1 mg, 48%) was obtained as a yellow solid by the same procedure as in Example 87.3 using (3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (17 mg, 0.041 mmol), 8-cyclopentyl-7H-purine-6-carboxylic acid (9.5 mg, 0.041 mmol), EDC (9.4 mg, 0.049 mmol), HOBt (6.65 mg, 0.049 mmol), DIPEA (21 μL, 0.12 mmol) and THF (2 mL).

[2121] 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 9.80 (t, J=6.3Hz, 1H), 8.96 (s, 1H), 7.91 (s, 1H), 7.63-7.54 (m, 2H), 7.43-7.36 (m, 2H), 7.36 (s, 1H), 7.21 (d, J=9.8Hz, 1 H), 7.12 (d, J=9.6Hz, 1H), 4.61 (d, J=6.3Hz, 2H), 3.57-3.48 (m, 1H), 2.37 (s, 3H ), 2.13-2.00(m, 2H), 2.02-1.85(m, 2H), 1.86-1.74(m, 2H), 1.73-1.60(m, 2H).

[2122] LC-MS, m / z 514[M+H]+

[2123] Example 148

[2124] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(phenyl-d5)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[2125]

[2126] The title compound (42 mg, 70.3%) was obtained by the same procedure as in Example 87.3 using (3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate (44 mg, 0.11 mmol), 8-(3,3-difluorocyclopentyl)-7H-purine-6-carboxylic acid (30.6 mg, 0.11 mmol), EDC (26.2 mg, 0.14 mmol), HOBt (18.5 mg, 0.14 mmol), DIPEA (58 μL, 0.34 mmol) and THF (2 mL).

[2127] 1H NMR (400MHz, DMSO-d6) δ13.33 (s, 1H), 9.80 (t, J = 6.3Hz, 1H), 9.06 (s, 1H), 9.01 (s, 1H), 8.24 (s, 1H), 7.59 (s, 1H), 7.48 (d, J = 10.0 Hz, 1H), 7.06 (d, J=9.5Hz, 1H), 4.61 (d, J=6.2Hz, 2H), 3.88-3.75 (m, 1H), 2.60-2.57 (m, 2H), 2.39-2.26 (m, 2H), 2.25-2.07 (m, 2H).

[2128] LC-MS, m / ...

Claims

1. A compound of the following formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein: <Formula I> X is C or N, R1 is hydrogen, amino-C 1-3 Alkyl, C 3-8 1 to 2 rings of cycloalkyl (wherein hydrogen is protium or deuterium) or R s , R1 may or may not be replaced by one or more independent R 1a replace, Where R 1a It is C 1-5 Alkyl, halogen, oxo or -C(O)OR 1b , and R 1b It is hydrogen, C 1-3 Alkyl or arylalkyl, R2 is hydrogen, C 1-3 Alkyl or tri-C 1-3 Alkyl-Silyl-C 1-3 Alkoxy-C 1-3 alkyl, R3 is hydrogen, C 1-3 Alkyl or halogen, R4 is hydrogen or C 1-3 alkyl, p and q are independently integers 0 or 1, When p is 1, R 5a and R 5b are independently hydrogen or C 1-3 Alkyl, or R 5a and R 5b Connect to each other to form C 3-6 ring, R6 is hydrogen or halogen, R7 is hydrogen, halogen, R s , R u , -NH-aryl, -NH-ring C 3-7 Alkyl, -NHR s 、-NHR u or -NHC(O)R u , R8 is hydrogen, halogen or 4- to 6-membered heteroaryl having 1 to 3 N, R7 and R8 are independently or not independently one or more independent R m replace, R m C 1-3 Alkyl (wherein hydrogen is protium or deuterium), C 3-10 Cycloalkyl, C 1-3 Alkoxy, sulfonyl, amino, halogen, cyano, haloalkyl, carbamoyl, carboxyl, aryl (wherein hydrogen is protium or deuterium), arylalkyl, R u or R s , R m By or without one or more independent R n replace, R n C 1-3 Alkyl, C 1-3 Alkylsulfonyl, C 1-3 alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, oxygen bridge or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl, R9 and R 10 are independently hydrogen or halogen, R s is a 4- to 8-membered saturated heterocycloalkyl group having 1 to 2 heteroatoms selected from N and O, R u is a 4- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O and S.

2. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R1 is hydrogen, aminomethyl, cyclobutyl, cyclopentyl (wherein hydrogen is protium or deuterium), spiro[2.3]hexyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, pyrrolidinyl, tetrahydrofuranyl or piperidinyl, and R 1a is methyl, propyl, isopropyl, fluoro, oxo, -C(O)OH, -C(O)O-methyl or -C(O)O-benzyl.

3. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R2 is hydrogen, methyl or trimethyl-silyl-ethoxy-methyl.

4. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R3 is hydrogen, methyl, ethyl or chlorine.

5. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R4 is hydrogen or methyl.

6. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R 5a and R 5b are independently hydrogen or methyl, or R 5a and R 5b are connected to each other to form a cyclopropyl group.

7. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R6 is hydrogen or fluorine.

8. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R7 is hydrogen, Br, piperazinyl, diazepanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, isothiazolyl, triazolyl, oxadiazolyl, -NH-phenyl, -NH-cyclopentyl, -NH-piperidinyl, -NH-pyrrolyl, -NH-thienyl, -NH-pyrazolyl, -NH-isothiophene Azolyl, -NH- oxadiazolyl, -NH-thiadiazolyl, -NH-pyridinyl or -NHC(O)-pyrazolyl.

9. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R8 is hydrogen, fluorine, chlorine or pyrazolyl.

10. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, Where R m is methyl (wherein hydrogen is protium or deuterium), methoxy, sulfonyl, amino, fluoro, chloro, cyano, trifluoromethyl, difluoroethyl, trifluoroethyl, carbamoyl, carboxyl, cyclopentyl, cyclohexyl, phenyl (wherein hydrogen is protium or deuterium), benzyl, thienyl, furanyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl or tetrahydrofuranyl, R n It is methyl, ethyl, methylsulfonyl, methoxy, fluorine, chlorine, iodine, bromine, cyano, trifluoromethyl, carbamoyl, carboxyl, acetyl, phenyl, benzyl, oxygen bridge or methylcarboxyl-(8-cyclopentyl-7H-purine-6-carboxamido)-ethyl.

11. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R9 is hydrogen, fluorine or chlorine.

12. The compound according to claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein R 10 It is hydrogen or fluorine.

13. The compound of claim 1, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, wherein the compound represented by formula I is any one selected from the following: [1] 8-cyclopentyl-N-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [2] 8-cyclopentyl-N-(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide, [3] 8-cyclopentyl-N-(3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [4] (S)-8-cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide, [5] 8-cyclopentyl-N-(3-fluoro-5-(1-methyl-1H-pyrazole-4-carboxamido)benzyl)-7H-purine-6-carboxamide, [6] 8-cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-7H-purine-6-carboxamide, [7] 8-cyclopentyl-N-(3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [8] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, [9] N-(3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [10] 8-cyclopentyl-N-(3-fluoro-5-(pyridin-3-ylamino)benzyl)-7H-purine-6-carboxamide, [11] 8-cyclopentyl-N-(3-fluoro-5-(1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [12] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [13] 8-cyclopentyl-N-(3-fluorobenzyl)-7H-purine-6-carboxamide, [14] N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [15] 8-cyclopentyl-N-(3-fluoro-5-(phenylamino)benzyl)-7H-purine-6-carboxamide, [16] 8-cyclopentyl-N-(3-fluoro-5-(pyridin-4-ylamino)benzyl)-7H-purine-6-carboxamide, [17] 8-cyclopentyl-N-(3-fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide, [18] 8-cyclopentyl-N-(3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzyl)-7H-purine-6-carboxamide, [19] 8-cyclopentyl-N-(3-fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide, [20] N-(3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [21] 8-cyclopentyl-N-(3-fluoro-5-((4-fluorophenyl)amino)benzyl)-7H-purine-6-carboxamide, [22] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide, [23] N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [24] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [25] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [26] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [27] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [28] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [29] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [30] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [31] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [32] 8-cyclopentyl-N-(3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [33] 8-cyclopentyl-N-(3-fluoro-5-((2-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide, [34] 8-cyclopentyl-N-(3-fluoro-5-((3-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide, [35] 8-cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide, [36] 8-cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7-methyl-7H-purine-6-carboxamide, [37] N-(3-(1-(3-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [38] 8-cyclopentyl-N-(3-fluoro-5-(isothiazol-4-yl)benzyl)-7H-purine-6-carboxamide, [39] 8-cyclopentyl-N-(3-fluoro-5-(furan-2-yl)benzyl)-7H-purine-6-carboxamide, [40] 8-cyclopentyl-N-(3-fluoro-5-(thien-3-yl)benzyl)-7H-purine-6-carboxamide, [41] 8-cyclopentyl-N-(3-fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide, [42] 8-cyclopentyl-N-(3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [43] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [44] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [45] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [46] 8-cyclopentyl-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [47] 8-cyclopentyl-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [48] ​​8-cyclopentyl-N-(3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [49] 3-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid, [50] N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [51] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)-7H-purine-6-carboxamide, [52] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)-7H-purine-6-carboxamide, [53] N-(3-(1-(4-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [54] 4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid, [55] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7-methyl-7H-purine-6-carboxamide, [56] 8-cyclopentyl-N-(2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [57] 8-cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [58] N-(3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [59] N-(3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [60] 8-cyclopentyl-N-(3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide, [61] 2-chloro-8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [62] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride, [63] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide, [64] benzyl (R)-2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate, [65] (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride, [66] (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide, [67] (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-isopropylpyrrolidin-2-yl)-7H-purine-6-carboxamide, [68] (R)-N-(3-fluorobenzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide, [69] benzyl 4-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)piperidine-1-carboxylate, [70] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(piperidin-4-yl)-7H-purine-6-carboxamide hydrochloride, [71] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpiperidin-4-yl)-7H-purine-6-carboxamide, [72] benzyl ((6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)methyl)carbamate, [73] 8-(aminomethyl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [74] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [75] benzyl 3-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate, [76] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-3-yl)-7H-purine-6-carboxamide hydrochloride, [77] 8-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [78] 8-(bicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [79] N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-3-yl)-7H-purine-6-carboxamide, [80] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [81] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [82] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [83] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [84] (E1, E2) 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [85] (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-2-yl)-7H-purine-6-carboxamide, [86] (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide, [87] N-(3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [88] (S)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide, [89] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-3-yl)-7H-purine-6-carboxamide, [90] (R)-8-cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide, [91] (S)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide [92] 8-(3,3-difluorocyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [93] 2-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide, [94] 8-cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethyl)-7H-purine-6-carboxamide, [95] 8-cyclopentyl-N-(2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [96] 8-cyclopentyl-N-(4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [97] 8-(3,3-dimethylcyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [98] 8-(6,6-difluorospiro[3.3]hept-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [99] 8-(bicyclo[1.1.1]pentan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [100] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[3.3]hept-2-yl)-7H-purine-6-carboxamide, [101] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorobicyclo[1.1.1]pentan-1-yl)-7H-purine-6-carboxamide, [102] (A, B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclobutyl)-7H-purine-6-carboxamide, [103] (A, B) methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate, [104] N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [105] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-7H-purine-6-carboxamide, [106] 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylic acid, [107] 2-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide, [108] 8-cyclopentyl-N-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [109] 8-cyclopentyl-N-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [110] (A, B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclopentyl)-7H-purine-6-carboxamide, [111] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[2.3]hexan-5-yl)-7H-purine-6-carboxamide, [112] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-N-methyl-7H-purine-6-carboxamide, [113] 8-(bicyclo[3.1.0]hex-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [114] 8-(bicyclo[2.2.1]hept-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [115] 8-(bicyclo[2.1.1]hex-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [116] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7H-purine-6-carboxamide, [117] 8-cyclopentyl-N-(3-fluoro-5-(1-(thien-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [118] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzyl)-7H-purine-6-carboxamide, [119] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzyl)-7H-purine-6-carboxamide, [120] N-(3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [121] 8-cyclopentyl-N-(3-fluoro-5-(iso [122]N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [123] N-(3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [124] 8-cyclopentyl-N-(3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [125] N-(3-(1'-benzyl-1'H-[1,4'-bipyrazole]-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [126] N-(3-((4-carbamoylphenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [127] ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate, [128] 8-cyclopentyl-N-(3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzyl)-7H-purine-6-carboxamide, [129] 8-cyclopentyl-N-(3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzyl)-7H-purine-6-carboxamide, [130] 8-cyclopentyl-N-(3-fluoro-5-(thiophen-3-ylamino)benzyl)-7H-purine-6-carboxamide, [131] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)benzyl)-7H-purine-6-carboxamide, [132] 8-cyclopentyl-N-(3-fluoro-5-(5-(4-fluorophenyl)-1,3,4- oxadiazole-2-yl)benzyl)-7H-purine-6-carboxamide, [133] 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoic acid, [134]N-(3-((1,3,4- oxadiazole-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [135] 8-cyclopentyl-N-(3-(cyclopentylamino)-5-fluorobenzyl)-7H-purine-6-carboxamide, [136] N-(3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [137] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepan-1-yl)benzyl)-7H-purine-6-carboxamide, [138] 8-cyclopentyl-N-(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide, [139] N-(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide, [140] 8-cyclopentyl-N-(3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [141] 8-cyclopentyl-N-(3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [142] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)-7H-purine-6-carboxamide, [143] 8-cyclopentyl-N-(3-fluoro-5-(1-(1-oxothiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [144] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, [145] 8-cyclopentyl-N-(3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [146] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [147] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [148] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(phenyl-d5)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [149] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)benzyl)-7H-purine-6-carboxamide, [150] methyl 2-(8-cyclopentyl-7H-purine-6-carboxamido)-3-(4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)phenyl)propanoate, [151] 8-cyclopentyl-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, [152] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide and [153] 8-(Cyclopentyl-2,2,3,3,4,4,5,5-d8)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide.

14. A pharmaceutical composition for preventing or treating a disease associated with HIF-1α (hypoxia-inducible factor 1α) or VEGF (vascular endothelial growth factor), the pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 13, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14, characterized in that Prevention or treatment of diseases associated with HIF-1α or VEGF is through inhibition of angiogenesis.

16. The pharmaceutical composition according to claim 15, characterized in that The inhibition of angiogenesis is through the inhibition of HIF-1α expression or the inhibition of VEGF expression.

17. The pharmaceutical composition according to claim 14, characterized in that The disease associated with HIF-1α or VEGF is at least one selected from the following: stroke, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head and neck cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal cancer, skin cancer, fallopian tube cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, oral cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, ureteral cancer, spleen cell carcinoma, renal pelvis cancer, medulloblastoma, neuroblastoma, brain tumor, central nervous system tumor, melanoma, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, cancer disease, cervical cancer, thyroid cancer, blood cancer, renal cell carcinoma, hepatocellular carcinoma, metastatic cancer, hemangioma, pyogenic granuloma, Kaposi's sarcoma, hemangioendothelioma, solid tumors, follicular cysts, endometriosis, uterine sclerosis, ovarian hypertension, overactive ovaries, uterine dysfunction, warts, keloids, allergic edema, atherosclerosis, peritoneal sclerosis, heart dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, bone and cartilage destruction, malignant fibrous histiocytoma of bone, osteomyelitis, pannus growth, liver fibrosis, pulmonary fibrosis, fibrosis, NASH (non-alcoholic steatohepatitis), pneumonia, asthma, rhinitis, pulmonary hypertension, Ischemic acute kidney injury, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerulopathy, inflammatory neurodegenerative diseases, vascular diseases associated with nicotine addiction, chronic kidney disease, retinopathy of prematurity, diabetic retinopathy, corneal transplant rejection, ischemic retinopathy, erythroderma, proliferative retinopathy, psoriasis, hemophilic joints, keloids, wound granulation, vascular adhesions, autoimmune diseases, angiofibroma, retrolental fibroplasia, cataract, glaucoma, macular degeneration, age-related macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization Angiogenesis, intraocular neovascularization, neovascular glaucoma, neovascular macular degeneration, retinal artery occlusion, retinal vein occlusion, retinoblastoma, visual pathway and hypothalamic glioma, rhabdomyosarcoma, histiosarcoma, inflammation, corneal ulcer, proliferative vitreoretinopathy, sclerosis, asthma, periodontal disease, allergic dermatitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' orbitopathy, leukomalacia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, inflammatory bowel disease, Crohn's disease, ulcerative colitis and Behcet's colitis.

18. The pharmaceutical composition of claim 14, characterized in that The disease associated with HIF-1α or VEGF is neovascular eye disease.

19. The pharmaceutical composition according to claim 18, characterized in that The neovascular eye disease is at least one selected from the group consisting of corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, neovascular glaucoma, proliferative diabetic retinopathy, neovascular macular degeneration and retinopathy of prematurity.

20. The pharmaceutical composition of claim 18, characterized in that The neovascular eye disease is macular degeneration.

21. A preparation comprising the compound according to any one of claims 1 to 13, its hydrate, its solvate, its prodrug, its isomer or its pharmaceutically acceptable salt, and a pharmaceutically acceptable additive.

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