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

Abstract

The present invention provides a compound as an inhibitor of HIF-1α or an angiogenesis-inducing factor VEGF, and a pharmaceutical composition containing the same for preventing or treating HIF-1α or VEGF-related diseases. The novel compound according to the present invention has been confirmed to have excellent inhibitory effects on the expression of HIF-1α and the angiogenesis-inducing factor VEGF, and can be useful for preventing or treating HIF-1α and VEGF-related diseases.

Description

[Technical Field]

[0001] The present invention relates to a novel compound as a HIF-1 (Hypoxia Inducible Factor-1) protein inhibitor or a VEGF (Vascular Endothelial Growth Factor) inhibitor, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. [Background technology]

[0002] Hypoxia, a pathological condition characterized by a lack of adequate oxygen supply, is a typical characteristic of various intractable diseases, such as cancer, heart disease, ischemic disease, and vascular diseases. HIF-1 is a transcription factor induced by hypoxia. HIF-1 contains HIF-1α, which is degraded in an oxygen-dependent manner. HIF-1α induces the expression of genes such as hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGFA, MMP-2, uPAR, and MDR1, thereby acquiring traits such as resistance to apoptosis, increased angiogenesis, increased cell proliferation, cell migration, metastasis, and invasion.

[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. HIF-1α is an angiogenesis-regulating protein that, by inducing VEGF expression, is responsible for angiogenesis in terms of vascular destruction and vascular dysfunction. Angiogenesis is the process by which new capillaries are formed from existing microvessels. Normal angiogenesis occurs during embryonic development, tissue regeneration, wound healing, and the development of the corpus luteum, a cyclical change in the female reproductive system. Even in these cases, angiogenesis is strictly regulated. In adults, vascular endothelial cells grow very slowly and divide relatively slowly compared to other cell types. Angiogenesis generally involves the stimulation of angiogenic factors, followed by the degradation of the vascular basement membrane by proteases, the migration and proliferation of endothelial cells, and the differentiation of endothelial cells to form lumens, resulting in the remodeling of blood vessels and the generation of new capillaries. However, there are diseases caused by pathological growth due to unregulated angiogenesis. Excessive angiogenesis can induce diseases such as hemangiomas, angiofibromas, vascular malformations, and cardiovascular diseases such as arteriosclerosis, vascular adhesions, and scleredema. In particular, excessive angiogenesis has been shown to play a crucial role in diseases such as macular degeneration.

[0004] Although various hypotheses have been proposed regarding the causes and mechanisms of macular degeneration, including neovascularization, they are still unclear, and various studies are being conducted in the areas of diagnosis and treatment. Therefore, there is a continuous need to develop new substances that can be used to inhibit neovascularization. Summary of the Invention [Problem to be solved by the invention]

[0005] The problem to be solved by the present invention is to provide a compound with a novel structure that exhibits excellent inhibitory activity against HIF-1α or the angiogenesis induction factor VEGF.

[0006] Another problem to be solved by the present invention is to provide a pharmaceutical composition for preventing or treating diseases associated with HIF-1α or the angiogenesis induction factor VEGF, which comprises the compound having the novel structure.

[0007] Another problem to be solved by the present invention is to provide a method for preventing or treating diseases associated with HIF-1α or the angiogenesis-inducing factor VEGF, which comprises administering the compound having the novel structure to a subject or individual in need thereof.

[0008] Another problem to be solved by the present invention is to provide a use of the compound having the novel structure for producing a medicament for use in the prevention or treatment of diseases associated with HIF-1α or the angiogenesis induction factor VEGF.

[0009] The problems to be solved by the present invention are not limited to those described above, and other technical problems will be clearly understood by those skilled in the art from the following description of the invention. [Means for solving the problem]

[0010] In order to solve the above-mentioned problems, one aspect of the present invention provides a compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] In Formula I, X is C or N; R1 is hydrogen, amino-C 1-3 Alkyl, C 3-8 monocyclic or bicyclic cycloalkyl (wherein hydrogen is hydrogen or deuterium), or R s and R1 is one or more independent R 1a may or may not be substituted with Here, the R 1a is C 1-5 Alkyl, halogen, oxo, or -C(O)OR 1b and R 1b 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 is alkyl, R3 is hydrogen, C 1-3 alkyl or halogen; R4 is hydrogen or C 1-3 is alkyl, p and q are each independently an integer of 0 or 1; When p is 1, R 5a and R 5b are, independently of each other, hydrogen or C 1-3 alkyl or R 5a and R 5b are connected to each other to form C 3-6 forming a ring of R6 is hydrogen or halogen; R7 is hydrogen, halogen, R s , R u , -NH-aryl, -NH-cycloC 3-7 Alkyl, -NHR s , -NHR u , or -NHC(O)R u and R8 is hydrogen, halogen, or 4- to 6-membered heteroaryl containing 1 to 3 N; The R7 and R8 are each independently one or more independent R m may or may not be substituted with R m is C 1-3 Alkyl (where hydrogen is either protium or deuterium), C 3-10 Cycloalkyl, C 1-3Alkoxy, sulfonyl, amino, halogen, cyano, haloalkyl, carbamoyl, carboxyl, aryl (wherein hydrogen is hydrogen or deuterium), arylalkyl, R u , or R s and R m represents one or more independent R n may or may not be substituted with R n is C 1-3 Alkyl, C 1-3 Alkylsulfonyl, C 1-3 alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, oxide, or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl; R9 and R 10 are, independently of each other, hydrogen or halogen, R s is a 4- to 8-membered saturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O; R u is a 4- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0013] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a disease associated with HIF-1α or the angiogenesis-inducing factor VEGF, 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 as an active ingredient.

[0014] Yet another aspect of the present invention provides a method for preventing or treating a disease associated with HIF-1α or an angiogenesis-inducing factor (VEGF), comprising administering a compound represented by the chemical formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject or individual in need thereof.

[0015] Yet another aspect of the present invention provides use of the compound represented by formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the prevention or treatment of a disease associated with HIF-1α or the angiogenesis induction factor VEGF.

[0016] Yet another aspect of the present invention provides a dosage form 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 excipient. [Effects of the Invention]

[0017] The novel compound according to one aspect of the present invention has been confirmed to have an excellent inhibitory effect on the expression of HIF-1α and its subordinate gene, the angiogenesis-inducing factor VEGF, and can be usefully used for the prevention or treatment of diseases associated with HIF-1α and the angiogenesis-inducing factor VEGF.

[0018] The effects of the present invention are not limited to the effects described above, but should be understood to include all effects that can be inferred from the configuration of the invention described in the description of the present invention or the claims. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides a compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0020] [ka]

[0021] In Formula I, X is C or N; R1 is hydrogen, amino-C 1-3 Alkyl, C 3-8 monocyclic or bicyclic cycloalkyl (wherein hydrogen is hydrogen or deuterium), or Rs and R1 is one or more independent R 1a may or may not be substituted with Here, the R 1a is C 1-5 Alkyl, halogen, oxo, or -C(O)OR 1b and R 1b 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 is alkyl, R3 is hydrogen, C 1-3 alkyl or halogen; R4 is hydrogen or C 1-3 is alkyl, p and q are each independently an integer of 0 or 1; When p is 1, R 5a and R 5b are, independently of each other, hydrogen or C 1-3 alkyl or R 5a and R 5b are connected to each other to form C 3-6 forming a ring of R6 is hydrogen or halogen; R7 is hydrogen, halogen, R s , R u , -NH-aryl, -NH-cycloC 3-7 Alkyl, -NHR s , -NHR u , or -NHC(O)R u and R8 is hydrogen, halogen, or 4- to 6-membered heteroaryl containing 1 to 3 N; The R7 and R8 are each independently one or more independent R m may or may not be substituted with R m is C 1-3 Alkyl (where hydrogen is either protium or deuterium), C 3-10 Cycloalkyl, C1-3 Alkoxy, sulfonyl, amino, halogen, cyano, haloalkyl, carbamoyl, carboxyl, aryl (wherein hydrogen is hydrogen or deuterium), arylalkyl, R u , or R s and R m represents one or more independent R n may or may not be substituted with R n is C 1-3 Alkyl, C 1-3 Alkylsulfonyl, C 1-3 alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, oxide, or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl; R9 and R 10 are, independently of each other, hydrogen or halogen, R s is a 4- to 8-membered saturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O; R u is a 4- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

[0022] In one embodiment, R1 is hydrogen, aminomethyl, cyclobutyl, cyclopentyl (wherein hydrogen is protium or deuterium), spiro[2.3]hexanyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, pyrrolidinyl, tetrahydrofuranyl, or piperidinyl; 1a can be methyl, propyl, isopropyl, fluoro, oxo, —C(O)OH, —C(O)O-methyl, or —C(O)O-benzyl.

[0023] In one embodiment, R2 can be hydrogen, methyl, or trimethyl-silyl-ethoxy-methyl.

[0024] In one embodiment, R3 can be hydrogen, methyl, ethyl, or chloro.

[0025] In one embodiment, R4 may be hydrogen or methyl.

[0026] In one embodiment, the R 5a and R 5b are each independently hydrogen or methyl, or R 5a and R 5b may be linked together to form a cyclopropyl.

[0027] In one embodiment, R6 can be hydrogen or fluoro.

[0028] In one embodiment, R7 can be hydrogen, Br, piperazinyl, diazepanyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, isothiazolyl, triazolyl, oxadiazolyl, -NH-phenyl, -NH-cyclopentyl, -NH-piperidinyl, -NH-pyrrolyl, -NH-thiophenyl, -NH-pyrazolyl, -NH-isoxazolyl, -NH-oxadiazolyl, -NH-thiadiazolyl, -NH-pyridinyl, or -NHC(O)-pyrazolyl.

[0029] In one embodiment, R8 can be hydrogen, fluoro, chloro, or pyrazolyl.

[0030] In one embodiment, the R m is methyl (wherein hydrogen is hydrogen or deuterium), methoxy, sulfonyl, amino, fluoro, chloro, cyano, trifluoromethyl, difluoroethyl, trifluoroethyl, carbamoyl, carboxyl, cyclopentyl, cyclohexyl, phenyl (wherein hydrogen is hydrogen or deuterium), benzyl, thiophenyl, furanyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, or tetrahydrofuranyl, and said R ncan be methyl, ethyl, methylsulfonyl, methoxy, fluoro, chloro, iodo, bromo, cyano, trifluoromethyl, carbamoyl, carboxyl, acetyl, phenyl, benzyl, oxide, or methylcarboxyl-(8-cyclopentyl-7H-purine-6-carboxamido)-ethyl.

[0031] In one embodiment, R9 can be hydrogen, fluoro, or chloro.

[0032] In one embodiment, the R 10 can be hydrogen or fluoro.

[0033] When defining compounds of Formula I herein, the following definitions apply unless otherwise stated.

[0034] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon having a C 1-10 Alkyl is preferred, for example, alkyl includes, but is 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.

[0035] The term "cycloalkyl" refers to a partially or fully saturated single or fused ring hydrocarbon, C 3-10 The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic functional group. Examples of monocyclic functional groups within cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexynyl. Bicyclic functional groups within cycloalkyl include bicycloalkyl and spiro functional groups, and specific examples include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, spiro[2.3]hexanyl, and spiro[3.3]heptanyl.

[0036] The term "hydroxy" or "hydroxy" is defined as -OH, and the term "alkoxy", unless otherwise defined, means an alkyloxy radical in which the hydrogen atom of a hydroxy group is replaced with 1 to 10 alkyl groups.

[0037] The term "halogen" or "halo" means fluorine / fluoro (F), chlorine (Cl), bromine (Br) or iodine (I).

[0038] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy substituted with one or more halogen atoms.

[0039] The term "heteroatom" means N, O, or S.

[0040] The term "aryl" means an aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings. 5-12 Aryl, more preferably C 5-10 Aryl. For example, the aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc. Also included are groups in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocycle, such as indanyl or tetrahydrobenzopyranyl.

[0041] The term "heteroaryl" or "heteroaromatic ring" refers to a ring containing one or more heteroatoms selected from N, O, and S as ring atoms, and is not limited to benzo or C 3-8It means a 3- to 12-membered, more preferably 5- to 10-membered, aromatic hydrocarbon that forms a single or fused ring that can be fused to a cycloalkyl. For example, the heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, and the like.

[0042] The term "heterocycloalkyl" refers to a non-aromatic alkyl ring containing one or more heteroatoms, such as N, O, or S, within the ring. The ring may be 5-, 6-, 7-, or 8-membered or may be fused to another ring, such as a cycloalkyl or an aromatic ring. Examples of such compounds include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholino, and dioxanyl.

[0043] Arylalkyl, alkylaryl, and heteroarylalkyl refer to groups formed by combining an aryl and an alkyl, or a heteroaryl and an alkyl, as defined above, and include, but are not limited to, benzyl, thiopheneethyl, pyrimidinemethyl, etc.

[0044] The term "Cbz" means carbobenzyloxy.

[0045] Specific examples of compounds of formula I according to the present invention are as follows:

[0046] [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-(thiophen-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]hexan-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[78] 8-(bicyclo[3.1.0]hexan-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]heptan-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,

[0100] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[3.3]heptan-2-yl)-7H-purine-6-carboxamide,

[0101] 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,

[0102] (A,B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclobutyl)-7H-purine-6-carboxamide,

[0103] (A,B) methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate,

[0104] N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0105] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-7H-purine-6-carboxamide,

[0106] 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylic acid,

[0107] 2-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide,

[0108] 8-cyclopentyl-N-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0109] 8-cyclopentyl-N-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0110] (A,B) N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclopentyl)-7H-purine-6-carboxamide,

[0111] N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[2.3]hexan-5-yl)-7H-purine-6-carboxamide,

[0112] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-N-methyl-7H-purine-6-carboxamide,

[0113] 8-(bicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0114] 8-(bicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0115] 8-(bicyclo[2.1.1]hexan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0116] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7H-purine-6-carboxamide,

[0117] 8-cyclopentyl-N-(3-fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0118] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0119] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0120] N-(3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0121] 8-cyclopentyl-N-(3-fluoro-5-(isoxazol-3-ylamino)benzyl)-7H-purine-6-carboxamide,

[0122] N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0123] N-(3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0124] 8-cyclopentyl-N-(3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0125] N-(3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0126] N-(3-((4-carbamoylphenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0127] ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate,

[0128] 8-cyclopentyl-N-(3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzyl)-7H-purine-6-carboxamide,

[0129] 8-cyclopentyl-N-(3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0130] 8-cyclopentyl-N-(3-fluoro-5-(thiophen-3-ylamino)benzyl)-7H-purine-6-carboxamide,

[0131] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)benzyl)-7H-purine-6-carboxamide,

[0132] 8-cyclopentyl-N-(3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzyl)-7H-purine-6-carboxamide,

[0133] 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoic acid,

[0134] N-(3-((1,3,4-oxadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0135] 8-cyclopentyl-N-(3-(cyclopentylamino)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0136] N-(3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0137] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-1-yl)benzyl)-7H-purine-6-carboxamide,

[0138] 8-cyclopentyl-N-(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide,

[0139] N-(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide,

[0140] 8-cyclopentyl-N-(3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0141] 8-cyclopentyl-N-(3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0142] 8-cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0143] 8-cyclopentyl-N-(3-fluoro-5-(1-(1-oxidothiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0144] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0145] 8-cyclopentyl-N-(3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0146] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0147] 8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0148] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-(1-(phenyl-d5)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide,

[0149] 8-cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)benzyl)-7H-purine-6-carboxamide,

[0150] 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,

[0151] 8-cyclopentyl-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide,

[0152] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, and

[0153] 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.

[0047] The compound represented by Formula I according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility. Therefore, the prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention.

[0048] The term "prodrug" refers to a substance that is transformed into the parent drug in vivo. Prodrugs are sometimes used because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug may not. A prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. For example, a prodrug may be an in vivo hydrolyzable ester of a compound according to the invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group that is metabolically converted to reveal the active site.

[0049] The term "hydrate" means a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0050] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces, where preferred solvents are volatile, non-toxic, and / or suitable for human administration.

[0051] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but differs structurally or sterically. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans and cis), and diastereomers. All of these isomers and mixtures thereof are included within the scope of the present invention. In particular, when a compound of Formula I has optical isomers, stereoisomers, positional isomers, or rotamers, these are also included within the scope of Formula I and can be obtained as a single product by known synthesis and separation methods. For example, when a compound of Formula I contains optical isomers, the optical isomers resolved from this compound are also included within the scope of Formula I. Optical isomers can be prepared by known methods.

[0052] The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not induce significant irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt includes acid addition salts formed with acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid, etc., and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed with 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, triethylamine, etc. The compound of Formula 1 according to the present invention can be converted into its salt by a conventional method.

[0053] The synthesis methods of Examples 1 to 153 are exemplified as methods for producing the compound of formula I of the present invention, but these synthesis methods of Examples 1 to 153 do not limit the method for producing the compound of formula I of the present invention. It is obvious that the synthesis methods of Examples 1 to 153 are merely illustrative and can be easily modified by those skilled in the art depending on the specific substituents.

[0054] The present invention also provides a pharmaceutical composition for preventing or treating a disease associated with HIF-1α (Hypoxia Inducible Factor-1α) or the angiogenesis-inducing factor VEGF (Vascular Endothelial Growth Factor), 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 as an active ingredient.

[0055] The present invention also provides a method for preventing or treating a disease associated with HIF-1α or an angiogenesis-inducing factor (VEGF), comprising administering a compound represented by the chemical formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof to a subject or individual in need thereof.

[0056] The present invention also provides use of the compound represented by formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the prevention or treatment of a disease associated with HIF-1α or the angiogenesis induction factor VEGF.

[0057] In one embodiment, the prevention or treatment of HIF-1α or angiogenesis-inducing factor VEGF-related diseases may be achieved by inhibiting angiogenesis.

[0058] In one embodiment, the inhibition of angiogenesis may be due to the inhibition of HIF-1α expression or VEGF expression.

[0059] In one embodiment, the HIF-1α or VEGF-associated disease is stroke, brainstem 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, colorectal cancer, esophageal cancer, small intestine cancer, anal cancer, colon cancer, skin cancer, fallopian tube carcinoma, endometrial carcinoma, uterine cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, oral cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, ureter cancer, splenic cell carcinoma, renal pelvis carcinoma, medulloblastoma, neuroblastoma, brain tumor, central nervous system tumor, melanoma, non-small cell lung cancer, lymphoma, non-small cell lung cancer, 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 dental cyst, endometriosis, uterine sclerosis, ovarian hypertension, ovarian hyperactivity, uterine dysfunction, warts, scar keloid, allergic edema, atherosclerosis, peritoneal sclerosis, cardiac dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, osteochondral destruction, malignant fibrous histiocytoma of bone, osteomyelitis, pannus formation, liver fibrosis, pulmonary fibrosis, fibrosis, NASH (non-alcoholic steatohepatitis) hepatitis), pneumonia, asthma, rhinitis, pulmonary hypertension, ischemic acute kidney injury, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular disease, organ transplant rejection, glomerulopathy, inflammatory neurodegenerative diseases, nicotine poisoning-related vascular disease, chronic kidney disease, retinopathy of prematurity, diabetic retinopathy, corneal graft rejection, ischemic retinal disease, erythroderma, proliferative retinopathy, psoriasis, hemophilic joints, keloids, wound granulation, vascular adhesion, 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, retinoma, optic nerve hypothalamic glioma, rhabdomyosarcoma, tissue sarcoma, inflammation, corneal ulcer, proliferative vitreoretinopathy, liver cirrhosis, asthma, periodontal disease, allergic dermatitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' ophthalmopathy, leukomalacia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and Behcet's disease.

[0060] In one embodiment, the angiogenesis-related disease is cancer, cervical cancer, blood cancer, renal cell carcinoma, hepatocellular carcinoma, metastatic cancer, hemangioma, pyogenic granuloma, Kaposi's sarcoma, hemangioendothelioma, follicular dental cyst, endometriosis, uterine sclerosis, ovarian hypertension, ovarian hyperactivity, uterine dysfunction, warts, scar keloid, allergic edema, atherosclerosis, peritoneal sclerosis, cardiac dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, osteochondral destruction, osteomyelitis, pannus formation, liver fibrosis, NASH (non-alcoholic steatohepatitis), or the like. The angiogenesis-associated disease may be one or more selected from the group consisting of retinopathy of prematurity, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' ophthalmopathy, and leukomalacia. The angiogenesis-associated disease may be an angiogenic ocular disease, such as retinopathy of prematurity, proliferative diabetic retinopathy, neovascular glaucoma, macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, or intraocular neovascularization. The angiogenesis-associated disease may be macular degeneration.

[0061] In one embodiment, the HIF-1α or angiogenesis-inducing factor VEGF-related disease may be a neovascular ocular disease, and the neovascular ocular disease may be one or more 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.

[0062] 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).

[0063] The present invention also provides a dosage form 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 excipient.

[0064] The additives may include pharmaceutically acceptable carriers, such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and may be formulated by conventional methods into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral preparations such as topical solutions, topical suspensions, topical emulsions, gels (ointments, etc.), inhalants, sprays, and injections. For oral tablets, carriers such as lactose and corn starch and lubricants such as magnesium stearate are usually added. For oral capsules, lactose and / or dried corn starch may be used as diluents. When oral aqueous suspensions are required, 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, sterile solutions of the active ingredient are usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous administration, the total concentration of solutes is adjusted to render the formulation isotonic. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline at pH 7.4. The solution may be introduced into the patient's intramuscular bloodstream by local injection. The formulation may be formulated in a variety of forms, for example, single-dose or multi-dose dosage forms.

[0065] The individual to which the pharmaceutical composition of the present invention is administered may be, for example, a human, monkey, cow, horse, sheep, pig, chicken, turkey, cat, dog, mouse, rat, rabbit, or guinea pig, and may be, for example, a mammal, such as a human, but is not limited thereto.

[0066] The pharmaceutical composition of the present invention can be administered orally or parenterally. Parenteral administration can be via routes such as intradermal, transdermal, ocular, peritoneal, rectal, intravenous, intramuscular, subcutaneous, intracervical, intracerebroventricular injection, or topical administration. Topical ocular administration can include, for example, direct intraocular administration or administration to the ocular cavity, the back of the eye, the subretinal, the central retinal, the extrafoveal, the subconjunctival, the intravitreal, the intracameral, or the suprachoroidal. The pharmaceutical composition can be administered via an insertion device.

[0067] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the form of the active ingredient, the route of administration, and the duration of administration, and can be adjusted appropriately for each patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg per day, preferably 0.001 to 100 mg / kg per day, and can be administered once or in several divided doses per day. Furthermore, the pharmaceutical composition of the present invention can contain the active ingredient in an amount of 0.001 to 90% by weight based on the total weight of the composition.

[0068] The present invention will be explained in more detail below with reference to Production Examples, Examples and Test Examples. However, the following Production Examples, Examples and Test Examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0069] <Production Example 1> 1.1 Preparation of 8-cyclopentyl-7H-purine-6-carbonitrile

[0070] [ka]

[0071] 6-Chloro-8-cyclopentyl-7H-purine (1.5 g, 6.73 mmol), KCN (1.32 g, 20.3 mmol), and sodium p-toluenesulfinate (1.2 g, 6.75 mmol) were dissolved in sulfolane (25 mL) and stirred at 160-163 °C for 3 h. After cooling the reaction mixture to room temperature, silica gel was added to completely absorb the sulfolane. The silica gel was loaded in the solid state, and the product was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the target compound (5.43 g, 71%) as a yellow solid.

[0072] LC-MS, m / z 214 [M+H] + 1.2 Preparation of methyl 8-cyclopentyl-7H-purine-6-carboxylate

[0073] [ka]

[0074] 8-Cyclopentyl-7H-purine-6-carbonitrile (5.40 g, 25.3 mmol) obtained in Preparation 1.1 was dissolved in MeOH (220 mL) and TMSCl (chlorotrimethylsilane, 33.5 mL) was added. After stirring at 70 °C for 4.5 hours and quenching with saturated aqueous NaHCO3, the aqueous layer was extracted with DCM, and the organic layer was separated and dried over MgSO4. After concentration, the resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain the target compound (3.66 g, 59%) as a white solid.

[0075] LC-MS, m / z 247 [M+H] + 1.3 Preparation of 8-cyclopentyl-7H-purine-6-carboxylic acid

[0076] [ka]

[0077] Methyl 8-cyclopentyl-7H-purine-6-carboxylate (3.65 g, 14.8 mmol) obtained in Preparation 1.2 was dissolved in MeOH (111 mL) and 2 M NaOH (47.0 mL) was added, followed by stirring at room temperature. After 3.5 hours, the reaction mixture was acidified (to pH 2) with 1 M HCl, and the resulting solid was filtered and washed with hexane. The solid was dried under vacuum to obtain the target compound (3.02 g, 88%) as a white solid.

[0078] 1 H NMR (400 MHz, CD3OD) δ 9.00 (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). LC-MS, m / z 233 [M+H] + Example 1 1.1 3-Fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzonitrile

[0079] [ka]

[0080] 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), 2 M KCO (1.25 mL) was added, and the mixture was degassed with N for 10 minutes. The reaction mixture was reacted 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 obtained residue was purified by silica gel column chromatography (0-5% MeOH in CH2Cl2) to obtain the target compound (100 mg, 39%) as a white solid.

[0081] LC-MS, m / z 256 [M+H] + 1.2 (3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0082] [ka]

[0083] 3-Fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzonitrile (90 mg, 0.35 mmol) obtained in Example 1.1 was dissolved in THF (5 mL) and 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 with HO (2 mL), and the pH was adjusted to 10 using 2 M NaOH solution. EtOAc (5 mL) was added and stirred for 1 hour, followed by filtration to remove solids. The filtrate was concentrated and then redissolved in EtOAc. The organic layer was dried over MgSO, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH in CHCl) to obtain the target compound (44 mg, 49%) as an oil.

[0084] LC-MS, m / z 260 [M+H] + 1.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0085] [ka]

[0086] 8-Cyclopentyl-7H-purine-6-carboxylic acid (15 mg, 0.07 mmol) obtained in Preparation 1.3, (3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)methanamine (17 mg, 0.07 mmol), and T3P (propylphosphonic anhydride, 50 wt% solution in EtOAc, 128 mg) were dissolved in ethyl acetate (3 mL), followed by DIPEA (N,N-diisopropylethylamine, 30 μL) and the reaction was carried out at 50 °C. After 12 h, the reaction mixture was extracted with ethyl acetate and HO, and the organic layer was dried over NaSO and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the target compound (25 mg, 81%) as a white solid.

[0087] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 7.53 (s, 1H), 7.34 (d, J = 12 Hz, 1H), 7.11 (d, J = 8.0 Hz, 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). LC-MS, m / z 474 [M+H] + <Example 2> 2.1 3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzonitrile

[0088] [ka]

[0089] The target compound (251 mg, 100%) was obtained as a white solid in the same manner 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)Cl (([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 36.6 mg, 0.05 mmol), 2M KCO (1.25 mL), and dioxane (3.4 mL).

[0090] LC-MS, m / z 252 [M+H] + 2.2 (3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[0091] [ka]

[0092] The same method as in Example 1.2 was used to obtain the target compound (193 mg, 76%) in the form of a yellow syrup 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).

[0093] LC-MS, m / z 256 [M+H] + 2.3 8-Cyclopentyl-N-(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[0094] [ka]

[0095] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (3.4 mg, 11%) as a white solid.

[0096] 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.11 (d, J = 9.6 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.29 - 5.92 (m, 1H), 4.71 (d, J = 6.2 Hz, 2H), 4.49 (td, J = 13.5, 4.1 Hz, 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). LC-MS, m / z 470 [M+H] + Example 3 3.1 3-Fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzonitrile

[0097] [ka]

[0098] The same procedure as in Example 1.1 was repeated 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)Cl (36.6 mg, 0.05 mmol), 2M KCO (1.25 mL), and dioxane (3.4 mL) to obtain the target compound (269 mg, 100%) as a white solid.

[0099] LC-MS, m / z 270 [M+H] + 3.2 (3-Fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0100] [ka]

[0101] The same method as in Example 1.2 was used to obtain the target compound (222 mg, 81%) in the form of a yellowish syrup 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).

[0102] LC-MS, m / z 274 [M+H] + 3.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0103] [ka]

[0104] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (8.7 mg, 27%) as a white solid.

[0105] 1H NMR (400 MHz, CDCl3) δ 10.35 (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 = 9.1 Hz, 1H), 6.99 (d, J = 8.8 Hz, 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). LC-MS, m / z 488 [M+H] + Example 4 4.1 (S)-tert-butyl(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[0106] [ka]

[0107] To a solution of (S)-tert-butyl (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 aqueous K2CO3 (1.2 mL, 2.4 mmol). The mixture was degassed with N2 gas for 10 minutes, and then PdCl2(dppf) (26 mg, 0.035 mmol) was added and the reaction mixture was heated to 80 °C. After 3 h, the reaction mixture was diluted with H2O and extracted three times with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-3% MeOH in DCM) to give the desired compound (60 mg, 30%) as an off-white solid.

[0108] LC-MS, m / z 302 [M+H] + 4.2 (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethan-1-amine

[0109] [ka]

[0110] To a solution of 1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (60 mg, 0.20 mmol) in DCM (1 mL) was added TFA (0.2 mL) dropwise at 0 °C. The reaction temperature was gradually raised to room temperature and allowed to react for 1 hour. After completion of the reaction, the mixture was quenched with saturated aqueous Na2CO3 solution and extracted three times with DCM (1% MeOH). The filtrate was concentrated and purified by silica gel column chromatography (0-3% MeOH in DCM) to obtain the target compound (20 mg, 50%).

[0111] 1 H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.33 (dt, J = 15.2, 7.6 Hz, 2H), 7.20 (d, J = 7.0 Hz, 1H), 4.15 (q, J = 6.6 Hz, 1H), 3.94 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H). 4.3 (S)-8-Cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[0112] [ka]

[0113] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (13 mg, 63%).

[0114] 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (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 = 6.4 Hz, 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 = 4.8 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H). LC-MS, m / z 416 [M+H] + <Example 5> 5.1 N-(3-cyano-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0115] [ka]

[0116] 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), followed by the addition of DIPEA (333 μL, 1.91 mmol) and the reaction mixture was heated to 50 °C. After 12 h, the reaction mixture was extracted with ethyl acetate and HO. The organic layer was dried over NaSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (85 mg, 44%) as a yellow solid.

[0117] LC-MS, m / z 245 [M+H] + 5.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide

[0118] [ka]

[0119] To a solution of N-(3-cyano-5-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxamide (55 mg, 0.23 mmol) in EtOH (1 mL), 10% palladium on carbon (Pd / C; 50 mg) and AcOH (50% in water; 0.5 mL) were added. The reaction was carried out under H2 conditions at room temperature overnight. The reaction mixture was filtered through a Celite pad and concentrated to give the desired compound (56 mg, crude).

[0120] LC-MS, m / z 249 [M+H] + 5.3 8-Cyclopentyl-N-(3-fluoro-5-(1-methyl-1H-pyrazole-4-carboxamido)benzyl)-7H-purine-6-carboxamide

[0121] [ka]

[0122] The target compound (5 mg, 13%) was obtained in the same manner 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).

[0123] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (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 = 11.4 Hz, 1H), 7.40 (s, 1H), 6.89 (d, J = 9.8 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.86 (d, J = 7.8 Hz, 3H), 3.47 (s, 1H), 2.05 (m, 2H), 1.91 (m, 2H), 1.79 (m, 2H), 1.64 (m, 2H). LC-MS, m / z 463 [M+H] + Example 6 6.1 tert-Butyl (1-(3-bromophenyl)cyclopropyl)carbamate

[0124] [ka]

[0125] To a solution of 1-(3-bromophenyl)cyclopropanamine (300 mg, 1.4 mmol) in THF (6 mL) were added BocO (370 mg, 1.7 mmol) and NaCO (300 mg, 2.8 mmol). The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with H2O and extracted three times with DCM. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-3% MeOH in DCM) to give the desired compound (437 mg, 99%).

[0126] LC-MS, m / z 313 [M+H] + 6.2 tert-Butyl (1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)carbamate

[0127] [ka]

[0128] The same procedure as in Example 4.1 was repeated 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) to obtain the target compound (4 mg, 99%).

[0129] LC-MS, m / z 314 [M+H] + 6.3 1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropan-1-amine

[0130] [ka]

[0131] The target compound (318 mg, crude) was obtained in the same manner as in Example 4.2 using tert-butyl (1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)carbamate (430 mg, 1.4 mmol) and TFA (2 mL).

[0132] LC-MS, m / z 214 [M+H] + 6.4 8-Cyclopentyl-N-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropyl)-7H-purine-6-carboxamide

[0133] [ka]

[0134] The target compound (83 mg, 90%) was obtained in the same manner as in Example 1.3 using 1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)cyclopropanamine (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).

[0135] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (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 = 7.6 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 3.50 - 3.43 (m, 1H), 2.07 (d, J = 12.4 Hz, 2H), 1.92 (dd, J = 12.2, 7.4 Hz, 2H), 1.80 (s, 2H), 1.69 - 1.61 (m, 2H), 1.36 (s, 4H). LC-MS, m / z 428 [M+H] + Example 7 7.1 3-Fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzonitrile

[0136] [ka]

[0137] The same procedure as in Example 4.1 was repeated 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 aqueous K2CO3 solution (1.3 mL, 2.6 mmol), PdCl2(dppf) (27 mg, 0.037 mmol), and 1,4-dioxane (3 mL) to obtain the target compound (194 mg, 99%).

[0138] LC-MS, m / z 264 [M+H] + 7.2 (3-Fluoro-5-(1-phenyl-1H-pyrazol-4-yl)phenyl)methanamine

[0139] [ka]

[0140] 3-Fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzonitrile (100 mg, 0.38 mmol) was added to THF (3 mL), followed by the addition of LAH solution (2.0 M in THF, 380 μL, 0.76 mmol) at 0 °C. The mixture was reacted at room temperature under N2 for 1 h. After completion of the reaction, the mixture was quenched with 1 M NaOH (pH = 8-9), 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 (0-5% MeOH in DCM) to give the desired compound (70 mg, 70%).

[0141] LC-MS, m / z 268 [M+H] + 7.3 8-Cyclopentyl-N-(3-fluoro-5-(1-phenyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0142] [ka]

[0143] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (13 mg, 72%).

[0144] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.78 (s, 1H), 9.06 (s, 1H), 8.97 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.60 (s, 1H), 7.55 - 7.48 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 9.3 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 3.52 - 3.47 (m, 1H), 2.08 (d, J = 7.8 Hz, 2H), 1.94 (d, J = 7.7 Hz, 2H), 1.81 (s, 2H), 1.66 (s, 2H). LC-MS, m / z 482 [M+H] + Example 8 8.1 3-Fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile

[0145] [ka]

[0146] 3-Bromo-5-fluorobenzonitrile (260 mg, 1.3 mmol), 1-methyl-1H-pyrazol-4-amine (100 mg, 1.0 mmol), BINAP (240 mg), Pd(dba) (180 mg), and sodium tert-butoxide (190 mg) were added to toluene (4 mL) and reacted at 100 °C for 1 hour. After the reaction was complete, the mixture was diluted with HO and extracted three times with EtOAc. The organic layer was dried over NaSO and then concentrated. The resulting residue was purified by aminosilica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (160 mg, 58%).

[0147] LC-MS, m / z 217 [M+H] + 8.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine

[0148] [ka]

[0149] The same procedure as in Example 7.2 was repeated 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 target compound (100 mg, 70%).

[0150] LC-MS, m / z 221 [M+H] + 8.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[0151] [ka]

[0152] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (132 mg, 37%).

[0153] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (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 = 9.4 Hz, 1H), 6.31 (d, J = 11.8 Hz, 1H), 4.40 (d, J = 6.3 Hz, 2H), 3.73 (s, 3H), 3.46 (s, 1H), 2.05 (d, J = 5.7 Hz, 2H), 1.93 - 1.87 (m, 2H), 1.77 (s, 2H), 1.67 - 1.60 (m, 2H). LC-MS, m / z 435 [M+H] + Example 9 9.1 3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorobenzonitrile

[0154] [ka]

[0155] The same procedure as in Example 1.1 was repeated 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)Cl (36.6 mg, 0.05 mmol), and dioxane (3.4 mL) to obtain the target compound (276 mg, 99%) as a white solid.

[0156] LC-MS, m / z 277 [M+H] + 9.2 (3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[0157] [ka]

[0158] The target compound (104 mg, 39%) was obtained as an oil using 3-(1-benzyl-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) in the same manner as in Example 1.2.

[0159] LC-MS, m / z 282 [M+H] + 9.3 N-(3-(1-benzyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0160] [ka]

[0161] The target compound (17 mg, 57%) was obtained as a white solid in the same manner 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).

[0162] 1 H NMR (400 MHz, CD3OD) δ 8.93 (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). LC-MS, m / z 496 [M+H] + Example 10 10.1 3-Fluoro-5-(pyridin-3-ylamino)benzonitrile

[0163] [ka]

[0164] 3-Bromo-5-fluorobenzonitrile (256 mg, 1.28 mmol), pyridin-3-amine (100 mg, 1.06 mmol), Xantphos (30 mg, 0.05 mmol), Pd(dba) (15 mg, 0.016 mmol), and KCO (318 mg, 2.3 mmol) were added to dioxane (5 mL) and reacted at 80 °C. After 12 h, the reaction mixture was extracted with ethyl acetate and H2O. The organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (190 mg, 89%) as a white solid.

[0165] LC-MS, m / z 214 [M+H] + 10.2 N-(3-(aminomethyl)-5-fluorophenyl)pyridin-3-amine

[0166] [ka]

[0167] The target compound (70 mg, 38%) was obtained in the form of an oil using 3-fluoro-5-(pyridin-3-ylamino)benzonitrile (180 mg, 0.83 mmol) and LAH solution (2.0 M in THF, 0.84 mL) in the same manner as in Example 1.2.

[0168] LC-MS, m / z 218 [M+H] + 10.3 8-Cyclopentyl-N-(3-fluoro-5-(pyridin-3-ylamino)benzyl)-7H-purine-6-carboxamide

[0169] [ka]

[0170] The same procedure as in Example 1.3 was repeated 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 mml) to obtain the target compound (25 mg, 32%) as a white solid.

[0171] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.58 (d, J = 8.0 Hz, 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). LC-MS, m / z 432 [M+H] + Example 11 11.1 3-Fluoro-5-(1H-pyrazol-4-yl)benzonitrile

[0172] [ka]

[0173] The same procedure as in Example 1.1 was repeated 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 aqueous K2CO3 solution (12 mL, 24 mmol), Pd(dppf)Cl2 (240 mg, 0.33 mmol), and dioxane (24 mL) to obtain the target compound (360 mg, 29%).

[0174] LC-MS, m / z 188 [M+H] + 11.2 (3-Fluoro-5-(1H-pyrazol-4-yl)phenyl)methanamine

[0175] [ka]

[0176] The target compound (364 mg, crude) was obtained in the same manner 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).

[0177] LC-MS, m / z 192 [M+H] + 11.3 8-Cyclopentyl-N-(3-fluoro-5-(1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0178] [ka]

[0179] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (136 mg, 21%).

[0180] 1H NMR (400 MHz, DMSO-d6) δ 13.14 (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 = 9.8 Hz, 1H), 6.97 (d, J = 9.6 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 3.45 (d, J = 8.2 Hz, 1H), 2.05 (d, J = 8.3 Hz, 2H), 1.90 (dd, J = 12.4, 7.4 Hz, 2H), 1.78 (s, 2H), 1.68 - 1.60 (m, 2H). LC-MS, m / z 406 [M+H] + Example 12 12.1 3-Fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzonitrile

[0181] [ka]

[0182] 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), KCO (220 mg, 1.6 mmol), and NMP (1 mL) were added to a sealed microwave tube and reacted at 150 °C for 4 hours. After LC-MS confirmed that 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile had been completely consumed, the mixture was quenched with saturated aqueous NaHCO and extracted three times with DCM (1% MeOH). The organic layer was dried over NaSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-50% EtOAc in n-hexane) to give the desired compound (41 mg, 29%).

[0183] 1H 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 = 10.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H). LC-MS, m / z 265 [M+H] + 12.2 (3-Fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine

[0184] [ka]

[0185] The target compound (42 mg, crude) was obtained in the same manner 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).

[0186] LC-MS, m / z 265 [M+H] + 12.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0187] [ka]

[0188] The same procedure as in Example 1.3 was carried out 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) to obtain the target compound (5 mg, 7%).

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.80 (s, 1H), 9.25 (s, 1H), 8.93 (s, 1H), 8.66 (d, J = 6.2 Hz, 2H), 8.37 (s, 1H), 7.87 (d, J = 6.2 Hz, 2H), 7.60 (s, 1H), 7.49 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 9.4 Hz, 1H), 4.60 (d, J = 6.4 Hz, 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). LC-MS, m / z 483 [M+H] + Example 13 8-Cyclopentyl-N-(3-fluorobenzyl)-7H-purine-6-carboxamide

[0190] [ka]

[0191] The target compound (130 mg, 78%) was obtained as a white solid in the same manner 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).

[0192] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.36 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 12 Hz, 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). LC-MS, m / z 340 [M+H] + Example 14 N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0193] [ka]

[0194] The target compound (250 mg, 92%) was obtained as a white solid in the same manner 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).

[0195] 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 7.42 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 12 Hz, 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). LC-MS, m / z 419 [M+H] + Example 15 15.1 3-Fluoro-5-(phenylamino)benzonitrile

[0196] [ka]

[0197] The target compound (200 mg, 94%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0198] LC-MS, m / z 213 [M+H] + 15.2 3-(aminomethyl)-5-fluoro-N-phenylaniline

[0199] [ka]

[0200] The target compound (140 mg, 69%) was obtained in the form of an oil using 3-fluoro-5-(phenylamino)benzonitrile (200 mg, 0.94 mmol) and LAH solution (2.0 M in THF, 0.94 mL) in the same manner as in Example 1.2.

[0201] LC-MS, m / z 217 [M+H] + 15.3 8-Cyclopentyl-N-(3-fluoro-5-(phenylamino)benzyl)-7H-purine-6-carboxamide

[0202] [ka]

[0203] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (50 mg, 84%) as a white solid.

[0204] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.19 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.87 (m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 12 Hz, 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). LC-MS, m / z 431 [M+H] + Example 16 16.1 3-Fluoro-5-(pyridin-4-ylamino)benzonitrile

[0205] [ka]

[0206] The target compound (182 mg, 85%) was obtained as a white solid in the same manner 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), Pd(dba) (tris(dibenzylideneacetone)dipalladium(0), 15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0207] LC-MS, m / z 214 [M+H] + 16.2 N-(3-(aminomethyl)-5-fluorophenyl)pyridin-4-amine

[0208] [ka]

[0209] The target compound (130 mg, 80%) was obtained in the form of an oil 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) in the same manner as in Example 1.2.

[0210] LC-MS, m / z 218 [M+H] + 16.3 8-Cyclopentyl-N-(3-fluoro-5-(pyridin-4-ylamino)benzyl)-7H-purine-6-carboxamide

[0211] [ka]

[0212] The target compound (40 mg, 51%) was obtained as a white solid in the same manner 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).

[0213] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.11 (d, J = 4.0 Hz, 2H), 7.09 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 12 Hz, 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). LC-MS, m / z 432 [M+H] + Example 17 17.1 3-Fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzonitrile

[0214] [ka]

[0215] The target compound (80 mg, 29%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0216] LC-MS, m / z 281 [M+H] + 17.2 3-(Aminomethyl)-5-fluoro-N-(3-(trifluoromethyl)phenyl)aniline

[0217] [ka]

[0218] The target compound (50 mg, 62%) was obtained in the form of an oil 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) in the same manner as in Example 1.2.

[0219] LC-MS, m / z 285 [M+H] + 17.3 8-Cyclopentyl-N-(3-fluoro-5-((3-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0220] [ka]

[0221] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (30 mg, 37%) as a white solid.

[0222] 1H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.33 - 7.26 (m, 3H), 7.08 (d, J = 8.0 Hz, 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). LC-MS, m / z 499 [M+H] + Example 18 18.1 3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzonitrile

[0223] [ka]

[0224] The target compound (210 mg, 82%) was obtained as a white solid in the same manner 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).

[0225] LC-MS, m / z 256 [M+H] + 18.2 N1-(3-(aminomethyl)-5-fluorophenyl)-N4,N4-dimethylbenzene-1,4-diamine

[0226] [ka]

[0227] The target compound (80 mg, 79%) was obtained as an oil 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) in the same manner as in Example 1.2.

[0228] LC-MS, m / z 260 [M+H] + 18.3 8-Cyclopentyl-N-(3-((4-(dimethylamino)phenyl)amino)-5-fluorobenzyl)-7H-purine-6-carboxamide

[0229] [ka]

[0230] The target compound (31 mg, 44%) was obtained as a white solid in the same manner 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-dimethylbenzene-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).

[0231] 1 H NMR (400 MHz, CD3OD) δ 8.93 (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). LC-MS, m / z 474 [M+H] + Example 19 19.1 3-Fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzonitrile

[0232] [ka]

[0233] The target compound (280 mg, 96%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0234] LC-MS, m / z 291 [M+H] + 19.2 3-(aminomethyl)-5-fluoro-N-(4-(methylsulfonyl)phenyl)aniline

[0235] [ka]

[0236] The target compound (72 mg, 82%) was obtained in the form of an oil 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) in the same manner as in Example 1.2.

[0237] LC-MS, m / z 295 [M+H] + 19.3 8-Cyclopentyl-N-(3-fluoro-5-((4-(methylsulfonyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0238] [ka]

[0239] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (32 mg, 45%) as a white solid.

[0240] 1 H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 7.69 (d, J = 8 Hz, 2H), 7.17 (d, J = 8 Hz, 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). LC-MS, m / z 509 [M+H] + Example 20 20.1 3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzonitrile

[0241] [ka]

[0242] The target compound (100 mg, 38%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0243] LC-MS, m / z 265 [M+H] + 20.2 N-(3-(aminomethyl)-5-fluorophenyl)-4-chloro-2-fluoroaniline

[0244] [ka]

[0245] The target compound (50 mg, 55%) was obtained in the form of an oil 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) in the same manner as in Example 1.2.

[0246] LC-MS, m / z 269 [M+H] + 20.3 N-(3-((4-chloro-2-fluorophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0247] [ka]

[0248] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (60 mg, 83%) as a white solid.

[0249] 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.82 (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). LC-MS, m / z 483 [M+H] + Example 21 21.1 3-Fluoro-5-((4-fluorophenyl)amino)benzonitrile

[0250] [ka]

[0251] The target compound (90 mg, 36%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0252] LC-MS, m / z 231 [M+H] + 21.2 3-(aminomethyl)-5-fluoro-N-(4-fluorophenyl)aniline

[0253] [ka]

[0254] The target compound (20 mg, 22%) was obtained in the form of an oil using 3-fluoro-5-((4-fluorophenyl)amino)benzonitrile (90 mg, 0.34 mmol) and LAH solution (2.0 M in THF, 0.34 mL) in the same manner as in Example 1.2.

[0255] LC-MS, m / z 235 [M+H] + 21.3 8-Cyclopentyl-N-(3-fluoro-5-((4-fluorophenyl)amino)benzyl)-7H-purine-6-carboxamide

[0256] [ka]

[0257] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (8 mg, 28%) as a viscous oil.

[0258] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.07 (m, 2H), 6.93 (t, J = 8.0 Hz, 2H), 6.80 (s, 1H), 6.53 (t, J = 8.0 Hz, 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). LC-MS, m / z 449 [M+H] + Example 22 22.1 N-(3-Bromo-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide

[0259] [ka]

[0260] To a solution of N-(3-bromo-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide (30 mg, 0.072 mmol) in THF (1 mL), NaH (60% dispersion in mineral oil) (4 mg, 0.11 mmol) was added at 0 °C and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (19 μL, 0.11 mmol) was added. The mixture was then allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was diluted with HO and extracted three times with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-30% EtOAc in n-hexane) to give the desired compound (25 mg, 64%).

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (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 = 9.2 Hz, 1H), 7.12 (d, J = 9.7 Hz, 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 = 8.0 Hz, 2H), -0.07 (s, 9H). LC-MS, m / z 637 [M+H] + 22.2 N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide

[0262] [ka]

[0263] The same procedure as in Example 4.1 was repeated 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) to obtain the target compound (12 mg, 52%).

[0264] 1 H NMR (400 MHz, CD3OD) δ 8.99 (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 = 9.2 Hz, 1H), 7.12 (d, J = 9.7 Hz, 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 = 8.0 Hz, 2H), -0.07 (s, 9H). LC-MS, m / z 637 [M+H] + Example 23 N-(3-(1-(3-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0265] [ka]

[0266] 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 (0.4 mL, 0.39 mmol), and the mixture was reacted at 80 °C for 4 hours. The reaction mixture was neutralized with 2N aqueous NaOH, and the EtOH was evaporated. The reaction mixture was diluted with H2O and extracted three times with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (6 mg, 75%).

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.76 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.33 (d, J = 9.9 Hz, 2H), 8.22 (d, J = 7.5 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.58 (s, 1H), 7.46 (d, J = 10.1 Hz, 1H), 7.10 - 7.04 (m, 1H), 4.59 (d, J = 6.2 Hz, 2H), 3.51 - 3.44 (m, 1H), 2.05 (s, 2H), 1.91 (s, 2H), 1.78 (s, 2H), 1.64 (s, 2H). LC-MS, m / z 507 [M+H] + Example 24 24.1 3-Fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzonitrile

[0268] [ka]

[0269] To a solution of 3-fluoro-5-(1H-pyrazol-4-yl)benzonitrile (65 mg, 0.35 mmol) in 1,4-dioxane (2 mL), NaH (60% dispersion in mineral oil) (17 mg, 0.70 mmol) was added at 0 °C and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, and 1-(bromomethyl)-4-(methylsulfonyl)benzene (173 mg, 0.42 mmol) was added and allowed to react overnight at room temperature. After completion of the reaction, the mixture was diluted with HO and extracted three times with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-50% EtOAc in n-hexane) to give the desired compound (110 mg, 89%).

[0270] LC-MS, m / z 356 [M+H] + 24.2 (3-Fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0271] [ka]

[0272] The same procedure as in Example 7.2 was repeated 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) to obtain the target compound (40 mg, 36%).

[0273] LC-MS, m / z 360 [M+H]+ 24.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0274] [ka]

[0275] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (12 mg, 23%).

[0276] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.74 (s, 1H), 8.94 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.47 - 7.42 (m, 3H), 7.32 (d, J = 10.1 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 5.46 (s, 2H), 4.55 (d, J = 5.8 Hz, 2H), 3.46 (s, 1H), 3.17 (s, 3H), 2.05 (d, J = 10.3 Hz, 2H), 1.91 (d, J = 7.7 Hz, 2H), 1.78 (s, 2H), 1.63 (d, J = 5.1 Hz, 2H). LC-MS, m / z 574 [M+H] + Example 25 25.1 tert-Butyl 3-bromo-5-fluorobenzylcarbamate

[0277] [ka]

[0278] The target compound (2.95 g, 99%) was obtained as a colorless, transparent liquid using (3-bromo-5-fluorophenyl)methanamine (2 g, 9.802 mmol), (Boc)O (30% in THF, 4.3 g, 19.6040 mmol), and DCM (20 mL) in the same manner as in Example 6.1.

[0279] 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, 1H), 4.29 (d, J = 5.6 Hz, 1H), 1.47 (s, 9H). 25.2 tert-Butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate

[0280] [ka]

[0281] To a mixture of tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5 g, 1.64 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.48 g, 2.47 mmol), and Na2CO3 (0.61 g, 5.85 mmol), DMF (7.5 mL) and HO (3 mL) were added and the mixture was degassed with N2 for 10 minutes. Pd(PPh3)4 (0.095 g, 0.082 mmol) was then added and the mixture was reacted at 140 °C overnight. The reaction mixture was extracted with ethyl acetate and HO, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-65% EtOAc in n-hexane) to give the desired compound (374 mg, 78%) as a pale yellow solid.

[0282] 1 H NMR (400 MHz, CD3OD) δ 7.98 (broad, 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). LC-MS, m / z 292 [M+H] + 25.3 tert-Butyl (3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0283] [ka]

[0284] 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) were added to DMSO (1.5 mL) and reacted at 110 °C for 8 hours. After completion of the reaction, the reaction mixture was added with HO and 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 (0-3% MeOH in DCM) to give the desired compound (59.6 mg, 87%) as a light brown solid.

[0285] 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.94 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 7.25 (s, 1H), 7.13 (d, J = 10 Hz, 1H), 7.0 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 4.34 (d, J = 5.2 Hz, 2H), 3.86 (s, 3H), 1.48 (s, 9H). 25.4 (3-Fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0286] [ka]

[0287] 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), and trifluoroacetic acid (1.2 mL) was added and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was diluted with DCM and concentrated five times to obtain the target compound (56 mg, crude) as a viscous dark brown liquid.

[0288] LC-MS, m / z 298 [M+H] + 25.5 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0289] [ka]

[0290] The same procedure as in Example 1.3 was repeated using 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 μL), and DMF (2 mL) to obtain the target compound (27.1 mg, two-step yield 37%) in the form of a pale yellow foam.

[0291] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (1H, Broad), 9.77 (t, J = 6.8 Hz, 1H), 8.96 (d, J = 11.2 Hz, 2H), 8.19 (s, 1H), 7.78 (2H, J = 9.2 Hz, 2H), 7.58 (s, 1H), 7.47 (d, J = 9.6 Hz, 1H), 7.07 (m, 3H), 4.61 (d, J = 6.4 Hz, 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). LC-MS, m / z 512 [M+H] + Example 26 26.1 tert-Butyl (3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0292] [ka]

[0293] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (67 mg, 89%) as an off-white solid.

[0294] 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.00 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.14 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.96 (broad, 1H), 4.36 (d, J = 5.6 Hz, 2H), 1.48 (s, 9H). 26.2 (3-Fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0295] [ka]

[0296] The same procedure as in Example 25.4 was repeated 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 target compound (56 mg, crude) as a viscous dark brown liquid.

[0297] LC-MS, m / z 336 [M+H] + 26.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0298] [ka]

[0299] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (31 mg, two-step yield 39%) in the form of a pale yellow foam.

[0300] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (1H, Broad), 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 = 10 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 4.62 (d, J = 6.0 Hz, 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). LC-MS, m / z 550 [M+H] + Example 27 27.1 tert-Butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0301] [ka]

[0302] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (345 mg, 87%) as an off-white solid.

[0303] 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.96 (s, 1H), 7.69 (dd, J = 8.8, 4.4 Hz, 2H), 7.24 (s, 1H), 7.18 (t, J = 8 Hz, 2H), 7.13 (d, J = 9.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.93 (s, 1H), 4.35 (d, J = 5.6 Hz, 2H), 1.48 (s, 9H). LC-MS, m / z 386 [M+H] + 27.2 (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0304] [ka]

[0305] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (350 mg, crude) as an off-white solid.

[0306] LC-MS, m / z 286 [M+H] + 27.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0307] [ka]

[0308] 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), followed by DIPEA (690 μL) and the mixture was allowed to react overnight at room temperature. The reaction mixture was extracted with ethyl acetate and HO, and the organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-3% MeOH in DCM) to give the target compound (319 mg, 71% yield for two steps) as a pale yellow foam.

[0309] 1H 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), 7.39 (t, J = 8.8 Hz, 2H), 7.08 (d, J = 9.6 Hz, 1H), 4.61 (d, J = 6.4 Hz, 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). LC-MS, m / z 500 [M+H] + Example 28 28.1 tert-Butyl (3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0310] [ka]

[0311] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (59 mg, 78%) as an off-white solid.

[0312] 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.03 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.6 Hz, 1H), 4.96 (s, broad), 4.36 (d, J = 6 Hz, 2H), 3.11 (s, 3H), 1.49 (s, 9H). 28.2 (3-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0313] [ka]

[0314] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (58 mg, crude).

[0315] LC-MS, m / z 346 [M+H] + 28.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0316] [ka]

[0317] The target compound (56 mg, 80% yield in two steps) was obtained as a white solid in the same manner 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).

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (1H, brs), 9.79 (t, J = 6.4 Hz, 1H), 9.26 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 10 Hz, 1H), 7.10 (d, J = 10 Hz, 1H), 4.61 (d, J = 6 Hz, 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). LC-MS, m / z 560 [M+H] + Example 29 29.1 3-Fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzonitrile

[0319] [ka]

[0320] The same procedure as in Example 24.1 was repeated 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) to obtain the target compound (86 mg, 72%).

[0321] LC-MS, m / z 346 [M+H] + 29.2 (3-Fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0322] [ka]

[0323] The same procedure as in Example 7.2 was repeated 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) to obtain the target compound (50 mg, 57%).

[0324] LC-MS, m / z 350 [M+H] + 29.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0325] [ka]

[0326] Using the same method as in Example 1.3, 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) were used to obtain the target compound (5.7 mg, 8%).

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.73 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 6.99 (d, J = 9.6 Hz, 1H), 5.44 (s, 2H), 4.55 (d, J = 6.1 Hz, 2H), 3.48 - 3.43 (m, 1H), 2.04 (s, 2H), 1.90 (s, 2H), 1.78 (s, 2H), 1.63 (s, 2H). LC-MS, m / z 564 [M+H] + <Example 30> 30.1 3-Fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzonitrile

[0328]

Chemical Structure

[0329] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (62 mg, 88%).

[0330] LC-MS, m / z 265 [M+H] + 30.2 (3-Fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)phenyl)methanamine

[0331] [ka]

[0332] The target compound (66 mg, crude) was obtained 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) in the same manner as in Example 7.2, and then subjected to the next reaction without further purification.

[0333] LC-MS, m / z 269 [M+H] + 30.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0334] [ka]

[0335] The target compound (7 mg, 6%) was obtained in the same manner as in Example 1.3 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 (50 wt% solution in EtOAc, 1.8 mL, 0.74 mmol), DIPEA (110 μL, 0.62 mmol), and DMF (2 mL).

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.79 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 8.51 (d, J = 4.3 Hz, 1H), 8.35 (s, 1H), 8.05 - 7.95 (m, 2H), 7.70 (s, 1H), 7.59 (d, J = 10.3 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.08 (d, J = 9.5 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 3.52 - 3.46 (m, 1H), 2.07 (m, 2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H). LC-MS, m / z 483 [M+H] + Example 31 31.1 tert-Butyl (3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0337] [ka]

[0338] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (291 mg, 77%).

[0339] LC-MS, m / z 369 [M+H] + 31.2 (3-Fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0340] [ka]

[0341] The target compound (300 mg) was obtained using 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) in the same manner as in Example 25.4, and then subjected to the next reaction without further purification.

[0342] LC-MS, m / z 269 [M+H] + 31.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0343] [ka]

[0344] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (210 mg, 56%).

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.80 (s, 1H), 9.20 - 9.13 (m, 2H), 8.98 (s, 1H), 8.56 (d, J = 4.5 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.50 (d, J = 10.3 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 4.62 (d, J = 5.9 Hz, 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). LC-MS, m / z 483 [M+H] + Example 32 32.1 tert-Butyl (3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0346] [ka]

[0347] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (59 mg, 92%).

[0348] LC-MS, m / z 370 [M+H] + 32.2 (3-Fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0349] [ka]

[0350] The target compound (61 mg, crude) was obtained using 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) in the same manner as in Example 25.4, and then subjected to the next reaction without further purification.

[0351] LC-MS, m / z 270 [M+H] + 32.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(pyrimidin-5-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0352] [ka]

[0353] The same procedure as in Example 1.3 was repeated 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 (50 wt% solution in EtOAc, 280 μL, 0.47 mmol), DIPEA (120 μL, 0.70 mmol), and DMF (2 mL) to obtain the target compound (44 mg, 59%).

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.77 (t, J = 6.1 Hz, 1H), 9.32 (s, 2H), 9.16 (d, J = 16.5 Hz, 2H), 8.96 (s, 1H), 8.39 (s, 1H), 7.57 (s, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 6.1 Hz, 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 = 4.8 Hz, 2H). LC-MS, m / z 484 [M+H] + Example 33 33.1 3-Fluoro-5-((2-methoxyphenyl)amino)benzonitrile

[0355] [ka]

[0356] The target compound (80 mg, 30%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0357] LC-MS, m / z 243 [M+H] + 33.2 3-(Aminomethyl)-5-fluoro-N-(2-methoxyphenyl)aniline

[0358] [ka]

[0359] The target compound (55 mg, 68%) was obtained in the form of an oil using 3-fluoro-5-((2-methoxyphenyl)amino)benzonitrile (80 mg, 0.33 mmol) and LAH solution (2.0 M in THF, 0.33 mL) in the same manner as in Example 1.2.

[0360] LC-MS, m / z 247 [M+H] + 33.3 8-Cyclopentyl-N-(3-fluoro-5-((2-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0361] [ka]

[0362] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (40 mg, 72%) as a white solid.

[0363] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.22 (d, J = 8 Hz, 1H), 6.94 - 6.86 (m, 3H), 6.75 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 12 Hz, 1H), 6.56 (d, J = 12 Hz, 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). LC-MS, m / z 461 [M+H] + Example 34 34.1 3-Fluoro-5-((3-methoxyphenyl)amino)benzonitrile

[0364] [ka]

[0365] The target compound (110 mg, 45%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0366] LC-MS, m / z 243 [M+H] + 34.2 3-(Aminomethyl)-5-fluoro-N-(3-methoxyphenyl)aniline

[0367] [ka]

[0368] The target compound (70 mg, 63%) was obtained in the form of an oil using 3-fluoro-5-((3-methoxyphenyl)amino)benzonitrile (110 mg, 0.45 mmol) and LAH solution (2.0 M in THF, 0.45 mL) in the same manner as in Example 1.2.

[0369] LC-MS, m / z 247 [M+H] + 34.3 8-Cyclopentyl-N-(3-fluoro-5-((3-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0370] [ka]

[0371] The same procedure as in Example 1.3 was repeated 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, 59 mmol), and DIPEA (80 μL, 0.92 mmol) to obtain the target compound (50 mg, 60%) as a white solid.

[0372] 1H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.06 (t, J = 8 Hz, 1H), 6.91 (s, 1H), 6.65 - 6.61 (m, 3H), 6.57 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 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). LC-MS, m / z 461 [M+H] + Example 35 35.1 3-Fluoro-5-((4-methoxyphenyl)amino)benzonitrile

[0373] [ka]

[0374] The target compound (130 mg, 53%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0375] LC-MS, m / z 243 [M+H] + 35.2 3-(Aminomethyl)-5-fluoro-N-(4-methoxyphenyl)aniline

[0376] [ka]

[0377] The target compound (55 mg, 54%) was obtained in the form of an oil using 3-fluoro-5-((4-methoxyphenyl)amino)benzonitrile (100 mg, 0.41 mmol) and LAH solution (2.0 M in THF, 0.41 mL) in the same manner as in Example 1.2.

[0378] LC-MS, m / z 247 [M+H] + 35.3 8-Cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7H-purine-6-carboxamide

[0379] [ka]

[0380] The target compound (45 mg, 67%) was obtained as a white solid in the same manner 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).

[0381] 1 H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 7.03 (d, J = 8 Hz, 2H), 6.78 (d, J = 12 Hz, 2H), 6.70 (s, 1H), 6.46 (d, J = 12 Hz, 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). LC-MS, m / z 461 [M+H] + Example 36 8-Cyclopentyl-N-(3-fluoro-5-((4-methoxyphenyl)amino)benzyl)-7-methyl-7H-purine-6-carboxamide

[0382] [ka]

[0383] 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), and then CHCl (2.7 μL, 0.043 mmol) and KCO (30 mg, 0.22 mmol) were added and reacted 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. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (0-5% MeOH in CHCl) to give the target compound (16 mg, 78%) as a white solid.

[0384] 1 H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 7.03 (d, J = 8 Hz, 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). LC-MS, m / z 475 [M+H] + Example 37 N-(3-(1-(3-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0385] [ka]

[0386] 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), followed by KCO (22 mg, 0.16 mmol) and HO (35% aqueous solution, 105 μL) and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with HO and extracted three times with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to give the desired compound (33 mg, 81%).

[0387] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (1H, Broad), 9.78 (t, J = 6.4 Hz, 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 = 8.4 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.63-7.50 (m, 4H), 7.07 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 6.4 Hz, 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). LC-MS, m / z 525 [M+H] + Example 38 38.1 tert-Butyl 3-fluoro-5-(isothiazol-4-yl)benzylcarbamate

[0388] [ka]

[0389] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (12 mg, 0.016 mmol), 2 M aq. KCO (0.085 mL), and 1,4-dioxane (1.5 mL) to obtain the target compound (63 mg, 63%) as a white solid.

[0390] LC-MS, m / z 309 [M+H] + 38.2 (3-Fluoro-5-(isothiazol-4-yl)phenyl)methanamine, trifluoroacetate

[0391] [ka]

[0392] The same procedure as in Example 25.4 was repeated using tert-butyl 3-fluoro-5-(isothiazol-4-yl)benzylcarbamate (61 mg, 0.20 mmol), trifluoroacetic acid (0.7 mL) and DCM (2 mL) to obtain the target compound (94 mg, crude).

[0393] 38.3 8-Cyclopentyl-N-(3-fluoro-5-(isothiazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0394] [ka]

[0395] The target compound (56 mg, 68% yield over two steps) was obtained as a white solid in the same manner 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).

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.80 (t, J = 6.4 Hz, 1H), 9.42 (s, 1H), 9.07 (s, 1H), 8.98 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 10 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 4.63 (d, J = 6 Hz, 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). LC-MS, m / z 423 [M+H] + Example 39 39.1 tert-Butyl 3-fluoro-5-(furan-2-yl)benzylcarbamate

[0397] [ka]

[0398] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (12 mg, 0.016 mmol), 2 M aq. KCO (0.085 mL), and 1,4-dioxane (1.5 mL) to obtain the target compound (53 mg, 55%) as a yellow liquid.

[0399] 39.2 (3-Fluoro-5-(furan-2-yl)phenyl)methanamine, trifluoroacetate

[0400] [ka]

[0401] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (41 mg, crude).

[0402] 39.3 8-Cyclopentyl-N-(3-fluoro-5-(furan-2-yl)benzyl)-7H-purine-6-carboxamide

[0403] [ka]

[0404] The target compound (56 mg, 80% yield for two steps) was obtained as a white solid in the same manner 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).

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.82 (m, 1H), 8.97 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 3.2 Hz, 1H), 6.62-6.61 (m, 1H), 4.59 (d, J = 6.4 Hz, 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). LC-MS, m / z 406 [M+H] + <Example 40> 40.1 tert-Butyl (3-fluoro-5-(thiophen-3-yl)benzyl)carbamate

[0406] [ka]

[0407] The target compound (60 mg, 59%) was obtained as a pale yellow liquid in the same manner 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), PdCl(dppf) (12 mg, 0.016 mmol), 2 M aq. KCO (0.085 mL), and 1,4-dioxane (1.5 mL).

[0408] 40.2 (3-Fluoro-5-(thiophen-3-yl)phenyl)methanamine, trifluoroacetate

[0409] [ka]

[0410] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (63 mg, crude).

[0411] 40.3 8-Cyclopentyl-N-(3-fluoro-5-(thiophen-3-yl)benzyl)-7H-purine-6-carboxamide

[0412] [ka]

[0413] The target compound (54 mg, 65% yield over two steps) was obtained as a white solid in the same manner 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).

[0414] 1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.80 (t, J = 6.8 Hz, 1H), 8.97 (s, 1H), 7.94 (m, 1H), 7.66 (m, 1H), 7.60 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.47 (d, J = 11.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 6 Hz, 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). LC-MS, m / z 422 [M+H] + <Example 41> 41.1 3-Fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzonitrile

[0415] [ka]

[0416] The target compound (210 mg, 75%) was obtained as a white solid in the same manner 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), Pd(dba) (15 mg, 0.016 mmol), KCO (318 mg, 2.3 mmol), and dioxane (5 mL).

[0417] LC-MS, m / z 281 [M+H] + 41.2 3-(aminomethyl)-5-fluoro-N-(4-(trifluoromethyl)phenyl)aniline

[0418] [ka]

[0419] The target compound (70 mg, 35%) was obtained in the form of an oil 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) in the same manner as in Example 1.2.

[0420] LC-MS, m / z 285 [M+H] + 41.3 8-Cyclopentyl-N-(3-fluoro-5-((4-(trifluoromethyl)phenyl)amino)benzyl)-7H-purine-6-carboxamide

[0421] [ka]

[0422] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (6 mg, 9%) as a viscous oil.

[0423] 1 H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 7.41 (d, J = 8 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 6.99 (s, 1H), 6.76 (d, J = 8 Hz, 1H), 6.70 (d, J =12 Hz, 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). LC-MS, m / z 499 [M+H] + <Example 42> 42.1 tert-Butyl (3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0424] [ka]

[0425] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (45 mg, 68%).

[0426] LC-MS, m / z 383 [M+H] + 42.2 (3-Fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0427] [ka]

[0428] The same method as in Example 25.4 was used to obtain the target compound (47 mg, crude) using 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), and then the next reaction was carried out without separation or purification.

[0429] LC-MS, m / z 283 [M+H] + 42.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0430] [ka]

[0431] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (44 mg, 59%).

[0432] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.79 (s, 1H), 9.25 (s, 1H), 8.98 (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.37 (s, 1H), 7.79 (s, 1H), 7.70 (d, J = 5.3 Hz, 1H), 7.63 (s, 1H), 7.51 (d, J = 9.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 3.56 - 3.45 (m, 1H), 2.55 (s, 3H), 2.07 (s, 2H), 1.98 - 1.89 (m, 2H), 1.81 (s, 2H), 1.66 (s, 2H). LC-MS, m / z 497 [M+H] + <Example 43> 43.1 tert-Butyl (3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0433] [ka]

[0434] The same procedure as in Example 25.3 was repeated 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), KCO (36 mg, 0.26 mmol), and DMSO (3 mL) to obtain the target compound (61 mg, 89%).

[0435] LC-MS, m / z 399 [M+H] + 43.2 (3-Fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0436] [ka]

[0437] The same method as in Example 25.4 was used to obtain the target compound (4 mg, crude) using 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), and then the next reaction was carried out without separation or purification.

[0438] LC-MS, m / z 299 [M+H] + 43.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-methoxypyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0439] [ka]

[0440] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (42 mg, 54%).

[0441] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.76 (s, 1H), 8.95 (d, J = 3.5 Hz, 2H), 8.64 (d, J = 2.6 Hz, 1H), 8.23 ​​(s, 1H), 8.16 (dd, J = 8.9, 2.7 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J = 10.1 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.52 - 3.42 (m, 1H), 2.05 (d, J = 7.8 Hz, 2H), 1.90 (dt, J = 18.8, 7.0 Hz, 2H), 1.78 (s, 2H), 1.68 - 1.58 (m, 2H). LC-MS, m / z 513 [M+H] + <Example 44> 44.1 tert-Butyl (3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0442] [ka]

[0443] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (57 mg, 76%).

[0444] LC-MS, m / z 437 [M+H] + 44.2 (3-Fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0445] [ka]

[0446] To a solution of tert-butyl 3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (57 mg, 0.13 mmol) in DCM (2 mL), HCl (35-37%, 670 μL) was added dropwise at room temperature, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with MeOH and evaporated three times to obtain the target compound (49 mg, crude), which was then used in the next reaction without further purification.

[0447] LC-MS, m / z 337 [M+H] + 44.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0448] [ka]

[0449] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (60 mg, 83%).

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.77 (t, J = 6.0 Hz, 1H), 9.31 (s, 1H), 9.27 (s, 1H), 8.95 (s, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 9.8 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 3.52 - 3.43 (m, 1H), 2.05 (d, J = 7.8 Hz, 2H), 1.90 (dd, J = 12.2, 7.4 Hz, 2H), 1.78 (s, 2H), 1.68 - 1.58 (m, 2H). LC-MS, m / z 551 [M+H] + Example 45 45.1 tert-Butyl (3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0451] [ka]

[0452] The same procedure as in Example 25.3 was repeated 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 target compound (104 mg, 68%) as an off-white solid.

[0453] LC-MS, m / z 446 [M+H] + 45.2 (3-Fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0454] [ka]

[0455] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (350 mg, crude).

[0456] LC-MS, m / z 346 [M+H] + 45.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0457] [ka]

[0458] The same procedure as in Example 27.3 was repeated 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 wt% solution in EtOAc, 223 mg, 0.70 mmol), DIPEA (180 μL, 1.05 mmol), and DMF (2 mL) to obtain the target compound (66 mg, 50% yield over two steps) as an off-white foam.

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.79 (t, J = 6.4 Hz, 1H), 9.27 (s, 1H), 8.98 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.85 (m, 2H), 7.63 (s, 1H), 7.53 (d, J = 10 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 4.62 (d, J = 6.0 Hz, 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). LC-MS, m / z 560 [M+H] + <Example 46> 46.1 tert-Butyl (3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamate

[0460] [ka]

[0461] The same procedure as in Example 25.3 was repeated 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 target compound (100 mg, 75%) as an off-white solid.

[0462] LC-MS, m / z 386 [M+H] + 46.2 (3-Fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0463] [ka]

[0464] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (100 mg, crude).

[0465] LC-MS, m / z 286 [M+H] + 46.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0466] [ka]

[0467] The same procedure as in Example 27.3 was repeated 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 target compound (72 mg, two-step yield 51.6%) as an off-white solid.

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.78 (m, 1H), 9.13 (s, 1H), 8.98 (s, 1H), 8.29 (s, 1H), 7.76 (d, J = 9.2 Hz, 2H), 7.64 - 7.53 (m, 2H), 7.48 (d, J = 10.0 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 6 Hz, 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). LC-MS, m / z 500 [M+H] + Example 47 47.1 tert-Butyl (3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0469] [ka]

[0470] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (32 mg, 48%).

[0471] LC-MS, m / z 387 [M+H] + 47.2 (3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0472] [ka]

[0473] The same procedure as in Example 44.2 was repeated using tert-butyl 3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (32 mg, 0.083 mmol), HCl (35-37%, 330 μL), and DCM (1 mL) to obtain the target compound (28 mg, crude).

[0474] LC-MS, m / z 287 [M+H] + 47.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0475] [ka]

[0476] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (18 mg, 43%).

[0477] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (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 = 9.9 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 3.48 (d, J = 8.2 Hz, 1H), 2.07 (s, 2H), 1.93 (d, J = 5.9 Hz, 2H), 1.80 (s, 2H), 1.66 (s, 2H). LC-MS, m / z 501 [M+H] + <Example 48> 48.1 tert-Butyl (3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)carbamate

[0478] [ka]

[0479] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (32 mg, 48%).

[0480] LC-MS, m / z 495 [M+H] + 48.2 (3-Fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0481] [ka]

[0482] The same procedure as in Example 44.2 was repeated using tert-butyl 3-fluoro-5-(1-(6-iodopyridin-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.041 mmol), HCl (35-37%, 333 μL), and DCM (1 mL) to obtain the target compound (17 mg, crude).

[0483] 48.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(5-iodopyridin-2-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0484] [ka]

[0485] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (9 mg, 37%).

[0486] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.77 (s, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.73 (s, 1H), 8.36 (d, J = 10.8 Hz, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 3.49 (s, 1H), 2.06 (s, 2H), 1.93 (s, 2H), 1.80 (s, 2H), 1.66 (s, 2H). LC-MS, m / z 609 [M+H] + Example 49 3-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid

[0487] [ka]

[0488] 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 reacted at 85 °C for 7 hours. After completion of the reaction, the mixture was diluted with HO, acidified with 1 M HCl (pH 4-5), 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 (0-20% MeOH in DCM) to give the desired compound (12.8 mg, 41%).

[0489] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (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 = 8.4 Hz, 1H), 7.90 (d, J = 8 Hz, 1H), 7.71 - 7.44 (m, 3H), 7.07 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 6.4 Hz, 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). LC-MS, m / z 526 [M+H] + Example 50 50.1 tert-Butyl (3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)carbamate

[0490] [ka]

[0491] The same procedure as in Example 25.3 was repeated using tert-butyl (3-fluoro-5-(1H-pyrazol-4-yl)benzyl)carbamate (150 mg, 0.51 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 target compound (152 mg, 75%) as an off-white solid.

[0492] LC-MS, m / z 393 [M+H] + 50.2 4-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzonitrile, trifluoroacetate

[0493] [ka]

[0494] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (154 mg, crude).

[0495] LC-MS, m / z 293 [M+H] + 50.3 N-(3-(1-(4-cyanophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0496] [ka]

[0497] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (120 mg, 62.5% yield over two steps) as an off-white solid.

[0498] 1 H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.79 (m, 1H), 9.25 (s, 1H), 8.98 (s, 1H), 8.38 (s, 1H), 8.06 (dd, J = 23.6, 8.8 Hz, 4H), 7.61 (s, 1H), 7.51 (d, J = 10.0 Hz, 1H), 7.11 (d, J = 10 Hz, 1H), 4.62 (d, J = 6 Hz, 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). LC-MS, m / z 507 [M+H] + <Example 51> 51.1 tert-Butyl (3-fluoro-5-(1H-pyrazol-3-yl)benzyl)carbamate

[0499] [ka]

[0500] The same procedure as in Example 4.1 was repeated 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 aqueous K2CO3 solution (0.6 mL, 1.2 mmol), PdCl2(dppf) (12 mg, 0.017 mmol), and 1,4-dioxane (1.2 mL) to obtain the target compound (95 mg, 99%).

[0501] 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.51 - 7.45 (m, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.74 (s, 1H), 4.17 (d, J = 6.0 Hz, 2H), 1.41 (s, 9H). 51.2 tert-Butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)carbamate

[0502] [ka]

[0503] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (73 mg, 62%).

[0504] LC-MS, m / z 386 [M+H] + 51.3 (3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)phenyl)methanamine, hydrochloride

[0505] [ka]

[0506] The same procedure as in Example 44.2 was repeated using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzylcarbamate (73 mg, 0.19 mmol), HCl (35-37%, 700 μL), and DCM (2 mL) to obtain the target compound (61 mg, crude).

[0507] 51.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)benzyl)-7H-purine-6-carboxamide

[0508] [ka]

[0509] The same procedure as in Example 1.3 was carried out 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) to obtain the target compound (75 mg, 80%).

[0510] 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.85 (s, 1H), 8.97 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 9.0, 4.6 Hz, 2H), 7.83 (s, 1H), 7.62 (d, J = 10.4 Hz, 1H), 7.38 (t, J = 8.7 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.63 (d, J = 6.2 Hz, 2H), 3.48 (s, 1H), 2.06 (s, 2H), 1.93 (s, 2H), 1.80 (s, 2H), 1.65 (s, 2H). LC-MS, m / z 500 [M+H] + <Example 52> 52.1 tert-Butyl (3-fluoro-5-(1H-pyrrol-3-yl)benzyl)carbamate

[0511] [ka]

[0512] The same procedure as in Example 4.1 was repeated 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 aqueous K2CO3 solution (0.6 mL, 1.2 mmol), PdCl2(dppf) (12 mg, 0.017 mmol), and 1,4-dioxane (1.2 mL) to obtain the target compound (95 mg, 99%).

[0513] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.44 (s, 1H), 7.27 - 7.14 (m, 3H), 6.82 - 6.71 (m, J = 32.7 Hz, 2H), 6.43 (s, 1H), 4.12 (s, 2H), 1.40 (s, 9H). 52.2 tert-Butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)carbamate

[0514] [ka]

[0515] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (40 mg, 32%).

[0516] LC-MS, m / z 385 [M+H] + 52.3 (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)phenyl)methanamine, hydrochloride

[0517] [ka]

[0518] The same procedure as in Example 44.2 was repeated using tert-butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzylcarbamate (40 mg, 0.10 mmol), HCl (35-37%, 300 μL), and DCM (1 mL) to obtain the target compound (33 mg, crude).

[0519] 52.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrrol-3-yl)benzyl)-7H-purine-6-carboxamide

[0520] [ka]

[0521] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (42 mg, 81%).

[0522] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.77 (s, 1H), 8.97 (s, 1H), 7.94 (s, 1H), 7.69 (dd, J = 8.8, 4.7 Hz, 2H), 7.51 (s, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.9 Hz, 3H), 6.98 (d, J = 9.0 Hz, 1H), 6.72 (s, 1H), 4.58 (d, J = 6.2 Hz, 2H), 3.49 (s, 1H), 2.07 (s, 2H), 1.94 (d, J = 7.3 Hz, 2H), 1.80 (s, 2H), 1.66 (s, 2H). LC-MS, m / z 499 [M+H] + <Example 53> N-(3-(1-(4-carbamoylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0523] [ka]

[0524] 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) were added and reacted at 85 °C for 2 hours. After completion of the reaction, the mixture was diluted with HO, extracted twice with EtOAc, acidified with 1 M HCl (pH 4-5), and extracted three more times with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-20% MeOH in DCM) to give the desired compound (4.04 mg, 13%).

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (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 = 9.7 Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 10.3 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 3.50 (m, 1H), 2.13 - 2.03 (m, 2H), 1.98 - 1.88 (m, 2H), 1.86 - 1.76 (m, 2H), 1.71 - 1.59 (m, 2H). LC-MS, m / z 525 [M+H] + <Example 54> 4-(4-(3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)-1H-pyrazol-1-yl)benzoic acid

[0526] [ka]

[0527] The same procedure as in Example 53 was repeated 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 target compound (1.91 mg, 6%).

[0528] 1 H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.78 (s, 1H), 8.13 (m, 3H), 7.90 (d, J = 8 Hz, 2H), 7.57 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 10.4 Hz, 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). LC-MS, m / z 526 [M+H] + Example 55 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7-methyl-7H-purine-6-carboxamide

[0529] [ka]

[0530] 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide (40 mg, 0.08 mmol), K2CO3 (13.3 mg, 0.096 mmol), and DMF (0.8 mL) were added and stirred at room temperature for 20 minutes. Then, MeI (13.6 mg, 0.096 mmol) was added dropwise and the mixture was allowed to react at room temperature overnight. After the reaction was complete, the mixture was diluted with H2O and extracted three times with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (16.7 mg, yield 40.6%).

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (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 = 10.0 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.16 (d, J = 9.6 Hz, 1H), 4.64 (d, J = 5.6 Hz, 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). LC-MS, m / z 514 [M+H] + Example 56 56.1 tert-Butyl 5-bromo-2-fluorobenzylcarbamate

[0532] [ka]

[0533] The same procedure as in Example 6.1 was repeated using (5-bromo-2-fluorophenyl)methanamine (200 mg, 0.98 mmol), BocO (430 mg, 2.0 mmol), and DCM (5 mL) to obtain the target compound (273 mg, 92%) as a colorless oil.

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.36 (m, 3H), 7.15 (t, 1H), 4.13 (d, J = 6.0 Hz, 2H), 1.33 (s, 9H). 56.2 tert-Butyl 2-fluoro-5-(1H-pyrazol-4-yl)benzylcarbamate

[0535] [ka]

[0536] The same procedure as in Example 4.1 was repeated 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) to obtain the target compound (190 mg, 66%).

[0537] LC-MS, m / z 292 [M+H] + 56.3 tert-Butyl 2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0538] [ka]

[0539] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (120 mg, 50%).

[0540] LC-MS, m / z 386 [M+H] + 56.4 (2-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0541] [ka]

[0542] The same procedure as in Example 44.2 was repeated using tert-butyl 2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.052 mmol), HCl (35-37%, 0.25 mL), and DCM (0.50 mL) to obtain the target compound (17 mg, crude).

[0543] 56.5 8-Cyclopentyl-N-(2-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0544] [ka]

[0545] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (22 mg, 85%).

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.64 (t, J = 5.7 Hz, 1H), 8.96 (s, 1H), 8.89 (s, 1H), 8.12 (s, 1H), 7.94 - 7.83 (m, J = 9.0, 4.7 Hz, 2H), 7.77 (d, J = 7.0 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.36 (t, J = 8.8 Hz, 2H), 7.30 - 7.22 (m, 1H), 4.66 (d, J = 6.0 Hz, 2H), 3.54 - 3.44 (m, 1H), 2.07 (mz, J = 7.6 Hz, 2H), 1.97 - 1.87 (m, J = 12.6, 6.6 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.70 - 1.60 (m, 2H). LC-MS, m / z 500 [M+H] + Example 57 57.1 tert-Butyl 3-bromobenzylcarbamate

[0547] [ka]

[0548] The same procedure as in Example 6.1 was repeated using (3-bromophenyl)methanamine (200 mg, 1.1 mmol), BocO (470 mg, 2.2 mmol) and DCM (5 mL) to obtain the target compound (300 mg, 96%) as a colorless oil.

[0549] 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.36 (m, 3H), 7.30 - 7.20 (m, 2H), 4.09 (d, J = 6.1 Hz, 2H), 1.37 (s, 9H). 57.2 tert-Butyl 3-(1H-pyrazol-4-yl)benzylcarbamate

[0550] [ka]

[0551] The same procedure as in Example 4.1 was repeated 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 aqueous K2CO3 solution (1.8 mL, 3.7 mmol), PdCl2(dppf) (39 mg, 0.053 mmol), and 1,4-dioxane (3.6 mL) to obtain the target compound (57 mg, 20%).

[0552] LC-MS, m / z 274 [M+H] + 57.3 tert-Butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0553] [ka]

[0554] The same procedure as in Example 25.3 was repeated 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), KCO (45 mg, 0.32 mmol), and DMSO (2 mL) to obtain the target compound (54 mg, 68%).

[0555] LC-MS, m / z 386 [M+H] + 57.4 (3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, hydrochloride

[0556] [ka]

[0557] The same procedure as in Example 44.2 was repeated using tert-butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (20 mg, 0.054 mmol), HCl (35-37%, 0.25 mL), and DCM (0.50 mL) to obtain the target compound (17 mg, crude).

[0558] 57.5 8-Cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0559] [ka]

[0560] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (24 mg, 92%).

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.72 (t, J = 5.8 Hz, 1H), 8.96 (s, 2H), 8.18 (s, 1H), 7.97 - 7.88 (m, 2H), 7.73 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.27 (d, J = 7.8 Hz, 1H), 4.61 (d, J = 6.1 Hz, 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). LC-MS, m / z 482 [M+H] + <Example 58> 58.1 tert-Butyl 3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[0562] [ka]

[0563] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (54 mg, 78%) as an off-white solid.

[0564] LC-MS, m / z 402 [M+H] + 58.2 (3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine

[0565] [ka]

[0566] tert-Butyl 3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate (54 mg, 0.13 mmol) was dissolved in DCM (1.4 mL), and trifluoroacetic acid (0.47 mL) was added. The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, adjusted to pH 10-11 with 1 M aqueous NaOH, and extracted five times with DCM. The organic layer was dried over MgSO4 and concentrated to obtain the target compound (20 mg, crude).

[0567] LC-MS, m / z 302 [M+H] + 58.3 N-(3-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0568] [ka]

[0569] The target compound (16 mg, 93.5% yield over two steps) was obtained as a white solid in the same manner as in Example 27.3 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).

[0570] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.79 (t, J = 5.9 Hz, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.67 - 7.55 (m, 3H), 7.48 (d, J = 9.6 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H), 4.61 (d, J = 6.1 Hz, 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). LC-MS, m / z 516 [M+H] + Example 59 59.1 tert-Butyl 3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[0571] [ka]

[0572] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (76.5 mg, 96%) as an off-white solid.

[0573] LC-MS, m / z 522 [M−H] - 59.2 (3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[0574] [ka]

[0575] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (71 mg, crude).

[0576] LC-MS, m / z 293 [M+H] + 59.3 N-(3-(1-(4-bromo-2-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0577] [ka]

[0578] The same procedure as in Example 27.3 was repeated using 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 target compound (33 mg, 39% yield for two steps) as an off-white solid.

[0579] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.78 (t, J = 6.0 Hz, 1H), 8.97 (s, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.5, 2.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 9.4 Hz, 1H), 7.07 (d, J = 9.1 Hz, 1H), 4.59 (d, J = 5.8 Hz, 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). LC-MS, m / z 638 [M+H] + Example 60 60.1 tert-Butyl 3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[0580] [ka]

[0581] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (19.1 mg, 41%) as an off-white solid.

[0582] LC-MS, m / z 404 [M+H] + 60.2 (3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[0583] [ka]

[0584] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (19 mg, crude).

[0585] LC-MS, m / z 304 [M+H] + 60.3 8-Cyclopentyl-N-(3-(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[0586] [ka]

[0587] 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), followed by addition of DIPEA (10 μL, 0.059 mmol) and reaction at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and HO. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-4% MeOH in DCM) to afford the target compound (4.59 mg, 22.5% yield for two steps) as an off-white solid.

[0588] 1 H NMR (400 MHz, CD3OD) δ8.95 (s, 1H), 8.64 (s, 1H), 8.07 (s, 1H), 7.81 - 7.73 (m, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.38 (dd, J = 18.7, 9.0 Hz, 1H), 7.29 (d, J = 9.5 Hz, 1H), 7.04 (d, J = 9.1 Hz, 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). LC-MS, m / z 518 [M+H] + <Example 61> 61.1 Ethyl 2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidine-4-carboxylate

[0589] [ka]

[0590] Ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.15 g, 4.3 mmol) was dissolved in THF (20 mL) and cooled to 0 °C under a nitrogen stream. NaHCO (1.09 g, 12.9 mmol) was added, and a solution of (2,4-dimethoxyphenyl)methanamine (0.83 g, 4.96 mmol) in THF (3 mL) was added dropwise over 15 minutes. The mixture was stirred at room temperature. After 1 hour, the mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel column chromatography (20% EtOAc in n-hexane) to give the desired compound (886 mg, 52%) as a yellow solid.

[0591] LC-MS, m / z 397 [M+H] + 61.2 Ethyl 5-amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate

[0592] [ka]

[0593] Ethyl 2-chloro-6-((2,4-dimethoxybenzyl)amino)-5-nitropyrimidine-4-carboxylate (481 mg, 1.21 mmol) was added to EtOH (17 mL), and SnCl (1.16 g, 6.1 mmol) was added and stirred at room temperature. After 3 hours, the reaction mixture was concentrated, and then HO was added at 0 °C and stirred. The resulting solid was filtered. The filtered solid was added to EtOH and stirred, then filtered and dried to obtain the target compound (390 mg, 88%) as a yellow solid.

[0594] LC-MS, m / z 367 [M+H] + 61.3 5-Amino-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid

[0595] [ka]

[0596] 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), and then 2.0 M NaOH (9.2 mL) was added and reacted at room temperature for 1 hour. After the reaction was complete, the mixture was acidified (to pH 2) with 3 M HCl at 0°C, and the resulting solid was filtered to obtain the target compound (850 mg, 79%) as a pale yellow solid.

[0597] LC-MS, m / z 339 [M+H] + 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

[0598] [ka]

[0599] 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 reacted at 50 °C. After 12 h, the reaction mixture was extracted with ethyl acetate and HO, and the organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (13 mg, 55%) as a white solid.

[0600] LC-MS, m / z 607 [M+H] + 61.5 5,6-Diamino-2-chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[0601] [ka]

[0602] 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) and TFA (2 mL) was added. The mixture was reacted at room temperature for 12 hours. After completion of the reaction, the solvent was removed, the mixture was neutralized with aqueous NaOH, extracted with EtOAc, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (85 mg, 93%) as a white solid.

[0603] LC-MS, m / z 456 [M+H] + 61.6 2-Chloro-8-cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0604] [ka]

[0605] 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), followed by DIPEA (66 μL, 0.39 mmol). The mixture was heated at 150 °C for 5 hours under microwave conditions. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and HO. The organic layer was dried over NaSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (30 mg, 51%) as a white solid.

[0606] 1 H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.08 (s, 1H), 7.81 - 7.77 (m, 2H), 7.52 (s, 1H), 7.33 (d, J = 12 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.05 (d, J = 8.0 Hz, 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). LC-MS, m / z 534 [M+H] + <Example 62> 62.1 Benzyl (S)-2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0607] [ka]

[0608] 6-Chloropyrimidine-4,5-diamine (484 mg, 3.35 mmol) and benzyl (S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate (900 mg, 3.36 mmol) were added to POCl3 (5 mL) and reacted at 110 °C. After 2 hours, the reaction mixture was concentrated and neutralized with aqueous NaHCO3. The aqueous layer was extracted twice with CHCl2, and the organic layer was dried over NaSO4 and concentrated. The resulting residue was recrystallized from toluene to give the desired compound (420 mg, 35%).

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.36 (m, 3H), 6.96 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 5.15 - 4.98 (m, 2H), 3.70 (m, 1H), 3.50 (m, 2H), 2.41 (m, 2H), 1.96 (m, 2H). LC-MS, m / z 358 [M+H] + 62.2 Benzyl (S)-2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0610] [ka]

[0611] The target compound (160 mg, 75%) was obtained in the same manner as in Preparation 1.1 using benzyl (S)-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).

[0612] LC-MS, m / z 349 [M+H] + 62.3 Methyl (S)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylate

[0613] [ka]

[0614] The target compound (100 mg, 46%) was obtained in the same manner 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).

[0615] LC-MS, m / z 403 [M+Na] + 62.4 (S)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid

[0616] [ka]

[0617] The target compound (85 mg, 89%) was obtained in the same manner as in Preparation 1.3 using methyl (S)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylate (100 mg, 0.26 mmol) and 2M NaOH (834 μL).

[0618] 1 H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.02 (s, 1H), 7.36 (m, 3H), 6.91 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 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). LC-MS, m / z 368 [M+H] + 62.5 Benzyl (S)-2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0619] [ka]

[0620] The same procedure as in Example 1.3 was carried out 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) to obtain the target compound (110 mg, 86%).

[0621] 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.81 (s, 1H), 9.00 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.37 (m, 3H), 7.02 (d, J = 9.6 Hz, 1H), 6.98 - 6.89 (m, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 5.30 - 5.20 (m, 1H), 5.05 (m, 2H), 4.59 (d, J = 5.5 Hz, 2H), 3.86 (s, 3H), 3.70 (m, 2H), 2.45 - 2.26 (m, 2H), 2.04 - 1.80 (m, 2H). LC-MS m / z 368 [M+H] + 62.6 (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[0622] [ka]

[0623] Benzyl (S)-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), and then HCl (35-37%, 1.82 mL) was added and stirred at 80 °C. After 1 h, the reaction mixture was cooled to room temperature and concentrated, and then EtOAc was added and stirred. The solid was filtered and dried to obtain the desired compound (60 mg, 73%).

[0624] 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (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 = 10.0 Hz, 1H), 7.00 (d, J = 9.7 Hz, 1H), 5.09 (m, 1H), 4.59 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.74 - 3.68 (m, 2H), 3.50 - 3.46 (m, 2H), 2.20 - 2.06 (m, 2H). LC-MS m / z 421 [M+H] + Example 63 (S)—N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[0625] [ka]

[0626] (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 NaBH (9 mg) were refluxed in trifluoroethanol (3 mL). After 1 h, the resulting solid was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (15 mg, 31%).

[0627] 1 H NMR (400 MHz, 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 = 10.3 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 4.57 (d, J = 6.3 Hz, 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). LC-MS, m / z 435 [M+H] + <Example 64> 64.1 Benzyl (R)-2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0628] [ka]

[0629] The same procedure as in Example 62.1 was repeated using 6-chloropyrimidine-4,5-diamine (1.16 g, 8.0 mmol) and benzyl (R)-2-(chlorocarbonyl)pyrrolidine-1-carboxylate (2.14 g, 8.0 mmol) to obtain the target compound (960 mg, 34%).

[0630] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.36 (m, 3H), 7.09 (m, 1H), 6.85 (s, 1H), 5.07 (d, J = 10.3 Hz, 2H), 4.81 (m, 1H), 3.70 (m, 2H), 2.41 (m, 2H), 1.98 (m, 2H). LC-MS, m / z 358 [M+H] + 64.2 Benzyl (R)-2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0631] [ka]

[0632] The target compound (200 mg, 82%) was obtained using benzyl (R)-2-(6-chloro-7H-purin-8-yl)pyrrolidine-1-carboxylate (250 mg, 0.70 mmol) in the same manner as in Preparation Example 1.1.

[0633] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (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). LC-MS, m / z 349 [M+H] + 64.3 Methyl (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylate

[0634] [ka]

[0635] The target compound (200 mg, 61%) was obtained using benzyl (R)-2-(6-cyano-7H-purin-8-yl)pyrrolidine-1-carboxylate (300 mg, 0.86 mmol) in the same manner as in Preparation Example 1.2.

[0636] 1 H NMR (400 MHz, CD3OD) δ 9.02(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). LC-MS, m / z 382 [M+H] + 64.4 (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylic acid

[0637] [ka]

[0638] The target compound (140 mg, 72%) was obtained using methyl (R)-8-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-7H-purine-6-carboxylate (200 mg, 0.53 mmol) in the same manner as in Preparation 1.3.

[0639] 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 9.02 (s, 1H), 7.36 (m, 3H), 6.91 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.5 Hz, 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). LC-MS, m / z 368 [M+H] + 64.5 Benzyl (R)-2-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0640] [ka]

[0641] The same method as in Example 1.3 was used with (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 (198 μg, 1.17 mmol) to obtain the target compound (170 mg, 81%).

[0642] 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 9.81 (s, 1H), 9.01 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.43 (d, J = 10.7 Hz, 1H), 7.36 (m, 3H), 7.00 (d, J = 9.6 Hz, 1H), 6.92 (m,, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.25 (m, 1H), 5.04 (m, 2H), 4.58 (d, J = 12.7 Hz, 2H), 3.85 (s, 3H), 3.69 (m, 2H), 2.37 (m, 2H), 2.09 (m, 2H). LC-MS, m / z 555 [M+H] + Example 65 (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[0643] [ka]

[0644] The same procedure as in Example 62.6 was repeated 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 (35-37%, 2.9 mL) to obtain the target compound (100 mg, 75%).

[0645] 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (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 = 10.0 Hz, 1H), 7.00 (d, J = 9.7 Hz, 1H), 5.17 - 5.03 (m, 1H), 4.59 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.74 - 3.61 (m, 2H), 3.53 - 3.45 (m, 2H), 2.28 - 1.97 (m, 2H). LC-MS, m / z 421 [M+H] + <Example 66> (R)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[0646] [ka]

[0647] The same procedure as in Example 63 was repeated 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) to obtain the target compound (22 mg, 50%).

[0648] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.99 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 10.4 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 4.57 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.10 (m, 1H), 2.48 - 2.35 (m, 2H), 2.22 (s, 3H), 2.01 (m,2 H), 1.85 (. 2H). LC-MS, m / z 435 [M+H] + Example 67 (S)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-isopropylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[0649] [ka]

[0650] The same procedure as in Example 63 was repeated 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), NaBH (3.3 mg), and trifluoroethanol (1 mL) to obtain the target compound (11 mg, 48%).

[0651] 1 H NMR (400 MHz, CDCl3) δ 9.03 (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). LC-MS, m / z: 463 [M+H] + Example 68 68.1 Benzyl (R)-2-(6-((3-fluorobenzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0652] [ka]

[0653] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (155 mg, 93%).

[0654] 1 H NMR (400 MHz, CDCl3) δ 11.63 (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 = 12 Hz, 2H), 3.55 (m, 2H), 2.25 (m, 2H), 2.11 (m, 2H). LC-MS, m / z 475 [M+H] + 68.2 (R)-N-(3-Fluorobenzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride

[0655] [ka]

[0656] The same procedure as in Example 62.6 was repeated using benzyl (R)-2-(6-((3-fluorobenzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol) and HCl (35-37%, 1.85 mL) to obtain the target compound (70 mg, 88%).

[0657] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.91 (s, 1H), 9.43 (s, 1H), 9.11 (s, 1H), 7.39 (m, 1H), 7.21 (m, 2H), 7.08 (m, 1H), 5.09 (m, 1H), 4.58 (d, J = 4 Hz, 2H), 3.72 - 3.68 (m, 2H), 2.21 - 2.08 (m, 4H). LC-MS, m / z 341 [M+H] + 68.3 (R)-N-(3-Fluorobenzyl)-8-(1-methylpyrrolidin-2-yl)-7H-purine-6-carboxamide

[0658] [ka]

[0659] The same procedure as in Example 63 was repeated using (R)-N-(3-fluorobenzyl)-8-(pyrrolidin-2-yl)-7H-purine-6-carboxamide hydrochloride (70 mg, 0.19 mmol), paraformaldehyde (28 mg), NaBH (17 mg), and trifluoroethanol (3 mL) to obtain the target compound (6.7 mg, 10%).

[0660] LC-MS, m / z 355 [M+H] + Example 69 69.1 Benzyl 4-(6-chloro-7H-purin-8-yl)piperidine-1-carboxylate

[0661] [ka]

[0662] The same procedure as in Example 62.6 was repeated 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) to obtain the target compound (176 mg, 14%).

[0663] 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 7.35 (dd, J = 13.7, 7.0 Hz, 5H), 5.15 (s, 2H), 4.28 (d, J = 12.7 Hz, 2H), 3.06 (s, 3H), 2.10 (d, J = 12.0 Hz, 2H), 1.88 (d, J = 8.4 Hz, 2H). LC-MS, m / z 372 [M+H] + 69.2 Benzyl 4-(6-cyano-7H-purin-8-yl)piperidine-1-carboxylate

[0664] [ka]

[0665] The target compound (69 mg, 35%) was obtained in the same manner as in Preparation 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 sulfolane (3 mL).

[0666] 1 H NMR (400 MHz, DMSO-d6) δ 14.02 (s, 1H), 8.99 (s, 1H), 7.40 - 7.32 (m, 5H), 5.11 (s, 2H), 4.10 (d, J = 13.1 Hz, 2H), 3.07 (s, 3H), 2.08 (d, J = 10.2 Hz, 2H), 1.77 (d, J = 8.2 Hz, 2H). LC-MS, m / z 363 [M+H] + 69.3 Methyl 8-(1-((benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylate

[0667] [ka]

[0668] The target compound (104 mg, 50%) was obtained in the same manner as in Preparation 1.2 using benzyl 4-(6-cyano-7H-purin-8-yl)piperidine-1-carboxylate (190 mg, 0.52 mmol) and TMSCl (680 μL, 5.4 mmol).

[0669] 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.00 (s, 1H), 7.37 (t, J = 11.0 Hz, 5H), 5.12 (s, 2H), 4.13 (d, J = 12.7 Hz, 2H), 4.00 (s, 3H), 3.02 (s, 3H), 2.03 (d, J = 13.9 Hz, 2H), 1.82 (s, 2H). 69.4 8-(1-((benzyloxy)carbonyl)piperidin-4-yl)-7H-purine-6-carboxylic acid

[0670] [ka]

[0671] The target compound (95 mg, crude) was obtained 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) in the same manner as in Preparation 1.3.

[0672] LC-MS, m / z 382 [M+H] + 69.5 Benzyl 4-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)piperidine-1-carboxylate

[0673] [ka]

[0674] The same method as in Example 1.3 was used to obtain the target compound (50 mg, 42%) 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).

[0675] 1 H NMR (400 MHz, DMSO-d6) δ 13.24 (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 = 9.4 Hz, 1H), 5.11 (s, 2H), 4.57 (d, J = 6.2 Hz, 2H), 4.11 (d, J = 13.2 Hz, 2H), 3.85 (s, 3H), 3.00 (s, 3H), 1.99 (s, 2H), 1.81 (d, J = 8.9 Hz, 2H). LC-MS, m / z 569 [M+H] + Example 70 N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(piperidin-4-yl)-7H-purine-6-carboxamide hydrochloride

[0676] [ka]

[0677] 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), and then HCl (35-37%, 728 μL) was added and heated with stirring at 80 °C. After 1 h, the reaction mixture was concentrated, co-evaporated with toluene three times, and then dried in vacuo to obtain the target compound (32 mg, 99%).

[0678] 1 H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 7.42 (s, 1H), 7.20 (d, J = 10.2 Hz, 1H), 7.00 (d, J = 9.8 Hz, 1H), 4.69 (s, 2H), 3.92 (d, J = 10.2 Hz, 3H), 3.57 (d, J = 12.8 Hz, 2H), 3.48 (m, 1H), 3.25 - 3.18 (m, 2H), 2.35 (m, 2H), 2.21 (m, 2H). LC-MS, m / z 435 [M+H] + <Example 71> N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpiperidin-4-yl)-7H-purine-6-carboxamide

[0679] [ka]

[0680] The same procedure as in Example 63 was repeated 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), NaBH (6 mg, 0.15 mmol), and trifluoroethanol (2 mL) to obtain the target compound (8 mg, 23%).

[0681] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (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 = 10.4 Hz, 1H), 6.99 (d, J = 9.3 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.04 (s, 1H), 2.91 (d, J = 14.3 Hz, 2H), 2.24 (s, 3H), 2.09 - 1.88 (m, 6H). LC-MS, m / z 449 [M+H] + <Example 72> 72.1 Ethyl 5-amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate

[0682] [ka]

[0683] 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), and then ammonium formate (464 mg, 7.36 mmol) and 10% palladium on carbon (Pd / C; 100 mg) were added and stirred at 60 °C. After 30 minutes, the solids in the reaction mixture were removed by filtration, and the filtrate was concentrated to obtain the desired compound (163 mg, 67%).

[0684] LC-MS, m / z 333 [M+H] + 72.2 5-Amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid

[0685] [ka]

[0686] Ethyl 5-amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (130 mg, 0.39 mmol) was dissolved in THF / EtOH (1.6 mL / 3 mL), and then 2.0 M NaOH (1.02 mL) was added and stirred at room temperature. After 1 hour, the reaction mixture was cooled to 0°C, and the pH of the reaction mixture was adjusted to 5 using 3 M HCl. The resulting solid was filtered to obtain the desired compound (88 mg, 74%).

[0687] LC-MS, m / z 305 [M+H] + 72.3 5-Amino-6-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[0688] [ka]

[0689] To a solution of 5-amino-6-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid (80 mg, 0.26 mmol) and DMF (5 mL), (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 and the mixture was reacted at 50 °C. After stirring overnight, the reaction mixture was added with HO and extracted three times with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (46 mg, 36%).

[0690] LC-MS, m / z 492 [M+H] + 72.4 5,6-Diamino-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)pyrimidine-4-carboxamide

[0691] [ka]

[0692] 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 CHCl (5 mL), followed by addition of TFA (2 mL) and stirring at room temperature. After 12 hours, the reaction mixture was concentrated, neutralized with aqueous NaOH, and extracted with EtOAc. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (130 mg, 81%).

[0693] LC-MS, m / z 342 [M+H] + 72.5 Benzyl ((6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)methyl)carbamate

[0694] [ka]

[0695] 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 with ((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 reacted at 150 °C in a microwave reactor. After 1 h, the reaction mixture was concentrated, diluted with CHCl, and washed with H0. The organic layer was dried over MgSO and concentrated to give a residue, which was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (65 mg, 27%).

[0696] 1 H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 7.34 - 7.31 (m, 4H), 7.19 (d, J = 12 Hz, 1H), 6.98 (t, J = 8.0 Hz, 2H), 5.10 (s, 2H), 4.67 (s, 2H), 4.66(s, 2H), 3.88 (s, 3H). LC-MS, m / z 515 [M+H] + <Example 73> 8-(Aminomethyl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0697] [ka]

[0698] 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 (35-37%, 1.2 mL) was added. The mixture was heated and stirred at 80°C. After 1 hour, the reaction mixture was concentrated and recrystallized from toluene. The resulting solid was filtered. The solid was dried to obtain the target compound (45 mg, 90%).

[0699] 1 H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 8.23 ​​(s, 1H), 8.13 (s, 1H), 7.46 (s, 1H), 7.26 (d, J = 12 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 4.60 (s, 2H), 3.99 (s, 3H). LC-MS, m / z [M+H] + <Example 74> 74.1 Methyl 7H-purine-6-carboxylate

[0700] [ka]

[0701] The target compound (63 mg, 64%) was obtained using 7H-purine-6-carbonitrile (80 mg, 0.55 mmol) and TMSCl (760 μL) in the same manner as in Preparation Example 1.2.

[0702] LC-MS, m / z 247 [M+H] + 74.2 7H-purine-6-carboxylic acid

[0703] [ka]

[0704] The target compound (45 mg, 81%) was obtained using methyl 7H-purine-6-carboxylate (60 mg, 0.34 mmol) and 2M NaOH (850 μL) in the same manner as in Preparation Example 1.3.

[0705] LC-MS, m / z 165 [M+H] + 74.3 N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0706] [ka]

[0707] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (17 mg, 28%).

[0708] 1 H NMR (400 MHz, 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 = 12 Hz, 1H), 6.99 (d, J = 12 Hz, 1H), 4.57 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H). LC-MS, m / z 352 [M+H] + Example 75 Benzyl 3-(6-((3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)pyrrolidine-1-carboxylate

[0709] [ka]

[0710] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (45 mg, 54%).

[0711] 1 H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.35 - 7.31 (m, 5H), 7.20 (d, J = 12 Hz, 1H), 7.00 (d, J = 12 Hz, 1H), 5.13 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 3.89 (s, 3H), 3.71 (m, 1H), 3.56 (m, 4H), 2.44 (m, 2H). LC-MS m / z 555 [M+H] + <Example 76> N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrrolidin-3-yl)-7H-purine-6-carboxamide hydrochloride

[0712] [ka]

[0713] The same procedure as in Example 73 was repeated 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 (35-37%, 540 μL) to obtain the target compound (15 mg, 57%).

[0714] 1 H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.43 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 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). LC-MS, m / z 421 [M+H] + Example 77 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

[0715] [ka]

[0716] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (7 mg, 10%).

[0717] 1 H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.41 (s, 1H), 7.20 (d, J = 8 Hz, 1H), 7.00 (d, J = 12 Hz, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.63 (m, 1H), 2.24 (m, 4H), 2.06 (m, 2H). LC-MS, m / z 468 [M+H] + Example 78 8-(bicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0718] [ka]

[0719] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (3.3 mg, 5%).

[0720] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.40 (s, 1H), 7.19 (d, J = 8 Hz, 1H), 6.99 (d, J = 8 Hz, 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). LC-MS m / z 432 [M+H] + Example 79 N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(1-methylpyrrolidin-3-yl)-7H-purine-6-carboxamide

[0721] [ka]

[0722] The same procedure as in Example 63 was repeated 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), NaBH (3 mg, 0.075 mmol), and trifluoroethanol (1 mL) to obtain the target compound (7 mg, 45%).

[0723] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.42 (s, 1H), 7.21 (d, J = 12 Hz, 1H), 7.00 (d, J = 8.0 Hz, 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). LC-MS, m / z 435 [M+H] + <Example 80> 80.1 8-(3,3-Difluorocyclopentyl)-7H-purine-6-carboxylic acid

[0724] [ka]

[0725] The target compound (260 mg, 78%) was obtained as a white solid by the same method as in Preparation Example 1.

[0726] 1 H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 3.81 (m, 1H), 2.88 - 2.62 (m, 2H), 2.40 - 2.34 (m, 2H), 2.28 - 2.24 (m, 2H). LC-MS, m / z 269 [M+H] + 80.2 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0727] [ka]

[0728] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (115 mg, 57%).

[0729] 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.61 (s, 1H), 8.08 (s, 1H), 7.83 - 7.75 (m, 2H), 7.53 (s, 1H), 7.32 (d, J = 10 Hz, 1H), 7.24 (t, J = 8.4 Hz, 2H), 7.05 (d, J = 9.2 Hz, 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). LC-MS, m / z 536 [M+H] + <Example 81> 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0730] [ka]

[0731] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (18 mg, 43%).

[0732] 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 9.82 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H), 8.29 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.62 - 7.54 (m, J = 10.1 Hz, 2H), 7.49 (d, J = 9.9 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 9.1 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 3.80 (mzz, 1H), 2.69 - 2.58 (m, 2H), 2.37 - 2.27 (m, 2H), 2.23 - 2.09 (m, 2H). LC-MS, m / z 536 [M+H] + <Example 82> 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(6-fluoropyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0733] [ka]

[0734] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (11 mg, 54%).

[0735] 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 9.83 (s, 1H), 9.12 (s, 1H), 9.01 (s, 1H), 8.77 (s, 1H), 8.46 (t, J = 6.5 Hz, 1H), 8.33 (s, 1H), 7.59 (s, 1H), 7.48 (d, J = 10.0 Hz, 1H), 7.41 (dd, J = 8.9, 2.8 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 4.62 (d, J = 6.2 Hz, 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). LC-MS, m / z 537 [M+H] + <Example 83> 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0736] [ka]

[0737] The same procedure as in Example 1.3 was repeated 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) to obtain the target compound (31 mg, 75%).

[0738] 1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.80 (t, J = 5.7 Hz, 1H), 9.17 (s, 2H), 9.02 (s, 1H), 8.58 (s, 1H), 8.34 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.50 (d, J = 9.5 Hz, 1H), 7.10 (d, J = 9.5 Hz, 1H), 4.62 (d, J = 6.0 Hz, 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). LC-MS, m / z 519 [M+H] + <Example 84> 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide (E1,E2)

[0739] [ka]

[0740] 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 was separated by SFC (column: Daicel Chiralpak AD, 250 x 50 mm ID 10 μm, mobile phase: A is CO2, B is 2-propanol (0.1% NH3H2O), gradient: B% = 45% isocratic elution mode), and the fractions containing each isomer were concentrated and lyophilized to obtain the target compounds E1 (36 mg) and E2 (36 mg).

[0741] E1 (retention time: 2.04 min, column: Daicel Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, mobile phase: A is CO2, B is 2-propanol (0.1% isopropylamine, v / v), mobile phase: B% 5% to 50%, 2 min) 1 H NMR (400 MHz, DMSO-d6) δ 13.33 (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 = 10.1 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.07 (d, J = 9.5 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 3.88 - 3.74 (m, 1H), 2.73 - 2.55 (m, 2H), 2.41 - 2.26 (m, 2H), 2.25 - 2.07 (m, 2H). LC-MS, m / z 536 [M+H] + E2 (retention time: 2.29 min, column: Daicel Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm, mobile phase: A is CO2, B is 2-propanol (0.1% isopropylamine, v / v), mobile phase: B% 5% to 50%, 2 min) 1 H NMR (400 MHz, 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 = 10.2 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.07 (d, J = 9.3 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 3.87 - 3.71 (m, 1H), 2.73 - 2.55 (m, 2H), 2.40 - 2.25 (m, 2H), 2.24 - 2.07 (m, 2H). LC-MS, m / z 536 [M+H] + <Example 85> (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-2-yl)-7H-purine-6-carboxamide

[0742] [ka]

[0743] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (12 mg, 24%).

[0744] 1 H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.79 - 7.75 (m, 2H), 7.51 (s, 1H), 7.33 (d, J = 12 Hz, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 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). LC-MS, m / z 502 [M+H] + <Example 86> (R)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide

[0745] [ka]

[0746] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (2.02 mg, 5.5%).

[0747] 1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.81 - 7.78 (m, 2H), 7.53 (s, 1H), 7.32 (d, J = 9.8 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 7.05 (d, J = 8.9 Hz, 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). LCMS, m / z 514 [M+H] + <Example 87> 87.1 tert-Butyl 3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[0748] [ka]

[0749] The same procedure as in Example 25.3 was used to obtain the target compound (57 mg, 74%) in the form of an off-white solid 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).

[0750] LCMS, m / z 420 [M+H] + 87.2 (3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine, trifluoroacetate

[0751] [ka]

[0752] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (58 mg, crude).

[0753] LCMS, m / z 320 [M+H] + 87.3 N-(3-(1-(3-chloro-4-fluorophenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0754] [ka]

[0755] 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), followed by the addition of DIPEA (29 μL) and EDC (26 mg, 0.14 mmol). The mixture was allowed to react overnight at room temperature. The reaction mixture was extracted with ethyl acetate and HO, and the organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-2% MeOH in DCM) to give the target compound (34 mg, 56% yield for two steps) as an off-white solid.

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.77 (s, 1H), 9.12 (s, 1H), 8.97 (s, 1H), 8.29 (s, 1H), 8.13 (dd, J = 6.4, 2.4 Hz, 1H), 7.95 - 7.87 (m, 1H), 7.68 - 7.56 (m, 2H), 7.47 (d, J = 10.0 Hz, 1H), 7.09 (d, J = 9.3 Hz, 1H), 4.61 (d, J = 6.4 Hz, 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). LCMS, m / z 534 [M+H] + <Example 88> (S)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-oxocyclopentyl)-7H-purine-6-carboxamide

[0757] [ka]

[0758] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (30 mg, 49%).

[0759] 1 H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.83 - 7.75 (m, 2H), 7.51 (s, 1H), 7.30 (d, J = 8 Hz, 1H), 7.21 (t, 2H), 7.04 (d, J = 8 Hz, 1H), 4.69 (s, 2H), 3.91 (m, 1H), 2.75 (m, 2H), 2.57 - 2.27 (m, 4H). LCMS, m / z 514 [M+H] + <Example 89> N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(tetrahydrofuran-3-yl)-7H-purine-6-carboxamide

[0760] [ka]

[0761] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (0.83 mg, 5%).

[0762] 1 H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.63 (s, 1H), 8.09 (s, 1H), 7.80 (dd, J = 9.0, 4.6 Hz, 2H), 7.55 (s, 1H), 7.33 (d, J = 10.5 Hz, 1H), 7.24 (t, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.22 (t, J = 8.0 Hz, 1H), 4.14 - 4.04 (m, 2H), 4.00 - 3.84 (m, 2H), 2.51 - 2.40 (m, 2H). LCMS, m / z 502 [M+H] + <Example 90> 90.1 (R)-tert-butyl(1-(3-bromophenyl)ethyl)carbamate

[0763] [ka]

[0764] The same procedure as in Example 6.1 was used to obtain the target compound (140 mg, 95%) using a solution of (R)-1-(3-bromophenyl)ethanamine (200 mg, 1.1 mmol), BocO (470 mg, 2.2 mmol) and DCM (5 mL).

[0765] 1H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.37 (m, 6H), 7.31 - 7.24 (m, 4H), 4.64 - 4.54 (m, 2H), 1.36 (s, 17H), 1.28 (d, J = 7.0 Hz, 6H). 90.2 (R)-tert-butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[0766] [ka]

[0767] The same procedure as in Example 4.1 was repeated using (R)-tert-butyl(1-(3-bromophenyl)ethyl)carbamate (52 mg, 0.17 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (54 mg, 0.26 mmol), 2 M aqueous KCO solution (0.31 mL, 0.61 mmol), PdCl(dppf) (6.3 mg, 0.087 mmol), and 1,4-dioxane (0.62 mL) to obtain the target compound (49 mg, 74%).

[0768] LCMS, m / z 382 [M+H] + 90.3 (R)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[0769] [ka]

[0770] 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 4 M HCl (in dioxane) (400 μL) and the mixture was allowed to react at room temperature. After 90 minutes, MeOH was added to the reaction mixture, and the mixture was concentrated. This process was repeated three times to obtain the target compound (24 mg, crude) as a white solid.

[0771] LCMS, m / z 282 [M+H] + 90.4 (R)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[0772] [ka]

[0773] The same procedure as in Example 87.3 was repeated 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 target compound (38 mg, 72%) in the form of a light brown solid.

[0774] 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 9.40 (d, J = 5.8 Hz, 1H), 8.94 (s, 2H), 8.18 (s, 1H), 7.90 (dd, J = 8.9, 4.7 Hz, 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 = 6.8 Hz, 5H). LCMS, m / z 496 [M+H] + <Example 91> 91.1 (S)-tert-butyl(1-(3-bromophenyl)ethyl)carbamate

[0775] [ka]

[0776] The same procedure as in Example 6.1 was performed using (S)-1-(3-bromophenyl)ethanamine (100 mg, 0.50 mmol), BocO (220 mg, 1.0 mmol), and DCM (3 mL) to obtain the target compound (140 mg, 91%).

[0777] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.37 (m, 3H), 7.28 (d, J = 6.5 Hz, 2H), 4.64 - 4.55 (m, 1H), 1.36 (s, 8H), 1.28 (d, J = 7.0 Hz, 3H). 91.2 (S)-tert-butyl(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate

[0778] [ka]

[0779] The same procedure as in Example 4.1 was performed 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), PdCl(dppf) (6.0 mg, 0.0077 mmol), 2 M aqueous KCO solution (0.28 mL, 0.55 mmol), and 1,4-dioxane (0.55 mL) to obtain the target compound (49 mg, 74%).

[0780] LCMS, m / z 382 [M+H] + 91.3 (S)-1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[0781] [ka]

[0782] The same procedure as in Example 90.3 was performed using (S)-tert-butyl (1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)carbamate (60 mg, 0.16 mmol), 4 M HCl in dioxane (800 μL), and DCM (1.6 mL) to obtain the target compound (50 mg, crude).

[0783] LCMS, m / z 282 [M+H] + 91.4 (S)-8-Cyclopentyl-N-(1-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethyl)-7H-purine-6-carboxamide

[0784] [ka]

[0785] The same procedure as in Example 87.3 was repeated 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 target compound (37 mg, 57%) in the form of an off-white solid.

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.43 (d, J = 7.8 Hz, 1H), 8.97 (s, 2H), 8.20 (s, 1H), 7.92 (dd, J = 9.0, 4.7 Hz, 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 = 6.9 Hz, 5H). LCMS, m / z 496 [M+H] + <Example 92> 8-(3,3-Difluorocyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0787] [ka]

[0788] The same method as in Example 72.5 was used to obtain the target compound (14.9 mg, 30%) in the form of an off-white solid 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).

[0789] 1 H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.81 (s, 1H), 9.03 (s, 2H), 8.24 (s, 1H), 7.91 (dd, J = 9.1, 4.7 Hz, 2H), 7.58 (s, 1H), 7.47 (d, J = 10.3 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.07 (d, J = 9.5 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 3.87 - 3.74 (m, 1H), 3.18 - 2.99 (m, 4H). LCMS, m / z 522 [M+H] + <Example 93> 2-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[0790] [ka]

[0791] The same procedure as in Example 27.3 was repeated 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) to obtain the target compound (23 mg, 51%).

[0792] 1 H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.37 (d, J = 4 Hz, 1H), 8.05 (s, 1H), 7.78 - 7.75 (m, 2H), 7.69 (s, 1H), 7.51 (s, 1H), 7.30 (d, J = 12 Hz, 1H), 7.21 (t, 2H), 7.04 (d, J = 12 Hz, 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). LCMS, m / z 499 [M+H]+ <Example 94> 94.1 tert-Butyl 3-bromophenethylcarbamate

[0793] [ka]

[0794] The same procedure as in Example 6.1 was performed using 2-(3-bromophenyl)ethanamine (200 mg, 1.0 mmol), BocO (440 mg, 2.0 mmol), and DCM (3 mL) to obtain the target compound (290 mg, 96%).

[0795] 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 6.3 Hz, 2H), 7.28 - 7.18 (m, 2H), 6.88 (s, 1H), 3.18 - 3.10 (m, 2H), 2.69 (t, J = 7.0 Hz, 2H), 1.35 (s, 9H). 94.2 tert-Butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethylcarbamate

[0796] [ka]

[0797] The same procedure as in Example 4.1 was repeated using tert-butyl 3-bromophenethylcarbamate (54 mg, 0.18 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (56 mg, 0.27 mmol), PdCl(dppf) (6.6 mg, 0.0090 mmol), 2M aqueous KCO solution (0.31 mL, 0.63 mmol), and 1,4-dioxane (0.62 mL) to obtain the target compound (38 mg, 55%).

[0798] LCMS, m / z 382 [M+H] + 94.3 2-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[0799] [ka]

[0800] The same procedure as in Example 90.3 was performed using tert-butyl 3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethylcarbamate (38 mg, 0.10 mmol), 4 M HCl in dioxane (500 μL) and DCM (1 mL) to obtain the target compound (50 mg, crude).

[0801] LCMS, m / z 282 [M+H] + 94.4 8-Cyclopentyl-N-(3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenethyl)-7H-purine-6-carboxamide

[0802] [ka]

[0803] The same procedure as in Example 87.3 was performed 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) to obtain the target compound (33 mg, 80%).

[0804] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.23 (s, 1H), 8.94 (d, J = 7.3 Hz, 2H), 8.17 (s, 1H), 7.97 - 7.85 (m, 2H), 7.62 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.16 (d, J = 7.6 Hz, 1H), 3.74 - 3.65 (m, 2H), 3.55 - 3.46 (m, 1H), 2.98 (t, J = 7.3 Hz, 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). LCMS, m / z 496 [M+H] + <Example 95> 95.1 tert-Butyl 3-bromo-2-fluorobenzylcarbamate

[0805] [ka]

[0806] The same procedure as in Example 6.1 was performed using (3-bromo-2-fluorophenyl)methanamine (200 mg, 0.98 mmol), BocO (430 mg, 2.0 mmol), and DCM (3 mL) to obtain the target compound (290 mg, 97%).

[0807] 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (t, J = 7.1 Hz, 1H), 7.47 (t, J = 5.4 Hz, 1H), 7.30 (t, J = 6.9 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 4.19 (d, J = 5.8 Hz, 2H), 1.56 - 1.21 (m, 9H). 95.2 tert-Butyl 2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0808] [ka]

[0809] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (6.4 mg, 0.0088 mmol), 2M aqueous KCO solution (0.31 mL, 0.62 mmol), and 1,4-dioxane (0.62 mL) to obtain the target compound (50 mg, 73%).

[0810] LCMS, m / z 386 [M+H] + 95.3 2-Fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride

[0811] [ka]

[0812] The same procedure as in Example 90.3 was performed using tert-butyl 2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (50 mg, 0.13 mmol), 4 M HCl in dioxane (700 μL) and DCM (1.3 mL) to obtain the target compound (42 mg, crude).

[0813] LCMS, m / z 286 [M+H] + 95.4 8-Cyclopentyl-N-(2-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0814] [ka]

[0815] The same procedure as in Example 87.3 was performed 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) to obtain the target compound (35 mg, 65%).

[0816] 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.72 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.22 (s, 1H), 7.96 (dd, J = 9.0, 4.8 Hz, 2H), 7.74 (t, J = 7.3 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.33 (t, J = 7.0 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 4.70 (d, J = 6.1 Hz, 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). LCMS, m / z 500 [M+H] + <Example 96> 96.1 tert-Butyl 4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0817] [ka]

[0818] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (5.3 mg, 0.0073 mmol), 2M aqueous KCO solution (0.26 mL, 0.52 mmol), and 1,4-dioxane (0.52 mL) to obtain the target compound (37 mg, 66%).

[0819] LCMS, m / z 386 [M+H] + 96.2 (4-Fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine hydrochloride

[0820] [ka]

[0821] The same procedure as in Example 90.3 was performed using tert-butyl 4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (37 mg, 0.096 mmol), 4 M HCl in dioxane (500 μL) and DCM (1 mL) to obtain the target compound (31 mg, crude).

[0822] LCMS, m / z 2856 [M+H] + 96.3 8-Cyclopentyl-N-(4-fluoro-3-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0823] [ka]

[0824] The same procedure as in Example 87.3 was performed 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) to obtain the target compound (26 mg, 64%).

[0825] 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.74 (s, 1H), 8.96 (s, 1H), 8.87 (s, 1H), 8.17 (s, 1H), 7.95 (dd, J = 9.0, 4.7 Hz, 2H), 7.84 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H), 7.34 - 7.23 (m, 2H), 4.59 (d, J = 6.1 Hz, 2H), 3.55 - 3.44 (m, 1H), 2.13 - 2.02 (m, 2H), 1.99 - 1.88 (m, 2H), 1.80 (s, 2H), 1.71 - 1.60 (m, 2H). LCMS, m / z 500 [M+H] + <Example 97> 8-(3,3-Dimethylcyclobutyl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0826] [ka]

[0827] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (9.25 mg, 34.5%) as a yellow solid.

[0828] 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.76 (s, 1H), 9.03 (s, 1H), 8.98 (s, 1H), 8.25 (d, J = 7.3 Hz, 1H), 7.91 (dd, J = 9.0, 4.7 Hz, 2H), 7.58 (s, 1H), 7.47 (d, J = 9.5 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.07 (d, J = 9.3 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 3.94 - 3.81 (m, 1H), 2.28 (t, J = 10.2 Hz, 2H), 2.15 (t, J = 10.2 Hz, 2H), 1.24 (s, 3H), 1.15 (s, 3H). LC-MS, m / z 514 [M+H] + <Example 98> 8-(6,6-difluorospiro[3.3]heptan-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0829] [ka]

[0830] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (5 mg, 18%) as a pale yellow solid.

[0831] 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.82 - 7.74 (m, 2H), 7.51 (s, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.03 (d, J = 9.4 Hz, 1H), 4.69 (s, 2H), 3.90 - 3.79 (m, 1H), 2.81 -2.52 (m, 8H). LC-MS, m / z 562 [M+H] + Example 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

[0832] [ka]

[0833] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (14.15 mg, 59.9%) as a yellow solid.

[0834] 1H NMR (400 MHz, DMSO-d6) δ 13.36 (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, 1H), 7.47 (d, J = 9.7 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.07 (d, J = 9.9 Hz, 1H), 4.61 (s, 2H), 2.61 - 2.55 (m, 1H), 2.31 (s, 6H). LC-MS, m / z 498 [M+H] + Example 100 N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[3.3]heptan-2-yl)-7H-purine-6-carboxamide

[0835] [ka]

[0836] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (14.15 mg, 59.9%) as a pale yellow solid.

[0837] 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.57 (s, 1H), 8.04 (s, 1H), 7.81 - 7.72 (m, 2H), 7.50 (s, 1H), 7.28 (d, J = 9.8 Hz, 1H), 7.21 (t, J = 8.7 Hz, 2H), 7.02 (d, J = 9.2 Hz, 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 = 7.6 Hz, 2H), 1.90 - 1.82 (m, 2H). LC-MS, m / z 526 [M+H] + <Example 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

[0838] [ka]

[0839] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (8.43 mg, 34.4%) as an off-white solid.

[0840] 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.83 - 7.73 (m, 2H), 7.51 (s, 1H), 7.29 (d, J = 9.8 Hz, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.03 (d, J = 9.4 Hz, 1H), 4.70 (s, 2H), 2.64 (d, J = 2.2 Hz, 6H). LC-MS, m / z 516 [M+H] + <Example 102> N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclobutyl)-7H-purine-6-carboxamide

[0841] [ka]

[0842] The same procedure as in Example 72.5 was repeated 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), to obtain the target compounds A (3.18 mg, 13.3%) and B (5.29 mg, 22%) as partial diastereomers, respectively.

[0843] Partial stereoisomer A (retention time: 2.363 min, column: XSELECT CSH C18 3.0 × 50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v), B is acetonitrile (0.01% formic acid v / v), gradient: B% 30% to 100%, 4 min) / TLC, R f=0.6 (4% MeOH (in DCM), 4 elutions) 1 H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.60 (s, 1H), 8.07 (s, 1H), 7.79 (dd, J = 9.0, 4.6 Hz, 2H), 7.52 (s, 1H), 7.31 (d, J = 9.9 Hz, 1H), 7.23 (t, J = 8.7 Hz, 2H), 7.04 (d, J = 9.4 Hz, 1H), 5.53 - 5.29 (m, 1H), 4.70 (s, 2H), 3.96 (s, 1H), 2.93 - 2.69 (m, 4H). LC-MS, m / z 504 [M+H] + Partial Stereoisotrope B (Retention time: 2.309 minutes, Karamu: XSELECT CSH C18 3.0×50mm, 3.5μm, mobile phase: A water (0.01% acid v / v), B acid water (0.01% acid v / v), グラジエント: B% 30%~100%, 4 minutes) / TLC, R f =0.55 (4% ​​MeOH (in DCM), 4 elutions) 1 H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.78 (dd, J = 8.7, 4.5 Hz, 2H), 7.51 (s, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.22 (t, J = 8.5 Hz, 2H), 7.03 (d, J = 9.1 Hz, 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). LC-MS, m / z 504 [M+H] + <Example 103> Methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate

[0844] [ka]

[0845] The same procedure as in Example 72.5 was repeated 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). The target compounds A (4.05 mg, 15.7%) and B (4.05 mg, 15.7%) were obtained as partial stereoisomers, respectively.

[0846] Partial stereoisomer A (retention time: 2.308 min, column: XSELECT CSH C18 3.0 × 50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v), B is acetonitrile (0.01% formic acid v / v), gradient: B% 30% to 100%, 4 min) / TLC, R f =0.51 (4% MeOH in DCM, eluted four times) 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.77 (dd, J = 8.6, 4.6 Hz, 2H), 7.51 (s, 1H), 7.29 (d, J = 9.4 Hz, 1H), 7.22 (t, J = 8.5 Hz, 2H), 7.03 (d, J = 9.3 Hz, 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). LC-MS, m / z 544 [M+H] + Partial Stereoisotropy B (Retention time: 2.274 minutes, Karamu: XSELECT CSH C18 3.0×50mm, 3.5μm, mobile phase: A water (0.01% acid v / v), B acid water (0.01% acid v / v), グラジエント: B% 30%~100%, 4 minutes) / TLC, R f =0.47 (4% MeOH (in DCM), 4 elutions) 1 H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.60 (s, 1H), 8.06 (s, 1H), 7.78 (dd, J = 8.7, 4.7 Hz, 2H), 7.52 (s, 1H), 7.31 (d, J = 9.5 Hz, 1H), 7.23 (t, J = 8.6 Hz, 2H), 7.03 (d, J = 9.0 Hz, 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). LC-MS, m / z 544 [M+H] + <Example 104> 104.1 tert-ブチル3-ブロモ-5-クロロベンジルカルバメート

[0847]

change

[0848] The same procedure as in Example 6.1 was repeated using (3-bromo-5-chlorophenyl)methanamine (226.6 mg, 1.03 mmol), (Boc)O (30% in THF, 1.6 mL, 2.06 mmol), and DCM (3.4 mL) to obtain the target compound (329 mg, 99%) as a colorless, transparent oil.

[0849] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 1.47 (s, 9H). 104.2 tert-Butyl 3-chloro-5-(1H-pyrazol-4-yl)benzylcarbamate

[0850] [ka]

[0851] The same procedure as in Example 25.2 was repeated 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 HO (2 mL) to obtain the target compound (197 mg, 62.3%) as a colorless, transparent oil.

[0852] LC-MS, m / z 308 [M+H] + 104.3 tert-Butyl 3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0853] [ka]

[0854] The same procedure as in Example 25.3 was repeated 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), KCO (23 mg, 0.17 mmol), and DMSO (1 mL) to obtain the target compound (25 mg, 56%) as an off-white solid.

[0855] LC-MS, m / z 402 [M+H] + 104.4 (3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[0856] [ka]

[0857] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (25.6 mg, crude).

[0858] LC-MS, m / z 302 [M+H] + 104.5 N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0859] [ka]

[0860] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (15.0 mg, 47%) as a pale yellow solid.

[0861] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.80 (s, 1H), 9.07 (s, 1H), 8.97 (s, 1H), 8.26 (s, 1H), 7.91 (dd, J = 9.0, 4.7 Hz, 2H), 7.71 (d, J = 6.6 Hz, 2H), 7.39 (t, J = 8.8 Hz, 2H), 7.31 (s, 1H), 4.60 (d, J = 6.2 Hz, 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). LC-MS, m / z 516 [M+H] + <Example 105> 105.1 tert-Butyl (3-bromo-5-fluorophenyl)carbamate

[0862] [ka]

[0863] To a solution of 3-bromo-5-fluoroaniline (200 mg, 1.1 mmol) in DCM (5 mL) were added (Boc)O (200 mg, 0.93 mmol) and TEA (220 μL, 1.6 mmol). The mixture was reacted at 50 °C overnight. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (0-10% EtOAc in hexane) to give the desired compound (170 mg, 54%).

[0864] LC-MS, m / z 291 [M+H] + 105.2 tert-Butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)carbamate

[0865] [ka]

[0866] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (21 mg, 0.029 mmol), 2M aqueous KCO solution (1 mL), and 1,4-dioxane (2 mL) to obtain the target compound (160 mg, 77%) as a white solid.

[0867] LC-MS, m / z 372 [M+H] + 105.3 3-Fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)aniline

[0868] [ka]

[0869] The same procedure as in Example 58.2 was repeated using tert-butyl (3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)carbamate (80 mg, 0.22 mmol), 4 M HCl in dioxane (1 mL), and DCM (2 mL) to obtain the target compound (58 mg, crude) as a pale yellow solid.

[0870] LC-MS, m / z 272 [M+H] + 105.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-7H-purine-6-carboxamide

[0871] [ka]

[0872] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (4 mg, 4%) as a pale yellow solid.

[0873] 1H NMR (400 MHz, DMSO-d6) δ 13.36 (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, 4.7 Hz, 2H), 7.84 (d, J = 11.0 Hz, 1H), 7.41 (t, J = 8.7 Hz, 3H), 3.59 - 3.51 (m, 1H), 2.17 - 2.08 (m, 2H), 2.01 - 1.93 (m, 2H), 1.88 - 1.78 (m, 2H), 1.73 - 1.65 (m, 2H). LC-MS, m / z 486 [M+H] + <Example 106> 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylic acid

[0874] [ka]

[0875] Methyl 3-(6-((3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)carbamoyl)-7H-purin-8-yl)cyclobutanecarboxylate (18.69 mg, 0.034 mmol) was dissolved in MeOH (1 mL), followed by 0.1 M aqueous (aq.) NaOH solution (2 mL) and stirring at room temperature. After 3 h, the reaction mixture was diluted with HO, acidified (pH 4-5), and extracted with EtOAc. The organic layer was dried over MgSO and concentrated. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to afford the target compound (4.68 mg, 25.7% yield, mixture of partial stereoisomers) as a light brown solid.

[0876] 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 = 9.5 Hz, 1H), 6.95 (d, J = 9.1 Hz, 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 = 7.8 Hz, 4H), 2.71 - 2.59 (m, 2H). LC-MS, m / z 530 [M+H] + <Example 107> 107.1 2-Chloro-3-nitroisonicotinic acid

[0877] [ka]

[0878] Methyl 2-chloro-3-nitroisonicotinate (100 mg, 0.46 mmol) was dissolved in MeOH (9 mL) and then 0.1 M aqueous NaOH (17 mL) was added and stirred overnight at room temperature. The reaction mixture was acidified (pH 4-5) with 1 M aqueous HCl and extracted with EtOAc. The organic layer was dried over MgSO. The organic layer was concentrated to give the desired compound (88.24 mg, 94.4%) as a white solid.

[0879] LC-MS, m / z 201 [M−H] - 107.2 2-chloro-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide

[0880] [ka]

[0881] 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 overnight at room temperature. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was dried over MgSO and concentrated to obtain the target compound (189 mg, crude) as an off-white solid.

[0882] LC-MS, m / z 470 [M+H] + 107.3 2-((2,4-dimethoxybenzyl)amino)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-3-nitroisonicotinamide

[0883] [ka]

[0884] 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 overnight at room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to obtain the target compound (196.4 mg, crude) as a yellow solid.

[0885] LC-MS, m / z 601 [M+H] + 107.4 3-amino-N-(3-chloro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-2-((2,4-dimethoxybenzyl)amino)isonicotinamide

[0886] [ka]

[0887] The same procedure as in Example 61.2 was repeated 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) to obtain the target compound (51 mg, 54.7%).

[0888] LC-MS, m / z 571 [M+H] + 107.5 2,3-Diamino-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)isonicotinamide

[0889] [ka]

[0890] The same procedure as in Example 61.5 was repeated 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) to obtain the target compound (20.54 mg, 60.6%).

[0891] LC-MS, m / z 421 [M+H] + 107.6 2-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide

[0892] [ka]

[0893] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (2.13 mg, 8.7%).

[0894] 1H NMR (400 MHz, CDCl3+CD3OD) δ 9.42 - 8.34 (m, 2H), 8.01 (s, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.73 (dd, J = 8.9, 4.4 Hz, 2H), 7.49 (s, 1H), 7.30 - 7.18 (m, 3H), 7.10 (d, J = 8.9 Hz, 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). LC-MS, m / z 499 [M+H] + <Example 108> 108.1 tert-Butyl 4-bromobenzylcarbamate

[0895] [ka]

[0896] The same procedure as in Example 6.1 was repeated using (4-bromophenyl)methanamine (100 mg, 0.54 mmol), (Boc)O (30% in THF, 421 μL, 0.55 mmol), TEA (113 μL, 0.81 mmol), and DCM (1 mL) to obtain the target compound (149 mg, 96.9%) as a white solid.

[0897] 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 4.85 (broad, 1H), 4.26 (d, J = 5.4 Hz, 2H), 1.46 (s, 9H). 108.2 tert-Butyl 4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate

[0898] [ka]

[0899] The same procedure as in Example 4.1 was repeated using tert-butyl 4-bromobenzylcarbamate (144 mg, 0.50 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (156 mg, 0.76 mmol), PdCl(dppf) (7.2 mg, 0.0099 mmol), 2M KCO (0.9 mL, 1.76 mmol), and 1,4-dioxane (3.5 mL) to obtain the target compound (131 mg, 70.9%) as a white solid.

[0900] LC-MS, m / z 368 [M+H] + 108.3 (4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[0901] [ka]

[0902] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (63 mg, crude).

[0903] LC-MS, m / z 268 [M+H] + 108.4 8-Cyclopentyl-N-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0904] [ka]

[0905] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (36.25 mg, 54.95%) as a pale yellow solid.

[0906] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.72 (t, J = 6.2 Hz, 1H), 8.95 (d, J = 9.3 Hz, 2H), 8.18 (s, 1H), 7.90 (dd, J = 9.0, 4.8 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.46 - 7.32 (m, 4H), 4.56 (d, J = 6.2 Hz, 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). LC-MS, m / z 482 [M+H] + Example 109 109.1 3-Fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzonitrile

[0907] [ka]

[0908] The same procedure as in Example 4.1 was repeated using 4-bromo-3-fluorobenzonitrile (100 mg, 0.50 mmol), (1-(4-fluorophenyl)-1H-pyrazol-4-yl)boronic acid (155 mg, 0.75 mmol), PdCl(dppf) (18.3 mg, 0.025 mmol), 2M KCO (0.9 mL, 1.76 mmol), and 1,4-dioxane (3.5 mL) to obtain the target compound (116 mg, 82.6%) as a white solid.

[0909] 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.8 Hz, 1H), 8.11 (s, 1H), 7.77 - 7.67 (m, 3H), 7.54 - 7.43 (m, 2H), 7.24 - 7.15 (m, 2H). LC-MS, m / z 282 [M+H] + 109.2 (3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)methanamine

[0910] [ka]

[0911] The same procedure as in Example 7.2 was repeated using 3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzonitrile (46.2 mg, 0.16 mmol), LAH (2 M in THF, 0.16 mL, 0.36 mmol), and THF (2 mL) to obtain the target compound (20.34 mg, 40%) as a yellow solid.

[0912] LC-MS, m / z 286 [M+H] + 109.3 8-Cyclopentyl-N-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0913] [ka]

[0914] The same method as in Example 87.3 was used with (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 target compound (14.1 mg, 39.6%) as a pale yellow solid.

[0915] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.78 (t, J = 6.2 Hz, 1H), 8.97 (s, 1H), 8.86 (s, 1H), 8.16 (s, 1H), 7.93 (dd, J = 9.0, 4.8 Hz, 2H), 7.78 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 8.8 Hz, 2H), 7.33 - 7.25 (m, 2H), 4.58 (d, J = 6.3 Hz, 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). LC-MS, m / z 500 [M+H] + Example 110 N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(3-fluorocyclopentyl)-7H-purine-6-carboxamide

[0916] [ka]

[0917] The target compounds A (1.2 mg, 4.9%) and B (1.2 mg, 4.9%) were obtained as partial stereoisomers using the same method 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).

[0918] Partial stereoisomer A (retention time: 2.44 min, column: XSELECT CSH C18 3.0 × 50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v), B is acetonitrile (0.01% formic acid v / v), gradient: B% 30% to 100%, 4 min) / TLC, R f =0.49 (2% MeOH in DCM, eluted four times) 1 H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 9.05 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.68 (dd, J = 9.0, 4.6 Hz, 2H), 7.33 (s, 1H), 7.22 - 7.13 (m, 3H), 7.00 (d, J = 9.4 Hz, 1H), 5.47 - 5.27 (m, 1H), 4.74 (d, J = 6.1 Hz, 2H), 3.80 - 3.67 (m, 1H), 2.64 - 1.98 (m, 6H). LC-MS, m / z 518 [M+H] + Partial stereoisomer B (retention time: 2.36 min, column: XSELECT CSH C18 3.0 × 50 mm, 3.5 μm, mobile phase: A is water (0.01% formic acid v / v), B is acetonitrile (0.01% formic acid v / v), gradient: B% 30% to 100%, 4 min) / TLC, R f=0.47 (2% MeOH in DCM, eluted four times) 1 H NMR (400 MHz, CDCl3) δ 10.59 (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 = 8.6 Hz, 1H), 5.50 - 5.27 (m, 1H), 4.74 (d, J = 6.3 Hz, 2H), 3.83 (m, 1H), 2.59 - 1.94 (m, 6H). LC-MS, m / z 518 [M+H] + Example 111 N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-8-(spiro[2.3]hexan-5-yl)-7H-purine-6-carboxamide

[0919] [ka]

[0920] The same procedure as in Example 72.5 was repeated 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 target compound (1.6 mg, 4.8%) as an off-white solid.

[0921] 1H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.62 (s, 1H), 8.08 (s, 1H), 7.80 (dd, J = 7.7, 5.0 Hz, 2H), 7.55 (s, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.05 (d, J = 9.8 Hz, 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). LC-MS, m / z 512 [M+H] + <Example 112> 112.1 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl(methyl)carbamate

[0922] [ka]

[0923] tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzylcarbamate (100 mg, 0.26 mmol) was dissolved in THF (2.5 mL), and NaH (60% suspension in mineral oil) (7 mg, 0.29 mmol) was slowly added at 0 °C. The reaction temperature was raised to room temperature and stirred for 20 minutes. After that, MeI (19 μL, 0.31 mmol) was added and the mixture was stirred at 45 °C overnight. The reaction mixture was quenched with HO and extracted with EtOAc. The organic layer was dried over MgSO. The residue obtained after concentration was purified by silica gel column chromatography (0-15% EtOAc in hexane) to give the desired compound (18.89 mg, 18%).

[0924] LC-MS, m / z 400 [M+H] + 112.2 1-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)-N-methylmethanamine trifluoroacetate

[0925] [ka]

[0926] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (8.27 mg, crude).

[0927] LC-MS, m / z 300 [M+H] + 112.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-N-methyl-7H-purine-6-carboxamide

[0928] [ka]

[0929] The same method as in Example 87.3 was used to obtain the target compound (8.48 mg, 82.6%, rotamer mixture) as a white solid 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).

[0930] 1 H NMR (400 MHz, DMSO-d 6,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 = 9.6 Hz, 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). LC-MS, m / z 514 [M+H] + <Example 113> 8-(bicyclo[3.1.0]hexan-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0931] [ka]

[0932] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (2.4 mg, 6.6%) as an off-white solid.

[0933] 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.62 (s, 1H), 8.08 (s, 1H), 7.79 (dd, J = 8.9, 4.7 Hz, 2H), 7.53 (s, 1H), 7.32 (d, J = 10.3 Hz, 1H), 7.24 (t, J = 8.7 Hz, 2H), 7.04 (d, J = 9.1 Hz, 1H), 4.70 (s, 2H), 3.23 - 3.11 (m, 1H), 2.26 (d, J = 8.9 Hz, 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). LC-MS, m / z 512 [M+H] + <Example 114> 8-(bicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0934] [ka]

[0935] The same procedure as in Example 72.5 was repeated 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) to obtain the target compound (3.16 mg, 12.7%) as an off-white solid.

[0936] 1H NMR (400 MHz, CD3OD) δ 9.01 - 8.91 (m, J = 6.8 Hz, 1H), 8.61 (s, 1H), 7.79 (dd, J = 9.0, 4.6 Hz, 2H), 7.53 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 7.23 (t, J = 8.7 Hz, 2H), 7.05 (d, J = 9.4 Hz, 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). LC-MS, m / z 526 [M+H] + Example 115 8-(bicyclo[2.1.1]hexan-1-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0937] [ka]

[0938] The same procedure as in Example 72.5 was repeated 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 target compound (1.1 mg, 3%) as an off-white solid.

[0939] 1H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.81 (dd, J = 9.0, 4.6 Hz, 2H), 7.55 (s, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.25 (t, J = 8.7 Hz, 2H), 7.07 (d, J = 9.9 Hz, 1H), 4.72 (s, 2H), 2.63 (s, 1H), 2.21 - 1.89 (m, 7H), 1.71 - 1.55 (m, 2H). LC-MS, m / z 512 [M+H] + <Example 116> 116.1 tert-Butyl 3-azido-5-fluorobenzylcarbamate

[0940] [ka]

[0941] tert-Butyl 3-bromo-5-fluorobenzylcarbamate (300 mg, 0.99 mmol), NaN (128 mg, 1.97 mmol), CuI (38 mg, 0.20 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (47 μL, 0.30 mmol), and sodium ascorbate (20 mg, 0.099 mmol) were dissolved in EtOH (7 mL) and HO (3 mL) and stirred overnight at 100 °C. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was dried over NaSO. The organic layer was concentrated to give the desired compound (263 mg, 99%).

[0942] 116.2 tert-Butyl 3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzylcarbamate

[0943] [ka]

[0944] tert-Butyl 3-azido-5-fluorobenzylcarbamate (263 mg, 0.99 mmol), 1-ethynyl-4-fluorobenzene (119 mg, 0.99 mmol), 10% aqueous CuSO₄·5H₂O solution (767 μL, 0.30 mmol), and sodium ascorbate (59 mg, 0.30 mmol) were dissolved in t-BuOH (5 mL) and H₂O (5 mL) and stirred overnight at room temperature. The reaction mixture was diluted with H₂O and extracted with EtOAc. The organic layer was dried over MgSO₄. The organic layer was concentrated and the residue was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give the desired compound (222.7 mg, 57.6%).

[0945] 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.92 - 7.85 (m, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 8.5 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 5.05 (s, 1H), 4.42 (d, J = 5.9 Hz, 2H), 1.48 (s, 9H). 116.3 (3-Fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine trifluoroacetate

[0946] [ka]

[0947] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (34.4 mg, crude).

[0948] LC-MS, m / z 287 [M+H] + 116.4 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)benzyl)-7H-purine-6-carboxamide

[0949] [ka]

[0950] The same method as in Example 87.3 was used to obtain the target compound (29.57 mg, 68.7%) as a pale yellow solid 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).

[0951] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.90 (s, 1H), 9.32 (s, 1H), 8.98 (s, 1H), 7.95 (dd, J = 8.6, 5.6 Hz, 2H), 7.90 (s, 1H), 7.75 (d, J = 9.5 Hz, 1H), 7.42 - 7.30 (m, 3H), 4.68 (d, J = 6.2 Hz, 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). LC-MS, m / z 501 [M+H] + Example 117 117.1 tert-Butyl 3-fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[0952] [ka]

[0953] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (186.19 mg, 72.3%) as a yellow solid.

[0954] LC-MS, m / z 374 [M+H] + 117.2 (3-Fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[0955] [ka]

[0956] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (150 mg, crude).

[0957] LC-MS, m / z 274 [M+H] + 117.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(thiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0958] [ka]

[0959] The same method as in Example 87.3 was used to obtain the target compound (137.3 mg, 72.8%) as a yellow solid 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).

[0960] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.78 (t, J = 6.4 Hz, 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 = 10.0 Hz, 1H), 7.06 (d, J = 9.3 Hz, 1H), 4.60 (d, J = 6.1 Hz, 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). LC-MS, m / z 488 [M+H] + <Example 118> 118.1 3-Fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzonitrile

[0961] [ka]

[0962] The same procedure as in Example 10.1 was repeated using 3-bromo-5-fluorobenzonitrile (1 g, 5.00 mmol), 1-methyl-1H-pyrazol-3-amine (434 μL, 5.00 mmol), Pd(dba) (91.6 mg, 0.100 mmol), Xantphos (145 mg, 0.250 mmol), KCO (2.07 g, 15.0 mmol), and dioxane (31 mL) to obtain the target compound (0.364 g, 33.7%) as a yellow solid.

[0963] 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 2.0 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.78 (d, J = 7.9 Hz, 1H), 6.12 (s, 1H), 5.91 (d, J = 2.2 Hz, 1H), 3.84 (s, 3H). LC-MS, m / z 217 [M+H] + 118.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-3-amine

[0964] [ka]

[0965] 3-Fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzonitrile (0.36 g, 1.66 mmol) was dissolved in THF (17 mL), and LAH solution (2.0 M in THF; 1.7 mL) was added at 0 °C. The mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated and cooled to 0 °C. The mixture was quenched with MeOH and diluted with EtOAc. The organic layer was washed with brine, dried over Na SO , and concentrated to obtain the target compound (321 mg, 87.5%) as a yellow oil.

[0966] 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 12.3 Hz, 1H), 6.85 (s, 1H), 6.46 (d, J = 9.9 Hz, 1H), 5.75 (d, J = 2.2 Hz, 2H), 3.72 (s, 3H). LC-MS, m / z 221 [M+H] + 118.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrazol-3-yl)amino)benzyl)-7H-purine-6-carboxamide

[0967] [ka]

[0968] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (0.155 g, 25.6%) as a yellow solid.

[0969] 1H NMR (400 MHz, DMSO-d6) δ 13.15 (bs, 1H), 9.67 (t, J = 5.0 Hz, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 12.3 Hz, 1H), 6.92 (s, 1H), 6.48 (d, J = 8.9 Hz, 1H), 5.70 (d, J = 2.2 Hz, 1H), 4.46 (d, J = 6.1 Hz, 2H), 3.64 (s, 3H), 2.05 (s, 2H), 1.93 (d, J = 7.9 Hz, 2H), 1.79 (s, 2H), 1.68 - 1.62 (m, 2H). LC-MS, m / z 435 [M+H] + Example 119 119.1 tert-Butyl 3-fluoro-5-((trimethylsilyl)ethynyl)benzylcarbamate

[0970] [ka]

[0971] A mixture of tert-butyl 3-bromo-5-fluorobenzylcarbamate (100 mg, 0.33 mmol), TMSA (52 mg, 0.53 mmol), CuI (3 mg, 0.016 mmol), Pd(PPh) (19 mg, 0.016 mmol), and EtN (3 mL) was stirred at 110 °C overnight. The reaction mixture was diluted with H2O and extracted with DCM. The organic layer was dried over MgSO4. The residue obtained after concentration was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give the desired compound (42.8 mg, 40.5%) as a yellow oil.

[0972] 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.86 (broad, 1H), 4.28 (d, J = 5.4 Hz, 2H), 1.46 (s, 9H), 0.24 (s, 9H). 119.2 tert-Butyl 3-ethynyl-5-fluorobenzylcarbamate

[0973] [ka]

[0974] 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 resulting residue was purified by silica gel column chromatography (hexane) to obtain the target compound (31 mg, 99%).

[0975] 119.3 tert-Butyl 3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzylcarbamate

[0976] [ka]

[0977] A mixture of tert-butyl 3-ethynyl-5-fluorobenzylcarbamate (31 mg, 0.12 mmol), 1-azido-4-fluorobenzene (17 mg, 0.12 mmol), 10% aqueous CuSO₄·5H₂O solution (192 μL, 0.074 mmol), sodium ascorbate (14.8 mg, 0.074 mmol), and t-BuOH (2 mL) in H₂O (2 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with H₂O and extracted with EtOAc. The organic layer was dried over MgSO₄. The residue obtained after concentration was purified by silica gel column chromatography (0-2% MeOH in DCM) to give the desired compound (15 mg, 31.2%).

[0978] LC-MS, m / z 387 [M+H] + 119.4 (3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)methanamine trifluoroacetate

[0979] [ka]

[0980] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (14.4 mg, crude).

[0981] LC-MS, m / z 287 [M+H] + 119.5 8-Cyclopentyl-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)benzyl)-7H-purine-6-carboxamide

[0982] [ka]

[0983] The same method as in Example 87.3 was used to obtain the target compound (14.27 mg, 79.2%) as a yellow solid 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).

[0984] 1 H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.92 (s, 1H), 7.91 (dd, J = 8.9, 4.7 Hz, 2H), 7.80 (s, 1H), 7.56 (d, J = 9.7 Hz, 1H), 7.34 (t, J = 8.6 Hz, 2H), 7.18 (d, J = 9.2 Hz, 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). LC-MS, m / z 501 [M+H] + Example 120 120.1 tert-Butyl (3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)carbamate

[0985] [ka]

[0986] The same procedure as in Example 10.1 was repeated 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) to obtain the target compound (10.5 mg, 21%) as an off-white solid.

[0987] 1 HNMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 11.2 Hz, 1H), 6.78 (s, 1H), 6.47 (d, J = 8.8 Hz, 1H), 6.30 (s, 1H), 6.06 (d, J = 2.4 Hz, 1H), 4.87 (s, 1H), 4.24 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H). LC-MS, m / z 307 [M+H] + 120.2 N-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-3-amine trifluoroacetate

[0988] [ka]

[0989] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (17 mg, crude) as a yellow solid.

[0990] LC-MS, m / z 207 [M+H] + 120.3 N-(3-((1H-pyrazol-3-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[0991] [ka]

[0992] The target compound (5 mg, 36%) was obtained as a yellow solid in the same manner 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).

[0993] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (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 = 12.3 Hz, 1H), 6.93 (s, 1H), 6.49 (d, J = 9.6 Hz, 1H), 5.79 (s, 1H), 4.47 (d, J = 6.3 Hz, 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). LC-MS, m / z 421 [M+H] + <Example 121> 121.1 3-Fluoro-5-(isoxazol-3-ylamino)benzonitrile

[0994] [ka]

[0995] 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (30 mg, 0.121 mmol), isoxazol-3-amine (20 mg, 0.243 mmol), Cu(OAc) (22 mg, 0.121 mmol), and TEA (34 μL, 0.243 mmol) were dissolved in ACN / EtOH (115 μL / 6 μL) and reacted at 80 °C for 1 h. The reaction mixture was filtered through a Celite pad and washed several times with EtOAc. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (0-25% EtOAc in hexane) to give the desired compound (11 mg, 41.8%) as a white solid.

[0996] 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.70 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.29 (d, J = 1.7 Hz, 1H). LC-MS, m / z 202 [M−H] - 121.2 N-(3-(aminomethyl)-5-fluorophenyl)isoxazol-3-amine

[0997] [ka]

[0998] 3-Fluoro-5-(isoxazol-3-ylamino)benzonitrile (11 mg, 0.054 mmol) was dissolved in THF (0.53 mL), and then LAH solution (2.0 M in THF; 53 μL) was added at 0 °C and reacted at room temperature overnight. The reaction mixture was cooled to 0 °C again, quenched by adding HO, and stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to obtain the target compound (9.6 mg, 87.2%) as a yellow solid.

[0999] LC-MS, m / z 206 [M−H] - 121.3 8-Cyclopentyl-N-(3-fluoro-5-(isoxazol-3-ylamino)benzyl)-7H-purine-6-carboxamide

[1000] [ka]

[1001] The same procedure as in Example 1.3 was repeated using N-(3-(aminomethyl)-5-fluorophenyl)isoxazol-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) to obtain the target compound (3.8 mg, 18.4%) as a yellow solid.

[1002] 1 H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.32 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 11.1 Hz, 1H), 7.16 (s, 1H), 6.68 (d, J = 9.2 Hz, 1H), 6.10 (d, 1.77 (dd, J) = 6.9, 4.5 Hz, 2H). LC-MS, m / z 422 [M+H] + <Example 122> 122.1 tert-Butyl (3-((4-cyanophenyl)amino)-5-fluorobenzyl)carbamate

[1003] [ka]

[1004] The same procedure as in Example 10.1 was repeated using tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5 g, 1.64 mmol), 4-aminobenzonitrile (0.194 g, 1.64 mmol), Pd(dba) (30.1 mg, 0.033 mmol), Xantphos (47.6 mg, 0.082 mmol), KCO (0.523 g, 3.78 mmol), and dioxane (10.3 mL) to obtain the target compound (0.364 g, 33.7%) as a yellow solid.

[1005] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.42 (t, J = 6.2 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.80 (d, J = 10.9 Hz, 1H), 6.63 (d, J = 9.7 Hz, 1H), 4.08 (d, J = 6.1 Hz, 2H), 1.37 (s, 9H). 122.2 4-((3-(aminomethyl)-5-fluorophenyl)amino)benzonitrile trifluoroacetate

[1006] [ka]

[1007] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (0.123 mg, 78.4%, crude) as a yellow oil.

[1008] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.02 (bs, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.12 (s, 1H), 6.91 (d, J = 10.4 Hz, 2H), 4.00 (s, 2H). 122.3 N-(3-((4-cyanophenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1009] [ka]

[1010] The same procedure as in Example 87.3 was repeated 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 target compound (0.128 g, 79.5%) as a yellow solid.

[1011] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.94 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 6.86 - 6.76 (m, 2H), 4.51 (d, J = 6.4 Hz, 2H), 3.47 (s, 1H), 2.05 (s, 2H), 1.91 (s, 2H), 1.79 (s, 2H), 1.64 (s, 2H). LC-MS, m / z 456 [M+H] + <Example 123> 123.1 tert-Butyl 3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1012] [ka]

[1013] The same procedure as in Example 25.3 was repeated 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 target compound (30.89 mg, 73%) as an off-white solid.

[1014] LC-MS, m / z 410 [M+H] + 123.2 1-(4-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)phenyl)ethanone trifluoroacetate

[1015] [ka]

[1016] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (28 mg, crude).

[1017] LC-MS, m / z 310 [M+H] + 123.3 N-(3-(1-(4-acetylphenyl)-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1018] [ka]

[1019] The same procedure as in Example 87.3 was repeated 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 μL, 0.20 mmol) and THF (2 mL) to obtain the target compound (24.7 mg, 71.5%) as a yellow solid.

[1020] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.79 (t, J = 6.4 Hz, 1H), 9.22 (s, 1H), 8.97 (s, 1H), 8.34 (s, 1H), 8.12 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 9.8 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 4.61 (d, J = 6.2 Hz, 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). LC-MS, m / z 524 [M+H] + Example 124 124.1 tert-Butyl 3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1021] [ka]

[1022] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (32.29 mg, 26.3%) as a colorless, transparent oil.

[1023] LC-MS, m / z 358 [M+H] + 124.2 (3-Fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[1024] [ka]

[1025] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (33 mg, crude).

[1026] LC-MS, m / z 258 [M+H] + 124.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(furan-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1027] [ka]

[1028] The same procedure as in Example 87.3 was repeated 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 target compound (27.15 mg, 63.98%) as an off-white solid.

[1029] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (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 = 10.3 Hz, 1H), 7.11 - 6.99 (m, 2H), 4.59 (d, J = 6.3 Hz, 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). LC-MS, m / z 472 [M+H] + Example 125 125.1 tert-Butyl 3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzylcarbamate

[1030] [ka]

[1031] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (25.92 mg, 16.9%) as a pale yellow solid.

[1032] LC-MS, m / z 448 [M+H] + 125.2 (3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorophenyl)methanamine trifluoroacetate

[1033] [ka]

[1034] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (25 mg, crude).

[1035] LC-MS, m / z 348 [M+H] + 125.3 N-(3-(1'-benzyl-1'H-[1,4'-bipyrazol]-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1036] [ka]

[1037] The same procedure as in Example 87.3 was repeated 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 target compound (18.08 mg, 59.6%) as an off-white solid.

[1038] 1 H NMR (400 MHz, CD3OD) δ 8.95 (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 = 9.6 Hz, 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). LC-MS, m / z 562 [M+H] + <Example 126> N-(3-((4-carbamoylphenyl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1039] [ka]

[1040] 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), and then HO (35% in HO, 0.16 mL) was added at 0 °C. After stirring at room temperature for 2 hours, HO was added to the reaction mixture, which was further stirred at room temperature for 1 hour. The resulting solid was filtered to obtain the target compound (40 mg, 77.0%) as a white solid.

[1041] 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 2H), 8.92 (s, 1H), 8.76 - 8.69 (m, 1H), 7.74 - 7.70 (m, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 6.76 (d, J = 11.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.49 (d, J = 6.2 Hz, 2H), 3.46 (s, 1H), 2.04 (s, 2H), 1.91 (dd, J = 11.1, 7.1 Hz, 2H), 1.78 (s, 2H), 1.67 - 1.60 (m, 2H). LC-MS, m / z 474 [M+H] + <Example 127> 127.1 Ethyl 4-((3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)amino)benzoate

[1042] [ka]

[1043] The same procedure as in Example 10.1 was repeated using tert-butyl 3-bromo-5-fluorobenzylcarbamate (0.5 g, 1.64 mmol), ethyl 4-aminobenzoate (0.271 g, 1.64 mmol), Pd(dba) (30.1 mg, 0.033 mmol), Xantphos (47.6 mg, 0.082 mmol), KCO (0.523 g, 3.78 mmol), and dioxane (10.3 mL) to obtain the target compound (0.212 g, 32.3%) as a yellow solid.

[1044] 1 H NMR (400 MHz, CD3OD) δ7.87 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 6.74 (d, J = 10.5 Hz, 1H), 6.58 (d, J = 9.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.18 (s, 2H), 1.44 (s, 9H), 1.36 (d, J = 7.1 Hz, 3H). 127.2 Ethyl 4-((3-(aminomethyl)-5-fluorophenyl)amino)benzoate trifluoroacetate

[1045] [ka]

[1046] The same procedure as in Example 25.4 was repeated 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 target compound (0.138 g, 69.4%).

[1047] 127.3 Ethyl 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoate

[1048] [ka]

[1049] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (86.2 mg, 48.4%) as a yellow solid.

[1050] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.10 - 7.03 (m, 3H), 6.78 (d, J = 10.9 Hz, 1H), 6.73 (d, J = 9.5 Hz, 1H), 4.63 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.53 - 3.43 (m, 1H), 2.20 (d, J = 7.9 Hz, 2H), 2.06 - 1.99 (m, 2H), 1.94 - 1.88 (m, 2H), 1.80 - 1.72 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H). LC-MS, m / z 503 [M+H] + Example 128 128.1 tert-Butyl 3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzylcarbamate

[1051] [ka]

[1052] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (87.14 mg, 68%) as a colorless, transparent oil.

[1053] LC-MS, m / z 372 [M+H] + 128.2 (3-Fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)phenyl)methanamine trifluoroacetate

[1054] [ka]

[1055] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (41 mg, crude).

[1056] LC-MS, m / z 272 [M+H] + 128.3 8-Cyclopentyl-N-(3-fluoro-5-(1'-methyl-1'H-[1,4'-bipyrazol]-4-yl)benzyl)-7H-purine-6-carboxamide

[1057] [ka]

[1058] The same procedure as in Example 87.3 was repeated 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 target compound (15.15 mg, 29%) as an off-white solid.

[1059] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.77 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 8.13 (d, J = 12.4 Hz, 2H), 7.82 (s, 1H), 7.52 (s, 1H), 7.40 (d, J = 10.2 Hz, 1H), 7.04 (d, J = 9.5 Hz, 1H), 4.59 (d, J = 5.5 Hz, 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). LC-MS, m / z 486 [M+H] + Example 129 129.1 3-Fluoro-5-((1-methylpiperidin-4-yl)amino)benzonitrile

[1060] [ka]

[1061] In the same manner as in Example 10.1, 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) were reacted at 120 °C to obtain the target compound (39 mg, 33%) as a white solid.

[1062] 1 H NMR (400 MHz, CD3OD) δ 6.70 (s, 1H), 6.61 - 6.57 (m, 2H), 2.86 (d, J = 8 Hz, 2H), 2.30 (s, 3H), 2.26 - 2.20 (m, 2H), 2.01 (d, J = 8 Hz, 2H), 1.52 - 1.49 (m, 2H). LC-MS, m / z 234 [M+H] + 129.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methylpiperidin-4-amine

[1063] [ka]

[1064] The same procedure as in Example 1.2 was repeated 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) to obtain the target compound (30 mg, 84%) in the form of a yellow syrup.

[1065] LC-MS, m / z 238 [M+H] + 129.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methylpiperidin-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[1066] [ka]

[1067] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (14 mg, 27%) as a white solid.

[1068] 1 H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 6.44 (s, 1H), 6.34 (d, J = 12 Hz, 1H), 6.24 (d, J = 12 Hz, 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). LC-MS, m / z 452 [M+H] + Example 130 130.1 3-Fluoro-5-(thiophen-3-ylamino)benzonitrile

[1069] [ka]

[1070] In the same manner as in Example 10.1, 3-bromo-5-fluorobenzonitrile (100 mg, 0.50 mmol), thiophene-3-amine oxalate (113 mg, 0.60 mmol), 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) were reacted at 100 °C to obtain the target compound (70 mg, 64%) as a yellow solid.

[1071] 1 H NMR (400 MHz, CD3OD) δ 7.41 - 7.39 (t, J = 4 Hz, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 6.94 - 6.90 (m, 2H), 6.79 (d, J = 8 Hz, 1H). LC-MS, m / z 219 [M+H]+ 130.2 N-(3-(aminomethyl)-5-fluorophenyl)thiophen-3-amine

[1072] [ka]

[1073] The same procedure as in Example 1.2 was repeated 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) to obtain the target compound (50 mg, 70%) in the form of a yellow syrup.

[1074] LC-MS, m / z 223 [M+H]+ 130.3 8-Cyclopentyl-N-(3-fluoro-5-(thiophen-3-ylamino)benzyl)-7H-purine-6-carboxamide

[1075] [ka]

[1076] The target compound (24 mg, 27%) was obtained as a white solid in the same manner as in Example 1.3 using 8-cyclopentyl-7H-purine-6-carboxylic acid (47 mg, 0.20 mmol), N-(3-(aminomethyl)-5-fluorophenyl)thiophen-3-amine (50 mg, 0.22 mmol), T3P (50 wt% solution in EtOAc, 393 mg), and DIPEA (138 μL).

[1077] 1 H NMR (400 MHz, dmso-d6) δ 13.19 (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 = 12 Hz, 1H), 6.55 (d, J = 8 Hz, 1H), 4.50 (d, J = 8 Hz, 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). LC-MS, m / z 437 [M+H]+ <Example 131> 131.1 (3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)phenyl)methanamine

[1078] [ka]

[1079] The same procedure as in Example 8.1 was repeated 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), NaOtBu (160 mg, 1.66 mmol), and toluene (1.5 mL) to obtain the target compound (35 mg, 11%) as a brown viscous syrup.

[1080] 1 H NMR (400 MHz, CDCl3) δ 7.00 - 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). LC-MS, m / z 304 [M+H] + 131.2 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)piperazin-1-yl)benzyl)-7H-purine-6-carboxamide

[1081] [ka]

[1082] The same procedure as in Example 1.3 was used with 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) to obtain the target compound (5 mg, 9%) as an off-white solid.

[1083] 1H NMR (400 MHz, CDCl3) δ 10.37 (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 = 10.4 Hz, 2H), 4.64 (d, J = 6.2 Hz, 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, 7.8 Hz, 2H), 1.97 - 1.85 (m, 2H), 1.83 - 1.72 (m, 2H). LC-MS, m / z 518 [M+H] + <Example 132> 132.1 tert-Butyl (3-fluoro-5-(1H-tetrazol-5-yl)benzyl)carbamate

[1084] [ka]

[1085] tert-Butyl (3-cyano-5-fluorobenzyl)carbamate (80 mg, 0.32 mmol), NaN (42 mg, 0.64 mmol), and NH Cl (34 mg, 0.64 mmol) were dissolved in DMF (3 mL) and stirred at 140 °C overnight. After the reaction was complete, the mixture was diluted with a small amount of HO, acidified with 1 N HCl (pH 5), and extracted three times with EA. The organic layer was dried over MgSO and concentrated to obtain the target compound (100 mg, crude) as a light brown solid.

[1086] LC-MS, m / z 294 [M+H] + 132.2 tert-Butyl (3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzyl)carbamate

[1087] [ka]

[1088] A mixture of tert-butyl (3-fluoro-5-(1H-tetrazol-5-yl)benzyl)carbamate (86 mg, 0.29 mmol), 4-fluorobenzoic acid (97 mg, 0.35 mmol), 1 M DCC (in DCM) (350 μL, 0.35 mmol), and 1,2-dichloroethane (3 mL) was reacted at 100 °C for 24 h. After the reaction was completed, the mixture was diluted with a small amount of HO and extracted three times with EA. The organic layer was dried over MgSO and concentrated. The resulting residue was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give the desired compound (74 mg, 65%) as a white solid.

[1089] LC-MS, m / z 388 [M+H] + 132.3 (3-Fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)methanamine trifluoroacetate

[1090] [ka]

[1091] The same procedure as in Example 25.4 was repeated using tert-butyl (3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzyl)carbamate (74 mg, 0.19 mmol), trifluoroacetic acid (1 mL), and DCM (2 mL) to obtain the target compound (98 mg, crude) as a light brown oil.

[1092] LC-MS, m / z 288 [M+H] + 132.4 8-Cyclopentyl-N-(3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)benzyl)-7H-purine-6-carboxamide

[1093] [ka]

[1094] The same procedure as in Example 87.3 was repeated using (3-fluoro-5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-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) to obtain the target compound (38 mg, 37%) as an off-white solid.

[1095] 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.93 (t, J = 6.1 Hz, 1H), 8.99 (s, 1H), 8.21 (dd, J = 8.7, 5.3 Hz, 2H), 8.05 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.57 - 7.42 (m, 3H), 4.68 (d, J = 6.0 Hz, 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). LC-MS, m / z 502 [M+H] + <Example 133> 4-((3-((8-cyclopentyl-7H-purine-6-carboxamido)methyl)-5-fluorophenyl)amino)benzoic acid

[1096] [ka]

[1097] 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 reacted 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 residue obtained after concentration was purified by silica gel column chromatography (MPLC) (5-15% MeOH in DCM) to obtain the target compound (16.2 mg, 49.0%) as a yellow solid.

[1098] 1 H NMR (400 MHz, CD3OD) δ8.96 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.08(d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 6.78 (d, J = 11.0 Hz, 1H), 6.72 (d, J = 9.4 Hz, 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). LC-MS, m / z 475 [M+H] + Example 134 134.1 3-((1,3,4-Oxadiazol-2-yl)amino)-5-fluorobenzonitrile

[1099] [ka]

[1100] 3-Cyano-5-fluorophenylboronic acid (0.2 g, 1.21 mmol) was dissolved in DCM (4.9 mL), followed by the addition of 1,3,4-oxadiazol-2-amine (0.206 g, 2.43 mmol), Cu(OAc) (0.220 g, 1.21 mmol), and TEA (338 μL, 2.43 mmol). After stirring at room temperature under air for 8 hours, the reaction mixture was filtered through a Celite pad and washed several times with EtOAc. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the desired compound (59.1 mg, 23.9%) as a white solid.

[1101] 1 H NMR (400 MHz, CD3OD) δ8.56 (s, 1H), 8.23 ​​(s, 1H), 7.79 - 7.73 (m, 1H), 7.71 (s, 1H), 7.19 (d, J = 7.1 Hz, 1H). LC-MS, m / z 205 [M+H] + 134.2 N-(3-(aminomethyl)-5-fluorophenyl)-1,3,4-oxadiazol-2-amine

[1102] [ka]

[1103] 3-((1,3,4-Oxadiazol-2-yl)amino)-5-fluorobenzonitrile (59 mg, 0.289 mmol) was dissolved in THF (2.9 mL), and then LAH solution (2.0 M in THF; 0.29 mL) was added at 0 °C. The mixture was allowed to react overnight at room temperature. The reaction mixture was cooled again to 0 °C, quenched by adding H2O, filtered through a Celite pad, and washed several times with EtOAc. The filtrate was washed with H2O, and the organic layer was dried over Na2SO4 and concentrated. The target compound (31.4 mg, 87.5%) was obtained as a yellow solid, which was used for the next reaction without further purification.

[1104] LC-MS, m / z 209 [M+H]+ 134.3 N-(3-((1,3,4-oxadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1105] [ka]

[1106] The same procedure as in Example 87.3 was repeated using 8-cyclopentyl-7H-purine-6-carboxylic acid (34.6 mg, 0.149 mmol), N-(3-(aminomethyl)-5-fluorophenyl)-1,3,4-oxadiazol-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) to obtain the target compound (1.4 mg, 2.2%) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ8.95 (s, 1H), 8.48 (s, 1H), 7.36 (d, J = 10.3 Hz, 1H), 7.31 (s, 1H), 6.83 (d, J = 9.6 Hz, 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 = 5.8 Hz, 2H), 1.77 (dd, J = 6.7, 4.9 Hz, 2H). LC-MS, m / z 423 [M+H] + Example 135 8-Cyclopentyl-N-(3-(cyclopentylamino)-5-fluorobenzyl)-7H-purine-6-carboxamide

[1107] [ka]

[1108] The target compound (13 mg, 38%) was obtained as a white solid in the same manner as in Example 1.3 using 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).

[1109] 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 6.42 (s, 1H), 6.31 (d, J = 12 Hz, 1H), 6.20 (d, J = 12 Hz, 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). LC-MS, m / z 423 [M+H]+ <Example 136> 136.1 3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzonitrile

[1110] [ka]

[1111] The same procedure as in Example 121.1 was repeated 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) (22 mg, 0.12 mmol), TEA (34 μL, 0.52 mmol), and acetonitrile (115 μL) / ethanol (6 μL) to obtain the target compound (10 mg, 38%) as a white solid.

[1112] 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 12 Hz, 1H), 7.30 (d, J = 8 Hz, 1H). LC-MS, m / z 221 [M+H]+ 136.2 N-(3-(aminomethyl)-5-fluorophenyl)-1,3,4-thiadiazol-2-amine

[1113] [ka]

[1114] The same procedure as in Example 1.2 was repeated 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) to obtain the target compound (7 mg, 69%) in the form of a yellow syrup.

[1115] LC-MS, m / z 225 [M+H]+ 136.3 N-(3-((1,3,4-thiadiazol-2-yl)amino)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1116] [ka]

[1117] The target compound (1.7 mg, 13%) was obtained as a white solid in the same manner 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).

[1118] 1H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.78 (s, 1H), 7.53 (d, J = 12 Hz, 1H), 7.33 (s, 1H), 6.83 (d, J = 8 Hz, 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). LC-MS, m / z 439 [M+H]+ Example 137 137.1 tert-Butyl (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-1-yl)benzyl)carbamate

[1119] [ka]

[1120] The same procedure as in Example 8.1 was repeated using 1-(4-fluorophenyl)-1,4-diazepam (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, 0.0082 mmol), NaOtBu (39.6 mg, 0.412 mmol), and toluene (1.03 mL) to obtain the target compound (16 mg, 19%) as a yellow solid.

[1121] 1H NMR (400 MHz, CDCl3) δ 6.94 (t, J = 8.7 Hz, 2H), 6.64 (dd, J = 9.0, 4.2 Hz, 2H), 6.39 (s, 1H), 6.29 (d, J = 9.7 Hz, 2H), 4.82 (s, 1H), 4.22 (d, J = 5.5 Hz, 2H), 3.67 - 3.54 (m, 4H), 3.40 (dd, J = 11.3, 5.8 Hz, 4H), 2.09 (p, J = 6.3 Hz, 2H), 1.47 (s, 9H). LC-MS, m / z 418 [M+H] + 137.2 (3-Fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-1-yl)phenyl)methanamine trifluoroacetate

[1122] [ka]

[1123] The same procedure as in Example 25.4 was used to obtain the target compound (21.8 mg, crude) as a yellow solid using tert-butyl (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-1-yl)benzyl)carbamate (15.5 mg, 0.037 mmol), trifluoroacetic acid (57 μL), and DCM (0.74 mL).

[1124] LC-MS, m / z 318 [M+H] + 137.3 8-Cyclopentyl-N-(3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-1-yl)benzyl)-7H-purine-6-carboxamide

[1125] [ka]

[1126] The same procedure as in Example 1.3 was repeated using 8-cyclopentyl-7H-purine-6-carboxylic acid (9.1 mg, 0.039 mmol), (3-fluoro-5-(4-(4-fluorophenyl)-1,4-diazepam-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) to obtain the target compound (3.1 mg, 16%) as an off-white solid.

[1127] 1 H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 6.93 (t, J = 8.7 Hz, 2H), 6.70 - 6.57 (m, 2H), 6.45 (s, 1H), 6.36 (dd, J = 21.1, 10.4 Hz, 2H), 4.61 (d, J = 6.1 Hz, 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). LC-MS, m / z 532 [M+H] + <Example 138> 138.1 tert-Butyl 3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1128] [ka]

[1129] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (12.2 mg, 0.017 mmol), 2M KCO (0.6 mL, 1.17 mmol), and 1,4-dioxane (2 mL) to obtain the target compound (77.94 mg, 65%) as a colorless, transparent oil.

[1130] LC-MS, m / z 360 [M+H] + 138.2 (3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine trifluoroacetate

[1131] [ka]

[1132] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (81 mg, crude).

[1133] LC-MS, m / z 260 [M+H] + 138.3 8-Cyclopentyl-N-(3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-7H-purine-6-carboxamide

[1134] [ka]

[1135] The same procedure as in Example 87.3 was repeated 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 target compound (54.52 mg, 53%) as a pale yellow solid.

[1136] 1 H NMR (400 MHz, , DMSO-d6) δ 13.17 (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 = 10.1 Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 4.68 (dt, J = 13.8, 6.9 Hz, 1H), 4.56 (d, J = 6.2 Hz, 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). LC-MS, m / z 474 [M+H] + Example 139 139.1 tert-Butyl 3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzylcarbamate

[1137] [ka]

[1138] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (12.2 mg, 0.017 mmol), 2M KCO (0.6 mL, 1.17 mmol), and 1,4-dioxane (2 mL) to obtain the target compound (107.22 mg, 85.8%) as a yellow oil.

[1139] LC-MS, m / z 374 [M+H] + 139.2 (3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorophenyl)methanamine trifluoroacetate

[1140] [ka]

[1141] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (56 mg, crude).

[1142] LC-MS, m / z 274 [M+H] + 139.3 N-(3-(1-cyclohexyl-1H-pyrazol-4-yl)-5-fluorobenzyl)-8-cyclopentyl-7H-purine-6-carboxamide

[1143] [ka]

[1144] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (39.38 mg, 56.3%) as a yellow solid.

[1145] 1 H NMR (400 MHz, , DMSO-d6) δ 13.17 (s, 1H), 9.74 (s, 1H), 8.96 (s, 1H), 8.25 (s, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 7.32 (d, J = 9.8 Hz, 1H), 6.98 (d, J = 9.6 Hz, 1H), 4.56 (d, J = 6.4 Hz, 2H), 4.12 (t, J = 11.4 Hz, 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). LC-MS, m / z 488 [M+H] + <Example 140> 140.1 tert-Butyl 3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1146] [ka]

[1147] The same procedure as in Example 4.1 was repeated 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), PdCl(dppf) (4.8 mg, 0.0066 mmol), 2M KCO (0.23 mL, 0.46 mmol), and 1,4-dioxane (1.5 mL) to obtain the target compound (14.82 mg, 31%) as a colorless, transparent oil.

[1148] LC-MS, m / z 362 [M+H] + 140.2 (3-Fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[1149] [ka]

[1150] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (15 mg, crude).

[1151] LC-MS, m / z 262 [M+H] + 140.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1152] [ka]

[1153] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (11.82 mg, 60.6%) as an off-white solid.

[1154] 1 H NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.44 (s, 1H), 7.22 (d, J = 9.5 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 5.10 - 4.98 (m, 1H), 4.68 (s, 2H), 4.12 (dd, J = 15.3, 7.8 Hz, 1H), 4.04 (d, J = 4.7 Hz, 2H), 3.91 (dd, J = 14.2, 8.4 Hz, 1H), 3.58 - 3.41 (m, 1H), 2.60 - 2.41 (m, 1H), 2.41 - 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). LC-MS, m / z 476 [M+H] + <Example 141> 141.1 tert-Butyl 3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1155] [ka]

[1156] The same procedure as in Example 25.3 was repeated 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) to obtain the target compound (58 mg, 44%) as a pale yellow solid.

[1157] LC-MS, m / z 375 [M+H] + 141.2 (3-Fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)phenyl)methanamine, trifluoroacetate

[1158] [ka]

[1159] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (57.3 mg, crude).

[1160] LC-MS, m / z 275 [M+H] + 141.3 8-Cyclopentyl-N-(3-fluoro-5-(1-(thiazol-4-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1161] [ka]

[1162] The same method as in Example 87.3 was used to obtain the target compound (57.46 mg, 79.7%) as a pale yellow solid 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).

[1163] 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.77 (t, J = 6.6 Hz, 1H), 9.22 (d, J = 2.0 Hz, 1H), 8.97 (s, 1H), 8.91 (s, 1H), 8.28 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J = 9.7 Hz, 1H), 7.06 (d, J = 9.3 Hz, 1H), 4.60 (d, J = 6.0 Hz, 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). LC-MS, m / z 489 [M+H] + <Example 142> 142.1 tert-Butyl (3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)carbamate

[1164] [ka]

[1165] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (53.3 mg, 18.9%) as a yellow solid.

[1166] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.30 (t, J = 5.4 Hz, 1H), 6.57 (d, J = 10.9 Hz, 2H), 6.45 (s, 1H), 6.30 (d, J = 11.4 Hz, 1H), 6.15 (d, J = 9.0 Hz, 1H), 5.81 (s, 1H), 4.08 (dd, J = 10.6, 5.4 Hz, 1H), 3.95 (d, J = 6.2 Hz, 2H), 3.55 (s, 3H), 1.37 (s, 9H). LC-MS, m / z 320 [M+H] + 142.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrrol-3-amine hydrochloride

[1167] [ka]

[1168] In the same manner as in Example 90.3, the target compound (12 mg, 74.9%) was obtained as a brown solid using tert-butyl (3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)carbamate (20 mg, 0.063 mmol) and 4 M HCl (in dioxane) (0.31 mL), and then subjected to the next reaction without separation or purification.

[1169] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 6.62 (d, J = 5.8 Hz, 3H), 6.45 (d, J = 10.2 Hz, 2H), 5.85 (s, 1H), 3.86 (d, J = 5.8 Hz, 2H), 3.55 (d, J = 5.3 Hz, 3H). LC-MS, m / z 220 [M+H] + 142.3 8-Cyclopentyl-N-(3-fluoro-5-((1-methyl-1H-pyrrol-3-yl)amino)benzyl)-7H-purine-6-carboxamide

[1170] [ka]

[1171] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (2.6 mg, 12.8%) as a yellow solid.

[1172] 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H), 6.34 (t, J = 11.5 Hz, 3H), 5.86 (d, J = 2.8 Hz, 1H), 4.54 (s, 2H), 3.55 (s, 3H), 3.52 - 3.47 (m, 1H), 2.20 (d, J = 8.0 Hz, 2H), 2.05 - 2.00 (m, 2H), 1.94 - 1.90 (m, 2H), 1.80 - 1.75 (m, 2H). LC-MS, m / z 434 [M+H] + <Example 143> 143.1 3-Iodothiophene 1-oxide

[1173] [ka]

[1174] 3-Iodothiophene (500 mg, 2.38 mmol) was dissolved in DCE (12 mL), and then 3-chloroperbenzoic acid (1.3 g, 5.95 mmol) was added and stirred at 90° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane) to obtain the target compound (116 mg, 23%) as a red oil.

[1175] 143.2 tert-Butyl 3-fluoro-5-(1-(1-oxidothiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate

[1176] [ka]

[1177] The same procedure as in Example 25.3 was repeated 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 target compound (29.0 mg, 23%) in the form of a brown solid.

[1178] LC-MS, m / z 390 [M+H] + 143.3 3-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-pyrazol-1-yl)thiophene 1-oxide trifluoroacetate

[1179] [ka]

[1180] The same procedure as in Example 25.4 was repeated using tert-butyl 3-fluoro-5-(1-(1-oxidethiophen-3-yl)-1H-pyrazol-4-yl)benzylcarbamate (28.08 mg, 0.072 mmol), TFA (0.3 mL), and DCM (1 mL) to obtain the target compound (29 mg, crude).

[1181] LC-MS, m / z 290 [M+H] + 143.4 8-Cyclopentyl-N-(3-fluoro-5-(1-(1-oxidothiophen-3-yl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1182] [ka]

[1183] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (9.7 mg, 27%) as a white solid.

[1184] 1H NMR (400 MHz, DMSO-d6) δ 13.16 (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 = 11.0 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 5.75 (s, 1H), 5.50 (d, J = 13.4 Hz, 1H), 5.28 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 5.9 Hz, 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). LC-MS, m / z 504 [M+H] + <Example 144> 144.1 3-Fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzonitrile

[1185] [ka]

[1186] The same procedure as in Example 10.1 was repeated using 3-bromo-5-fluorobenzonitrile (1 g, 5.00 mmol), 1-methyl-1H-pyrazol-4-amine (426 μL, 5.00 mmol), Pd(dba) (91.6 mg, 0.100 mmol), Xantphos (145 mg, 0.250 mmol), KCO (1.59 g, 11.5 mmol), and dioxane (31 mL) to obtain the target compound (0.545 g, 50.4%) as a white solid.

[1187] 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.77 (s, 1H), 7.35 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 6.74 (d, J = 11.8 Hz, 1H), 3.80 (s, 3H). LC-MS, m / z 217 [M+H] + 144.2 N-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-amine

[1188] [ka]

[1189] The same procedure as in Example 7.2 was repeated 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) to obtain the target compound (0.518 g, 94.1%) as a brown solid.

[1190] 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.51 (s, 1H), 6.37 (d, J = 9.3 Hz, 1H), 6.28 (d, J = 11.8 Hz, 1H), 3.78 (s, 3H), 3.56 (s, 2H). LC-MS, m / z 221 [M+H] + 144.3 8-(3,3-Difluorocyclopentyl)-N-(3-fluoro-5-((1-methyl-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide

[1191] [ka]

[1192] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (29 mg, 27.6%) as a yellow solid.

[1193] 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 9.71 (s, 1H), 9.01 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.29 (d, J = 0.5 Hz, 1H), 6.59 (s, 1H), 6.42 (d, J = 9.4 Hz, 1H), 6.34 (dt, J = 11.8, 2.2 Hz, 1H), 4.44 (d, J = 6.3 Hz, 2H), 3.81 (dd, J = 8.7, 5.9 Hz, 1H), 3.77 (s, 3H), 2.70 - 2.59 (m, 2H), 2.36 - 2.27 (m, 2H), 2.26 - 2.09 (m, 2H). LC-MS, m / z 471 [M+H] + <Example 145> 145.1 tert-Butyl 3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzylcarbamate

[1194] [ka]

[1195] The same procedure as in Example 25.3 was repeated 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 target compound (7.27 mg, 18.95%) as a colorless, transparent oil.

[1196] LC-MS, m / z 373 [M+H] + 145.2 (3-Fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)phenyl)methanamine trifluoroacetate

[1197] [ka]

[1198] The same procedure as in Example 25.4 was repeated 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) to obtain the target compound (8 mg, crude).

[1199] LC-MS, m / z 275 [M+H] + 145.3 8-Cyclopentyl-N-(3-fluoro-5-(1-phenyl-d5-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide

[1200] [ka]

[1201] The same procedure as in Example 87.3 was repeated 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) to obtain the target compound (7.24 mg, 76.3%) as an off-white solid.

[1202] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.77 (t, J = 5.6 Hz, 1H), 9.06 (s, 1H), 8.97 (s, 1H), 8.24 (s, 1H), 7.61 (s, 1H), 7.49 (d, J = 9.9 Hz, 1H), 7.07 (d, J = 9.3 Hz, 1H), 4.61 (d, J = 6.4 Hz, 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). LC-MS, m / z 487 [M+H] + <Example 146> 146.1 tert-Butyl 3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)benzylcarbamate

[1203] [ka]

[1204] The same proced...

Claims

1. A compound represented by the following chemical formula I, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In Formula I, X is C or N; R １ is hydrogen, amino-C １－３ Alkyl, C ３－８ monocyclic or bicyclic cycloalkyl (wherein hydrogen is hydrogen or deuterium), or R ｓ and R １ represents one or more independent R １ａ may or may not be substituted with Here, the R １ａ is C １－５ Alkyl, halogen, oxo, or —C(O)OR １ｂ and R １ｂ is hydrogen, C １－３ alkyl, or arylalkyl; R ２ is hydrogen, C １－３ Alkyl or tri C １－３ Alkyl-silyl-C １－３ Alkoxy-C １－３ is alkyl, R ３ is hydrogen, C １－３ alkyl or halogen; R ４ is hydrogen or C １－３ is alkyl, p and q are each independently an integer of 0 or 1; When p is 1, R ５ａ and R ５ｂ are each independently hydrogen or C １－３ alkyl or R ５ａ and R ５ｂ are connected to each other to form C ３－６ forming a ring of R ６ is hydrogen or halogen, R ７ is hydrogen, halogen, R ｓ , R ｕ , —NH-aryl, —NH-cycloC ３－７ Alkyl, —NHR ｓ , -NHR ｕ , or -NHC(O)R ｕ and R ８ is hydrogen, halogen, or a 4- to 6-membered heteroaryl containing 1 to 3 N; The R ７ and R ８ are, independently of each other, one or more independent R ｍ may or may not be substituted with The R ｍ is 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 hydrogen or deuterium), arylalkyl, R ｕ , or R ｓ and R ｍ represents one or more independent R ｎ may or may not be substituted with The R ｎ is C １－３ Alkyl, C １－３ Alkylsulfonyl, C １－３ alkoxy, halogen, cyano, haloalkyl, carbamoyl, carboxyl, acetyl, aryl, arylalkyl, oxide, or alkylcarboxyl-(8-cycloalkyl-7H-carboxamido)-alkyl; R ９ and R １０ are, independently of each other, hydrogen or halogen, The R ｓ is a 4- to 8-membered saturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O; The R ｕ is a 4- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S.

2. The R １ is hydrogen, aminomethyl, cyclobutyl, cyclopentyl (wherein hydrogen is protium or deuterium), spiro[2.3]hexanyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, pyrrolidinyl, tetrahydrofuranyl, or piperidinyl; The R １ａ is methyl, propyl, isopropyl, fluoro, oxo, —C(O)OH, —C(O)O-methyl, or —C(O)O-benzyl, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof according to claim 1.

3. The R ２ The compound according to claim 1, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof, wherein is hydrogen, methyl, or trimethyl-silyl-ethoxy-methyl.

4. The R ３ The compound of claim 1, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof, wherein is hydrogen, methyl, ethyl, or chloro.

5. The R ４ The compound of claim 1, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

6. The R ５ａ and R ５ｂ are each independently hydrogen or methyl, or ５ａ and the R ５ｂ are linked together to form a cyclopropyl, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

7. The R ６ 2. The compound of claim 1, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

8. The R ７ is hydrogen, Br, piperazinyl, diazepanyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, isothiazolyl, triazolyl, oxadiazolyl, -NH-phenyl, -NH-cyclopentyl, -NH-piperidinyl, -NH-pyrrolyl, -NH-thiophenyl, -NH-pyrazolyl, -NH-isoxazolyl, -NH-oxadiazolyl, -NH-thiadiazolyl, -NH-pyridinyl, or -NHC(O)-pyrazolyl, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof according to claim 1.

9. The R ８ 2. The compound of claim 1, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, fluoro, chloro, or pyrazolyl.

10. The R ｍ is methyl (wherein hydrogen is hydrogen or deuterium), methoxy, sulfonyl, amino, fluoro, chloro, cyano, trifluoromethyl, difluoroethyl, trifluoroethyl, carbamoyl, carboxyl, cyclopentyl, cyclohexyl, phenyl (wherein hydrogen is hydrogen or deuterium), benzyl, thiophenyl, furanyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, or tetrahydrofuranyl; The R ｎ is methyl, ethyl, methylsulfonyl, methoxy, fluoro, chloro, iodo, bromo, cyano, trifluoromethyl, carbamoyl, carboxyl, acetyl, phenyl, benzyl, oxide, or methylcarboxyl-(8-cyclopentyl-7H-purine-6-carboxamido)-ethyl, or a hydrate, solvate, prodrug, isomer, or pharmaceutically acceptable salt thereof according to claim 1.

11. The R ９ 2. The compound of claim 1, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, fluoro, or chloro.

12. The R １０ 2. The compound of claim 1, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or fluoro.

13. The compound according to claim 1, wherein the compound represented by chemical formula (I) is any one selected from the group consisting of the following compounds, a hydrate thereof, a solvate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof: [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-(thiophen-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]hexan-3-yl)-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [78] 8-(bicyclo[3.1.0]hexan-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]heptan-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]heptan-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]hexan-3-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [114] 8-(bicyclo[2.2.1]heptan-2-yl)-N-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzyl)-7H-purine-6-carboxamide, [115] 8-(bicyclo[2.1.1]hexan-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-(thiophen-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-(isoxazol-3-ylamino)benzyl)-7H-purine-6-carboxamide, [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'-bipyrazol]-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-oxadiazol-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-oxadiazol-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-diazepam-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-oxidothiophen-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-d ５ -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-d ５ )-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-d ３ )-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, [152] 8-(3,3-difluorocyclopentyl)-N-(3-fluoro-5-((1-(methyl-d ３ )-1H-pyrazol-4-yl)amino)benzyl)-7H-purine-6-carboxamide, and [153] 8-(cyclopentyl-2,2,3,3,4,4,5,5-d ８ )-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 1 alpha) or VEGF (Vascular Endothelial Growth Factor), comprising the 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 as an active ingredient.

15. The pharmaceutical composition according to claim 14, wherein the prevention or treatment of the HIF-1α or VEGF-related disease is achieved by inhibiting angiogenesis.

16. The pharmaceutical composition according to claim 15, wherein the angiogenesis is inhibited by inhibiting HIF-1α expression or inhibiting VEGF expression.

17. The HIF-1α or VEGF-related disease is selected from the group consisting of stroke, brainstem 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, large intestine cancer, esophageal cancer, small intestine cancer, anal cancer, colon cancer, skin cancer, fallopian tube carcinoma, endometrial carcinoma, uterine cancer, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, oral cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, ureter cancer, splenic cell carcinoma, renal pelvis carcinoma, medulloblastoma, neuroblastoma, brain tumor, central nervous system tumor, melanoma, non-small cell lung cancer, lymphoma, and 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 dental cyst, endometriosis, uterine sclerosis, ovarian hypertension, ovarian hyperactivity, uterine dysfunction, warts, scar keloid, allergic edema, atherosclerosis, peritoneal sclerosis, cardiac dysfunction, amyotrophic lateral sclerosis, obesity, rheumatoid arthritis, synovitis, osteochondral destruction, malignant fibrous histiocytoma of bone, osteomyelitis, pannus formation, liver fibrosis, pulmonary fibrosis, fibrosis, NASH (non-alcoholic steatohepatitis) hepatitis), pneumonia, asthma, rhinitis, pulmonary hypertension, ischemic acute kidney injury, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis, microvascular disease, organ transplant rejection, glomerulopathy, inflammation, neurodegenerative diseases, nicotine poisoning-related vascular disease, chronic kidney disease, retinopathy of prematurity, diabetic retinopathy, corneal transplant rejection, ischemic retinopathy, erythroderma, proliferative retinopathy, psoriasis, hemophilic joints, keloids, wound granulation, vascular adhesion, autoimmune diseases, angiofibroma, retrolental fibroplasia, cataract, glaucoma, macular degeneration, age-related macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, neovascular glaucoma 15. The pharmaceutical composition according to claim 14, wherein the therapeutic agent is one or more selected from the group consisting of inflammatory bowel disease, neovascular macular degeneration, retinal artery occlusion, retinal vein occlusion, retinoma, optic nerve hypothalamic glioma, rhabdomyosarcoma, tissue sarcoma, inflammation, corneal ulcer, proliferative vitreoretinopathy, liver cirrhosis, asthma, periodontal disease, allergic dermatitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' ophthalmopathy, leukomalacia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and Behcet's disease.

18. The pharmaceutical composition according to claim 14, wherein the HIF-1α or VEGF-related disease is an angiogenic eye disease.

19. 19. The pharmaceutical composition according to claim 18, wherein the angiogenic ocular disease is one or more 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. 19. The pharmaceutical composition of claim 18, wherein the neovascular eye disease is macular degeneration.

21. A dosage form comprising the compound of 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, and a pharmaceutically acceptable excipient.

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