Novel heterocyclic compound and pharmaceutical composition for inhibiting autotaxin comprising same

Abstract

The present invention provides: a novel heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating diseases associated with autotaxin activity, comprising the same as an active ingredient. The heterocyclic compound according to the present invention exhibits excellent inhibitory activity against autotaxin, and thus can be used for treating and preventing diseases associated with autotaxin inhibition. The compounds can be used for treating diseases such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancers and cancer metastases, ocular diseases, chronic pruritus in cholestatic and other forms, and acute or chronic organ transplant rejection.

Description

Technical Field

[0001] The present invention relates to heterocyclic compounds, and more particularly, to novel heterocyclic compounds and pharmaceutical compositions containing the same for autotaxin inhibition. Background Art

[0002] Autotaxin (ATX), also known as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2), is a secreted enzyme that is essential for the production of the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Therefore, LPA levels in plasma and ascites are correlated with ATX activity.

[0003] Plasma LPA is a bioactive lipid that affects the migration, proliferation and survival of various cell types. In addition, the ATX-LPA signaling process is involved in the physiological and pathophysiological functions of various diseases, including nervous system function, vascular development, cardiovascular physiology, tissue regeneration, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis and obesity and / or other metabolic diseases (e.g., diabetes).

[0004] Thus, increased ATX activity and increased LPA levels, altered LPA receptor expression and altered responses to LPA can be associated with the initiation, progression and / or outcome of a variety of pathophysiological diseases involving the ATX / LPA signaling pathway. In particular, it is known to be associated with cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases (e.g., idiopathic pulmonary fibrosis (IPF)) and thrombosis. Therefore, in order to treat these diseases, it is necessary to reduce the level of LPA and / or the level of autotaxin (ATX) that induces LPA. Summary of the invention

[0005] Problem to be solved

[0006] The problem to be solved by the present invention is to provide an autotaxin inhibitory compound having a novel structure and showing excellent inhibitory activity against autotaxin.

[0007] Furthermore, the problem to be solved by the present invention is to provide a pharmaceutical composition for inhibiting autotaxin, the pharmaceutical composition comprising an autotaxin inhibitory compound having the novel structure.

[0008] Furthermore, the problem to be solved by the present invention is to provide a method for inhibiting autotaxin using the autotaxin inhibitory compound having the novel structure and treating and preventing diseases caused by the autotaxin.

[0009] In addition, the problem to be solved by the present invention is to provide the use of the autotaxin inhibitory compound with a novel structure for inhibiting autotaxin and correspondingly treating diseases.

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

[0011] Means of solving the problem

[0012] In order to solve the above problems, according to one aspect of the present invention, there is provided a heterocyclic compound represented by the following formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0013] <Formula 1>

[0014]

[0015] In the above formula,

[0016] X is aryl; a fused bicyclic ring in which an aryl ring is fused to a non-aromatic cycloalkyl ring; a fused bicyclic ring in which an aryl ring is fused to a non-aromatic heterocyclic ring having 1 to 3 Os; a fused bicyclic ring in which a heteroaryl ring having 1 to 3 Ns is fused to a non-aromatic cycloalkyl ring, wherein X is fused to a non-aromatic heterocyclic ring via one or more independent R x substituted or unsubstituted,

[0017] R x C 1-4 Alkoxy or halogen,

[0018] p is an integer from 0 to 2,

[0019] R N is hydrogen or C 1-4 alkyl,

[0020] A is a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O, wherein A is R a substituted or unsubstituted,

[0021] R a C 1-4 alkyl,

[0022] L is -(CH2) 1-5 CO-; -(CHCH) 1-2 CO-; or a 5-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from N and O,

[0023] Y Ring through R y substituted or unsubstituted,

[0024] R y C 1-4 Alkyl or halogen,

[0025] m is 0 or 1,

[0026] B is cyano; OH; COOH; CH2COOH; sulfonyl; sulfonate (-O-SO2-); or a 5- to 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from N and O, wherein B is R b or oxo (O) substituted or unsubstituted,

[0027] Where R b C 1-4 Alkyl, C 1-4 Haloalkyl, amino, or C 1-4 Alkyl pivalate.

[0028] According to another aspect of the present invention, provided is a pharmaceutical composition for preventing or treating a disease associated with autotaxin activity, the pharmaceutical composition comprising a heterocyclic compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] According to another aspect of the present invention, provided is a method for inhibiting autotaxin and preventing or treating a disease caused by the autotaxin using a heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0030] According to another aspect of the present invention, there is provided use of a heterocyclic compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof for inhibiting autotaxin and preventing or treating a disease caused by autotaxin.

[0031] According to another aspect of the present invention, provided is a pharmaceutical composition comprising a heterocyclic compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0032] Beneficial Effects

[0033] It was found that the novel heterocyclic compounds of the present invention exhibit excellent inhibitory activity against autotaxin.

[0034] Therefore, the novel heterocyclic compounds of the present invention can be usefully used for the treatment and prevention of diseases associated with the inhibition of autotaxin, such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0035] The effects of the present invention are not limited to the above effects but should be understood to include all effects that can be inferred from the composition of the present invention or the description of the present invention as recorded in the claims of this patent. DETAILED DESCRIPTION

[0036] In the present specification, autotaxin (ATX) is a secreted enzyme that plays an important role in the production of lysophosphatidic acid (LPA), also known as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity, which converts lysophosphatidylcholine (LPC) into LPA. Therefore, LPA levels in plasma and ascites are correlated with ATX activity.

[0037] The present invention provides a heterocyclic compound represented by the following formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0038] <Formula 1>

[0039]

[0040] In the above formula,

[0041] X is aryl; a fused bicyclic ring in which an aryl ring is fused to a non-aromatic cycloalkyl ring; a fused bicyclic ring in which an aryl ring is fused to a non-aromatic heterocyclic ring having 1 to 3 Os; a fused bicyclic ring in which a heteroaryl ring having 1 to 3 Ns is fused to a non-aromatic cycloalkyl ring, wherein X is fused to a non-aromatic heterocyclic ring via one or more independent R x substituted or unsubstituted,

[0042] R x C 1-4 Alkoxy or halogen,

[0043] p is an integer from 0 to 2,

[0044] R N is hydrogen or C 1-4 alkyl,

[0045] A is a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O, wherein A is R a substituted or unsubstituted,

[0046] R a C 1-4 alkyl,

[0047] L is -(CH2) 1-5 CO-; -(CHCH) 1-2 CO-; or a 5-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from N and O,

[0048] Y Ring R y substituted or unsubstituted,

[0049] R y C 1-4 Alkyl or halogen,

[0050] m is 0 or 1,

[0051] B is cyano; OH; COOH; CH2COOH; sulfonyl; sulfonate (-O-SO2-); or a 5- to 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from N and O, wherein B is R b or oxo (O) substituted or unsubstituted,

[0052] Where R b C 1-4 Alkyl, C 1-4 Haloalkyl, amino, or C 1-4 Alkyl pivalate.

[0053] In one embodiment, X may be one selected from phenyl, indanyl, benzodioxolyl, dihydro-cyclopentylpyrazinyl, and dihydro-cyclopentylpyridinyl.

[0054] In one embodiment, R x It may be one selected from the group consisting of a methoxy group, F, Cl, and Br.

[0055] In one embodiment, R N It may be hydrogen or methyl.

[0056] In one embodiment, A may be selected from pyridine, pyrimidine, pyrazine and One of the oxadiazoles.

[0057] In one embodiment, R a It may be methyl.

[0058] In one embodiment, L can be selected from -(CH2)2CO-, -(CH2)3CO-, -(CH)2CO-, dihydroisocyanate Azolyl, iso Azolyl and One of the oxadiazole groups.

[0059] In one embodiment, R y It can be methyl or F.

[0060] In one embodiment, B can be selected from OH, cyano, carboxyl, carboxymethyl, sulfonyl, sulfonate, imidazole, triazole, tetrazolyl, Oxazolyl, One of oxadiazolone and morpholino.

[0061] In one embodiment, R b The methyl group may be one selected from the group consisting of a methyl group, a difluoromethyl group, a trifluoromethyl group, an amino group, and a methylpivalate group.

[0062] Representative examples of heterocyclic compounds according to the present invention are as follows:

[0063] [1] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0064] [2] (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0065] [3] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0066] [4] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0067] [5] (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0068] [6] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine,

[0069] [7] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine,

[0070] [8] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine,

[0071] [9] (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[0072]

[10] 1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[0073]

[11] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[0074]

[12] (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0075]

[13] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0076]

[14] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine,

[0077]

[15] methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylate,

[0078]

[16] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[0079]

[17] 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-4-yl oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0080]

[18] 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0081]

[19] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0082]

[20] (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[0083]

[21] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine,

[0084]

[22] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylic acid,

[0085]

[23] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1,3,4- oxadiazol-2(3H)-one,

[0086]

[24] methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetate,

[0087]

[25] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetic acid,

[0088]

[26] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-ol,

[0089]

[27] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl methanesulfonate,

[0090]

[28] 5-(5-(3-(1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0091]

[29] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0092]

[30] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0093]

[31] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0094]

[32] N-(3,5-dichlorophenethyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0095]

[33] N-(3,5-difluorobenzyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0096]

[34] (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one,

[0097]

[35] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0098]

[36] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0099]

[37] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0100]

[38] 5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0101]

[39] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0102]

[40] (E)-1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one,

[0103]

[41] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0104]

[42] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0105]

[43] 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisocyanate oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0106]

[44] 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[0107]

[45] 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0108]

[46] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-sulfonamide,

[0109]

[47] methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylate,

[0110]

[48] ​​5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine,

[0111]

[49] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-ol,

[0112]

[50] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylic acid,

[0113]

[51] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0114]

[52] methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetate,

[0115]

[53] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetic acid,

[0116]

[54] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine,

[0117]

[55] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl methanesulfonate,

[0118]

[56] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0119]

[57] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carbonitrile,

[0120]

[58] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0121]

[59] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[0122]

[60] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine,

[0123]

[61] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0124]

[62] (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0125]

[63] (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0126]

[64] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0127]

[65] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0128]

[66] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2(3H)-one,

[0129]

[67] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[0130]

[68] 5-(5-(3-(1H-tetrazolyl-5-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0131]

[69] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0132]

[70] (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0133]

[71] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0134]

[72] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0135]

[73] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0136]

[74] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine,

[0137]

[75] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0138]

[76] 5-(5-(3-(1H-imidazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0139]

[77] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine,

[0140]

[78] (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one,

[0141]

[79] 5-(5-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0142]

[80] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0143]

[81] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-morpholinoazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0144]

[82] (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one,

[0145]

[83] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0146]

[84] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0147]

[85] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-amine,

[0148]

[86] (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[0149]

[87] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine,

[0150]

[88] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine,

[0151]

[89] N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine,

[0152]

[90] 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazol-2-yl)butan-1-one,

[0153]

[91] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[0154]

[92] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine, and

[0155]

[93] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine.

[0156] Unless otherwise defined, the present specification uses the following definitions when defining the compounds of Formula 1.

[0157] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon, preferably C1-10 Alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like.

[0158] The term "alkylene" refers to a divalent functional group derived from an alkyl group (preferably having 1 to 10 carbon atoms), but is not limited thereto. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0159] The term "cycloalkyl" refers to a partially or fully saturated monocyclic or condensed ring hydrocarbon, preferably C 3-10 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexynyl, and the like.

[0160] The term "hydroxy" or "hydroxyl" is defined as -OH, and unless otherwise defined, the term "alkoxy" means an alkyloxy group (a group in which the hydrogen atom of the hydroxy group is replaced by 1 to 10 alkyl atoms).

[0161] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0162] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0163] The term "heteroatom" means N, O or S.

[0164] The term "aryl" means an aromatic hydrocarbon, including polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused to one or more other rings, preferably C 5-12 Aryl, more preferably C 5-10 Aryl. For example, aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0165] The term "heteroaryl" or "aromatic heterocycle" means a ring containing one or more heteroatoms selected from N, O and S as ring atoms, and which may be combined with benzo or C 3-8 A 3- to 12-membered, more preferably a 5- to 10-membered aromatic hydrocarbon having a cycloalkyl-fused monocyclic or fused ring. For example, heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, Oxazolyl, iso Oxazolyl, tetrazolyl, indolyl, indazolyl, iso Azolyl, oxazolyl, thiazolyl, isothiazolyl, furyl, benzofuranyl, thienyl, benzothiazolyl, benzo oxazolyl, benzimidazolyl, quinolyl, isoquinolyl, etc. In addition, the heteroaryl group includes a group in which a heteroaryl ring is fused with a cycloalkyl or a non-aromatic heterocyclic ring, for example, dihydrocyclopentylpyrazinyl, etc.

[0166] Non-aromatic heterocycle is a non-aromatic carbocyclic ring containing one or more heteroatoms (e.g. nitrogen, oxygen or sulfur) in the ring. The ring can be 5-, 6-, 7- or 8-membered and / or can be fused with another ring (e.g. cycloalkyl or aromatic ring). The example of such compound includes 3-1H-benzimidazol-2-one, 3-1-alkyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted sulfadiazinyl, 1-phthalimidinyl, benzoic acid, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzooxolane, benzothiolane and benzothiane, etc.

[0167] Arylalkyl, alkylaryl and heteroarylalkyl refer to groups formed by combining an aryl group with an alkyl group or a heteroaryl group with an alkyl group as defined above, and examples thereof include, but are not limited to, benzyl, thephenylmethyl and pyrimidinylmethyl groups.

[0168] The compound represented by Chemical Formula 1 according to the present invention can be manufactured and used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts to promote in vivo absorption or increase solubility, so the prodrugs, hydrates, solvates and pharmaceutically acceptable salts also fall within the scope of the present invention. In addition, the compound represented by Chemical Formula 1 has chiral carbon, so there are stereoisomers thereof, and such stereoisomers are also included in the scope of the present invention.

[0169] The term "prodrug" refers to a substance that is converted into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they can be biologically active by oral administration, while the parent drug may not be. Prodrugs can also have improved solubility than the parent drug in a pharmaceutical composition. For example, a prodrug can be a hydrolyzable ester and a pharmaceutically acceptable salt thereof in vivo of a compound according to the present invention. Another example of a prodrug can be a short peptide (polyamino acid) connected to an acidic group, which is metabolized to display the active site of the peptide.

[0170] The term "hydrate" refers to a compound of the present invention or a salt thereof that has a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0171] The term "solvate" refers to a compound of the invention or a salt thereof having a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefore include those that are volatile, non-toxic and / or suitable for administration to humans.

[0172] The term "isomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different in structure or space. Such isomers include structural isomers (e.g., tautomers) and stereoisomers (e.g., R or S isomers with an asymmetric carbon center) and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0173] The term "pharmaceutically acceptable salt" means a salt form of a compound that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. Pharmaceutically acceptable salts include acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylates include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine. The compound of Formula 1 according to the present invention can be converted into a salt thereof by a conventional method.

[0174] In addition, the present invention provides a method for preparing a compound of Formula 1. The synthetic methods of Examples 1 to 93 are exemplified as methods for preparing a compound of Formula 1 of the present invention, and the synthetic methods of Examples 1 to 93 do not limit the method for preparing a compound of Formula 1 according to the present invention. The synthetic methods of Examples 1 to 93 are merely examples, and it is obvious that they can be easily modified by those skilled in the art according to specific substituents.

[0175] The present invention also provides a pharmaceutical composition for preventing or treating a disease associated with the activity of autotaxin, which comprises the heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt as an active ingredient.

[0176] The present invention also provides a method for inhibiting autotaxin and preventing or treating a disease caused by the autotaxin by administering the heterocyclic compound, its hydrate, its solvate or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0177] The present invention also provides the use of the heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt for inhibiting autotaxin and thereby preventing or treating diseases.

[0178] As a result of measuring the autotaxin protein inhibitory activity of the heterocyclic compound of the present invention, it was determined that the compound exhibited excellent autotaxin inhibitory activity even at a very low compound concentration (nM level), and thus it can be used for treating and preventing diseases associated with autotaxin activity.

[0179] In one embodiment, the disease associated with the activity of the autotaxin factor can be selected from fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0180] The above fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, nonalcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, skin fibrosis, glomerulosclerosis, myocardial fibrosis and vascular fibrosis.

[0181] The above inflammatory diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma.

[0182] The above autoimmune diseases include, but are not limited to, multiple sclerosis and scleroderma.

[0183] The above respiratory diseases include but are not limited to asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS).

[0184] The above cardiovascular diseases include but are not limited to arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, arrhythmia, stroke and other vascular damage.

[0185] The above metabolic diseases include but are not limited to obesity and diabetes.

[0186] The above cancers and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion.

[0187] The above eye diseases include, but are not limited to, proliferative and non-proliferative retinopathy, diabetic retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury and glaucoma.

[0188] The present invention also provides a pharmaceutical composition or preparation comprising the heterocyclic compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

[0189] The above additives may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants or flavoring agents, and may be formulated into oral preparations such as tablets, capsules, powders, granules and suspensions, emulsions or syrups according to conventional methods; or parenteral preparations such as external solutions, external suspensions, external emulsions, gels (ointments, etc.), inhalants, sprays and injections. The preparations may be formulated into various forms, such as single-dose or multi-dose dosage forms.

[0190] The pharmaceutical composition of the present invention may include excipients (such as lactose and corn starch), lubricants (such as magnesium stearate), emulsifiers, suspending agents, stabilizers and isotonic agents. If necessary, sweeteners and / or flavoring agents may be added.

[0191] The pharmaceutical composition of the present invention can be applied to mammals such as livestock and humans by various routes such as oral, percutaneous, subcutaneous, intramuscular, intravenous, intraperitoneal, rectal, intrauterine, intradural or intracerebral injection and topical administration. Therefore, the composition of the present invention can be prepared in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral administration, carriers (such as lactose and corn starch) and lubricants (such as magnesium stearate) can usually be added. In the case of capsules for oral administration, lactose and / or dry corn starch can be used as diluents. When oral aqueous suspensions are needed, active ingredients can be combined with emulsifiers and / or suspending agents. If necessary, specific sweeteners and / or flavorings can be added. In the case of intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of active ingredients are usually prepared, and the pH of the solution should be appropriately adjusted and buffered. In the case of intravenous administration, the total concentration of the solute should be adjusted to give isotonicity to the preparation. The composition according to the invention may be in the form of an aqueous solution comprising a pharmaceutically acceptable carrier, for example saline at a pH of 7.4. The solution may be introduced into the patient's intramuscular blood stream by local injection.

[0192] The dosage of the active ingredient included in the pharmaceutical composition of the present invention varies according to the patient's symptoms and body weight, the degree of the disease, the form of the active ingredient, the route and time of administration, and can be appropriately adjusted according to the patient. For example, the active ingredient can be administered at a dosage of 0.0001mg / kg to 1000mg / kg per day, preferably 0.01mg / kg to 100mg / kg, and the administration can be administered once a day or divided into several times. In addition, based on the gross weight of the composition, the pharmaceutical composition of the present invention can include the active ingredient in a weight percentage of 0.001% to 90%.

[0193] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock and humans by various routes such as orally, percutaneously, intraperitoneally, perrectally, or by intravenous, intramuscular, subcutaneous, intrauterine or intracerebroventricular injection.

[0194] Hereinafter, the present invention will be described in more detail through preparation examples, embodiments and test examples. However, the following preparation examples, embodiments and test examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0195] Preparation Example 1. Preparation of (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0196] Step 1: Preparation of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0197]

[0198] Pivalic acid azidomethyl ester (0.2 g, 1.27 mmol) and tert-butyl 3-ethynyl-1-pyrrolidinecarboxylate (0.249 g, 1.27 mmol) were dissolved in THF (2.5 mL) / DW (2.5 mL), and CuOAc (15.6 mg, 0.127 mmol) and NaOAc (0.313 g, 3.82 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. DW was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated, and the residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (0.23 g, 50.4%) as a colorless oil.

[0199] 1 H NMR (400MHz, DMSO-d6) δ7.58 (s, 1H), 6.20 (s, 2H), 3.84-3.78 (m, 1H), 3.52 (dd , J=15.6, 7.8Hz, 2H), 3.46-3.37 (m, 2H), 2.31 (s, 2H), 1.46 (s, 9H), 1.19 (s, 9H)

[0200] Step 2: Preparation of (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0201]

[0202] To a solution of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (0.222 g, 0.630 mmol) in DCM (6.3 mL) was added TFA (2.1 mL) at 0°C and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (quantitatively), which was used in the next step reaction without purification. (180 mg).

[0203] 1 H NMR (400MHz, CDCl3) δ7.76 (s, 1H), 6.20 (s, 2H), 3.75 (s, 2H), 2.52 (s, 5H), 1.19 (s, 9H)

[0204] Preparation Example 2. Preparation of 4-(pyrrolidin-3-yl)-1H-1,2,3-triazole trifluoroacetic acid

[0205] Step 1: tert-Butyl 3-(1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0206]

[0207] A mixture of tert-butyl 3-ethynyl-1-pyrrolidinecarboxylate (0.3 g, 1.54 mmol), TMSN3 (221 μL, 1.69 mmol), CuI (29.3 mg, 0.154 mmol) and DMF / MeOH (5.1 mL / 0.67 mL) was stirred at 80° C. overnight. After the reaction mixture was concentrated, DW was added and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated, and the obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (0.154 g, 42.0%) as a light green oil.

[0208] 1 H NMR (400MHz, CDCl3) δ7.54 (s, 1H), 3.91-3.77 (m, 1H), 3.65-3.35 (m, 4H), 2.37-2.04 (m, 2H), 1.47 (s, 9H)

[0209] Step 2: Preparation of 4-(pyrrolidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0210]

[0211] To a solution of tert-butyl 3-(1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (0.150 g, 0.629 mmol) in DCM (6.3 mL) was added TFA (2.1 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound as a yellow oil (quantitative), which was used in the next step reaction without purification (148 mg).

[0212] Preparation Example 3. 5-(2-((2,3-hydrogen-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Preparation of oxadiazole-2(3H)-one

[0213] Step 1: Preparation of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate

[0214]

[0215] 2,3-Dihydro-1H-inden-2-amine (1 g, 7.5 mmol) was dissolved in anhydrous 1,4-dihydro- 1.26 g, 6.76 mmol) was added to 1.5 mL of 4-nitropropane (25 mL), and N,N-diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (1.26 g, 6.76 mmol) were added sequentially. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, DW (20 mL) was added, and the mixture was stirred for 2 hours. The resulting solid was filtered and washed with DW and dihydrogen phosphate. The obtained product was washed with oxane and dried in vacuo to afford the title compound (1.5 g, yield 70.5%) as a white solid.

[0216] 1 H NMR (400MHz, DMSO-d6) δ8.80 (s, 1H), 8.72 (s, 1H), 8.46 (d, J=6.9Hz, 1H), 7.32-7.04 (m, 4H), 4.75-4.67 (m, 1H) , 4.27 (q, J=7.1Hz, 2H), 3.27 (dd, J=15.8, 7.6Hz, 2H), 2.92 (dd, J=15.8, 6.8Hz, 2H), 1.29 (t, J=7.1Hz, 3H); LCMS m / z 284[M+H] +

[0217] Step 2: Preparation of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide

[0218]

[0219] The reaction mixture of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (0.5 g, 1.77 mmol), hydrazine monohydrate (2.8 mL, 35.3 mmol) and EtOH (20 mL) was stirred at 80°C overnight. After cooling to room temperature, DW was added and stirred at 0°C for 2 hours. The resulting solid was filtered and dried under vacuum to obtain the title compound as a white solid. (0.4 g, 84.6%).

[0220] LCMS m / z 270[M+H] +

[0221] Step 3: 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Preparation of oxadiazole-2(3H)-one

[0222]

[0223] 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide (0.35 g, 1.31 mmol) was dissolved in THF (7 mL) and cooled to 0 ° C. TEA (0.18 mL, 1.31 mmol) and CDI (0.26 g, 1.57 mmol) were slowly added, and the mixture was stirred at 0 ° C for 20 minutes and at room temperature for 20 minutes. The reaction mixture was concentrated, EtOAc was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered, washed once with cold EtOAc, and dried in vacuo to obtain the title compound (0.33 g, 86%) as a white solid.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (broad, 1H), 8.64 (d, J = 13.2 Hz, 2H), 8.31 (s, 1H), 7.24-7.12 (m, 4H), 4.73-4.64 (m, 1H), 3.30-3.23 (m, 2H), 2.92 (dd, J = 15.7, 6.8 Hz ， 2H); LCMS m / z 296 [M+H] +

[0225] Preparation Example 4. 5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- Preparation of oxadiazole-2(3H)-one

[0226] Step 1: Ethyl 2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidine-5-carboxylate

[0227]

[0228] 6,7-Dihydro-5H-cyclopentyl[b]pyridin-6-amine dihydrochloride (346 mg, 1.67 mmol) was dissolved in anhydrous distilled water. To the mixture was added 4-nitropropane (5.6 mL), DIPEA (0.85 mL, 5.01 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (280 mg, 1.50 mmol), and the mixture was stirred at 100 ° C for 4 hours. DW (20 mL) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography (0% to 33% EtOAc / Hex->3% MeOH / DCM) to obtain the title compound (125 mg, 29%) as a brown solid.

[0229] 1H NMR (400MHz, CDCl3) δ8.85 (d, J=32.9Hz, 2H), 8.39 (d, J=4.9Hz, 1H), 7.52 (d, J=7.4Hz, 1H), 7.09 (dd, J=7.2, 5.3Hz, 1H), 5.89 (d, J= 7.1Hz, 1H), 4.98-4.85 (m, 1H), 4.35 (q, J=7.0Hz, 2H), 3.58-3.39 (m, 2H), 2.98 (ddd, J=36.1, 16.5, 5.1Hz, 2H), 1.37 (t, J=7.1Hz, 3H)

[0230] Step 2: 2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidine-5-carbohydrazide

[0231]

[0232] Ethyl 2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidine-5-carboxylate (120 mg, 0.42 mmol) and hydrazine monohydrate (0.45 mL, 9.28 mmol) were dissolved in EtOH (4.6 mL) and stirred at 100 °C for 22 hours. The reaction mixture was concentrated and solidified by adding DCM. The resulting solid was filtered and dried to obtain the title compound as a light orange solid. (81 mg, 71%)

[0233] LCMS m / z 272[M+H] +

[0234] Step 3: 5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0235]

[0236] 2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidine-5-carbohydrazide (80 mg, 0.30 mmol) was dissolved in acetonitrile (1.6 mL), and TEA (43.3 μL, 0.31 mmol) and CDI (63 mg, 0.39 mmol) were added at 0 ° C. The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 6 hours. After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (0% to 2% MeOH / DCM) to obtain the title compound (83 mg, 94%) as an off-white solid.

[0237] 1H NMR(400MHz,DMSO-d6)612.12(br s, 1H), 8.66 (d, J=15.9Hz, 2H), 8.36 (d, J=6.8Hz, 1H), 8.30 (d, J=4.9Hz, 1H), 7.59 (d, J=8.1Hz, 1H), 7.13 (dd, J=7.4, 5.2Hz, 1H), 4.76-4.65 (m, 1H), 3.28-3.22 (m, 2H), 3.03-2.88 (m, 2H); LCMS m / z 297[M+H] +

[0238] Preparation Example 5. Preparation of (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0239] Step 1: Preparation of tert-butyl 3-methyl-3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0240]

[0241] Pivalic acid azidomethyl ester (101mg, 0.65mmol) and tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (135mg, 0.65mmol) are dissolved in t-BuOH (1.2mL) / DW (1.2mL), and 10% CuSO45H2O aqueous solution (0.5mL, 0.19mmol) and sodium ascorbate (38mg, 0.19mmol) are added sequentially, and the mixture is stirred at room temperature overnight. DW is added to the reaction mixture, extracted with EtOAc, and the organic layer is washed with brine. The organic layer is dried over MgSO4, filtered, concentrated, and the resulting residue is purified by column chromatography (0% to 2% MeOH / DCM) to obtain the title compound (244mg, 99%) as a colorless oil.

[0242] 1 H NMR (400MHz, CDCl3) δ7.57 (s, 1H), 6.20 (s, 2H), 3.68 (t, J=9.8Hz, 1H), 3.56- 3.32(m, 4H), 2.43-2.26(m, 1H), 2.02-1.89(m, 1H), 1.46(s, 9H), 1.19(s, 9H)

[0243] Step 2: Preparation of (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0244]

[0245] By the same method as in Step 2 of Preparation Example 1, using tert-butyl 3-methyl-3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate (244 mg, 0.67 mmol), TFA (2 mL) and DCM (6.5 mL) to obtain the title compound as a pale pink oil (quantitative), which was used in the next reaction without purification (326 mg).

[0246] LCMS m / z 267[M+H] +

[0247] Preparation Example 6. Preparation of 4-(azetidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0248] Step 1: Preparation of tert-butyl 3-(1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0249]

[0250] By the same method as in Step 1 of Preparation Example 2, using tert-butyl 3-ethynylazetidine-1-carboxylate (40 mg, 0.221 mmol), TMSN3 (32 μL, 0.243 mmol), CuI (4.2 mg, 0.022 mmol) and DMF (0.7 mL) / MeOH (96 μL) to obtain the title compound (29.2 mg, 59.0%) as a colorless oil.

[0251] 1 H NMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 4.19 (s, 2H), 3.88 (s, 3H), 1.37 (s, 9H)

[0252] Step 2: Preparation of 4-(azetidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0253]

[0254] By the same method as in Step 2 of Preparation Example 2, using tert-butyl 3-(1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (25 mg, 0.111 mmol), TFA (372 μL) and DCM (1.1 mL) to obtain the title compound as a yellow oil (quantitatively), which was used in the next reaction without purification (24 mg).

[0255] Preparation Example 7. Preparation of 4-(azetidin-3-yl)-1H-1,2,3-triazole dihydrochloride

[0256]

[0257] Tert-butyl 3-(1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (13.3 g, 59.3 mmol) was dissolved in DCM (94 mL) and 4 M HCl was added slowly in a water bath. The product was stirred at room temperature for 4 hours in 2% dextrin. The solid was filtered and washed with cold DCM. The solid was dissolved in MeOH and concentrated. The residue was then azeotropically concentrated with toluene three times to obtain the title compound (11.4 g, 97.5%) as an off-white solid.

[0258] 1 H NMR (400MHz, DMSO-d6) δ9.63 (br s, 1H), 9.33 (br s, 1H), 8.29 (br s, 1H), 7.92 (s, 1H), 4.27~3.95 (m, 4H), 3.67~3.64 (m, 1H).

[0259] Preparation Example 8. Preparation of (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0260] Step 1: Preparation of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0261]

[0262] By the same method as in Step 1 of Preparation Example 1, using azidomethyl pivalate (0.3 g, 1.91 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.22 g, 1.91 mmol), CuOAc (23.4 mg, 0.191 mmol), NaOAc (0.47 g, 5.73 mmol) and THF (3.8 mL) / DW (3.8 mL) to obtain the title compound (0.361 g, 55.9%) as a white solid.

[0263] 1 H NMR (400MHz, CDCl3) δ7.70 (s, 1H), 6.22 (s, 2H), 4.32 (t, J=8.6Hz, 2H), 4.13-4.02 (m, 2H), 3.94-3.87 (m, 1H), 1.45 (s, 9H), 1.20 (s, 9H)

[0264] Step 2: (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0265]

[0266] By the same method as in Step 2 of Preparation Example 1, using tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (0.355 g, 1.05 mmol), TFA (3.5 mL) and DCM (10.5 mL) to obtain the title compound (quantitatively), which was used in the next reaction without purification (282 mg).

[0267] Example 1. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0268] Step 1: (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0269]

[0270] 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (23.8 mg, 0.08 mmol) and (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (29.5 mg, 0.08 mmol) were dissolved in DMF (2 mL), and DIPEA (69 μL, 0.4 mmol) and BOP reagent (42.7 mg, 0.097 mmol) were added sequentially. After stirring at room temperature overnight, the reaction mixture was washed with DW, extracted with EtOAc, and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered and concentrated, and the resulting residue was purified by column chromatography (0% to 10% MeOH / DCM) to obtain the title compound (34.5 mg, 80.9%) as a white solid.

[0271] LCMS m / z 530[M+H] +

[0272] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0273]

[0274] (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (33.2 mg, 0.063 mmol) was dissolved in MeOH (2 mL), KCO (17.3 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 1 hour. DW was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO, filtered and concentrated. The obtained residue was purified by column chromatography (0% to 10% MeOH / DCM) to give the title compound (19 mg, 72.9%) as a white solid.

[0275] 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J=14.2Hz, 2H), 8.24 (d, J=6.8Hz, 1H), 7.88-7.72 (m, 1H), 7.29-7.07 (m, 4H), 4.73-4.62 (m, 1H), 3.99- 3.88 (m, 1H), 3.76-3.53 (m, 4H), 3.27 (dd, J=15.9, 7.6Hz, 2H), 2.45-2.33 (dd, J=15.9, 6.7Hz, 2H), 2.24-2.11 (m, 1H), 2.16 (m, 1H); LCMS m / z 416[M+H] +

[0276] Example 2. (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0277] Step 1: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0278]

[0279] The title compound was prepared by the same method as in Preparation Example 3, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0280] 1 H NMR (400MHz, DMSO-d6) δ12.45 (s, 1H), 8.65 (d, J = 14.6Hz, 2H), 8.33 (d, J = 6.8Hz, 1H), 7.27 (t, J = 9.3H z, 2H), 4.68 (dq, J=13.8.6.9Hz, 1H), 3.24 (dd, J=16.1, 7.6Hz, 2H), 2.87 (dd, J=16.0, 6.4Hz, 2H); LCMS m / z 332[M+H] +

[0281] Step 2: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0282]

[0283] By the same method as in Step 1 of Example 1, using (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (0.1 g, 0.302 mmol), 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazol-2(3H)-one (0.127 g, 0.362 mmol), DIPEA (154 μL, 0.906 mmol), BOP reagent (0.160 g, 0.362 mmol) and DMF (1.5 mL) were added to obtain the title compound (69.8 mg, 40.8%) as a white solid.

[0284] 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 2H), 8.23 ​​(d, J = 6.9Hz, 1H), 8.18 (s, 1H), 7.27 (t, J = 9.4Hz, 2H), 6.26 (s, 2H), 4.68 (dd, J = 14.4, 7.4Hz , 1H), 3.94-3.88 (m, 1H), 3.73-3.64 (m, 2H), 3.64-3.54 (m, 4H), 3.24 (d, J=8.4Hz, 2H), 2.88 (dd, J=16.0, 6.5Hz, 2H), 1.10 (s, 9H); LCMS m / z566[M+H] +

[0285] Example 3. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0286]

[0287] (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (68 mg, 0.120 mmol) was dissolved in MeOH (0.6 mL), KCO (33.2 mg, 0.240 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated, and the resulting residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (47.2 mg, 87.0%) as a white solid.

[0288] 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 2H), 8.23 ​​(d, J = 6.7Hz, 1H), 7.79 (s, 1H), 7.27 (tJ = 9.3Hz, 2H), 4.68 (dd, J = 13.9, 7.0Hz, 1H), 3.94-3.87 ( LCMS m / z 452[M+H] +

[0289] Example 4. (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0290]

[0291] By the same method as in step 1 of Example 1, using 5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0138] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr. [0139 ...7] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0138] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0292] 1 H NMR (400MHz, DMSO-d6) 68.75 (s, 2H), 8.29 (dd, J=17.1, 5.7Hz, 2H), 8.20 (s, 1H), 7.61 (d, J=7.4Hz, 1H), 7.15 (dd, J=7.3, 5.1Hz, 1H), 6.28 (s, 2H), 4.79-4.66 (m, 1H), 3.93 (dd, J=9 .3, 7.5Hz, 1H), 3.71 (dt.J=14.1, 7.0Hz, 1H), 3.67-3.55 (m, 3H), 3.38-3.34 (m, 1H), 3.30 -3.27(m, 1H), 3.06-2.90(m, 2H), 2.45-2.35(m, 1H), 2.24-2.11(m, 1H), 1.12(s, 9H); LCMS m / z 531[M+H] +

[0293] Example 5. (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0294] Step 1: 5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0295]

[0296] The title compound was prepared by the same method as in Preparation Example 3, except that benzo[d][1,3]dioxol-5-ylmethanamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0297] 1 H NMR (400MHz, DMSO-d6) δ 12.42 (s, 1H), 8.64 (s, 2H), 8.45 (t, J=6.3Hz, 1H), 6.92-6.73 (m, 3H), 5.97 (s, 2H), 4.47 (d, J=6.3Hz, 2H); LCMS m / z 314[M+H] +

[0298] Step 2: (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0299]

[0300] By the same method as in step 1 of Example 1, using 5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-

[0266] The product was stirred at 40 °C for 24 h at 4 °C for 3 hours at 4 °C for 1 h.

[0267] The product was stirred at 40 °C for 24 h at 4 °C for 3 hours at 4 °C for 1 h.

[0268] The product was stirred at 40 °C for 3 hours at 4 °C for 1 h.

[0269] The product was stirred at 40 °C for 24 h at 4 °C for 3 hours at 4 °C for 1 h.

[0269] The product was stirred at 40 °C for 3 hours at 4 °C for 1 h.

[0269] The product was stirred at 40 °C for 3 hours at 4 °C for 1 h.

[0269] The product was stirred at 40 °C for 3 hours at 4 °C for 1 h.

[0301] 1H NMR (400MHz, DMSO-d6) δ8.71 (s, 2H), 8.34 (t, J=6.3Hz, 1H), 8.19 (s, 1H), 6.89 (s, 1H), 6.85-6.77 (m, 2H), 6.28 (s, 2H), 5.97 (s, 2H), 4. 46 (d, J=6.2Hz, 2H), 3.95-3.89 (m, 1H), 3.74-3.67 (m, 1H), 3.64-3.56 (m, 3H), 2.44-2.36 (m, 1H), 2.22-2.13 (m, 1H), 1.11 (s, 9H); LCMS m / z548[M+H] +

[0302] Example 6. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

[0303]

[0304] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (36 mg, 0.066 mmol), K2CO3 (18 mg, 0.13 mmol) and MeOH (1 mL) to obtain the title compound as a white solid (22 mg, 76%).

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.71 (s, 2H), 8.35 (t, J=6.3Hz, 1H), 7.81 (s, 1H), 6.89 (s, 1H), 6.85-6.77 (m, 2H), 5.97 ( s, 2H), 4.46 (d, J=6.2Hz, 2H), 3.95-3.89 (m, 1H), 3.71-3.59 (m, 4H), 2.44-2.36 (m, 1H), 2.21-2.10 (m, 1H); LCMS m / z 434[M+H] +

[0306] Example 7. N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine

[0307] Step 1: 5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0308]

[0309] The title compound was prepared by the same method as in Preparation 4, except that 6,7-dihydro-5H-cyclopenta[b]pyrazine-6-amine dihydrochloride was used instead of 6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine dihydrochloride.

[0310] 1H NMR(400MHz, DMSO-d6)δ12.03(br s, 1H), 8.68 (s, 2H), 8.42 (d, J=6.8Hz, 1H), 8.36 (s, 2H), 4.88-4.76 (m, 1H), 3.46-3.41 (m, 2H), 3.05 (dd, J=17.3, 5.5Hz, 2H); LCMS m / z298[M+H] +

[0311] Step 2: (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0312]

[0313] By the same method as in step 1 of Example 1, using 5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0138] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0314] 1H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 8.36 (s, 2H), 8.33 (d, J=6.9Hz, 1H), 8. 20 (s, 1H), 6.28 (s, 2H), 4.88-4.74 (m, 1H), 3.93 (dd, J=9.4, 7.0Hz, 1H), 3.7 7-3.66 (m, 1H), 3.66-3.54 (m, 3H), 3.43 (dd, J=17.3, 7.9Hz, 2H), 3.05 (dd, J =17.3, 5.6Hz, 2H), 2.44-2.35(m, 1H), 2.24-2.13(m, 1H), 1.12(s, 9H); LCMS m / z 532[M+H] +

[0315] Step 3: N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine

[0316]

[0317] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (12.6 mg, 0.024 mmol) was dissolved in MeOH (0.47 mL), and KCO (6.6 mg, 0.047 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (0% to 8% MeOH / DCM) to give the title compound (8 mg, 81%) as a white solid.

[0318] 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 8.46-8.22 (m, 3H), 7.81 (s, 1H), 4.87-4.76 (m, 1H), 3.93 (dd, J=9.2, 7.3Hz, 1H), 3.77-3.52 (m , 4H), 3.43 (dd, J=17.4, 8.0Hz, 2H), 3.17 (d, J=5.1Hz, 1H), 3.05 (dd, J=17.2, 5.6Hz, 2H), 2.45-2.35 (m, 1H), 2.22-2.10 (m, 1H); LCMS m / z 418[M+H] +

[0319] Example 8. N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine

[0320]

[0321] By the same method as in step 3 of Example 7, using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0147] The product was prepared by mixing 1H-1,2,3-triazol-1-yl)methyl pivalate (22.8 mg, 0.043 mmol), K2CO3 (11.9 mg, 0.086 mmol) and MeOH (0.86 mL) to obtain the title compound (9 mg, 50%) as a white solid.

[0322] 1 H NMR (400MHz, DMSO-d6) 68.75 (s, 2H), 8.30 (dd, J=14.0, 5.8Hz, 2H), 7.82 (s, 1 H), 7.61 (d, J=7.9Hz, 1H), 7.15 (dd, J=7.4, 5.1Hz, 1H), 4.80-4.65 (m, 1H), 3.9 3(dd,J=9.3,7.4Hz,1H),3.75-3.54(m,4H),3.38-3.35(m,1H),3.31-3.27(m , J=9.0Hz, 1H), 3.07-2.89(m, 2H), 2.44-2.35(m, 1H), 2.21-2.09(m, 1H); LCMS m / z 417[M+H]+

[0323] Example 9. (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0324] Step 1: Ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate

[0325]

[0326] 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (0.507 g, 1.86 mmol), ethyl (E)-3-(2-chloropyrimidin-5-yl)acrylate (0.789 g, 3.71 mmol), DIPEA (6.3 mL, 37.1 mmol) were dissolved in n-BuOH (3.7 mL) and reacted in a microwave reactor at 150° C. for 2 hours. After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (EtOAc / Hex) to obtain the title compound (0.348 g, 54.4%) as a brown solid.

[0327] 1 H NMR (400MHz, DMSO-d6) δ 8.67 (s, 2H), 8.09 (d, J = 6.8Hz, 1H), 7.48 (d, J = 16.1Hz, 1H), 7.26 (t, J = 9.3Hz, 2H), 6.51 (d, J = 16.1Hz, 1H), 4.66 (dd , J=13.8, 6.8Hz, 1H), 4.15 (dd, J=14.1, 7.0Hz, 2H), 3.22 (dd, J=16.1, 7.7Hz, 2H), 2.86 (dd, J=15.8, 6.3Hz, 2H), 1.22 (t, J=7.1Hz, 3H); LCMS m / z 346[M+H] +

[0328] Step 2: (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid

[0329]

[0330] To a mixture of ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (0.345 g, 0.999 mmol) in MeOH / THF (2 mL / 20 mL) was added a solution of LiOH (0.119 g, 4.99 mmol) in DW (2 mL), and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated, DW was added, the pH was adjusted to 1 to 2 with 3M HCl, and extracted with EtOAc. The organic layer was washed with DW, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound (0.147 g, 46.4%) as an off-white solid.

[0331] 1H NMR (400MHz, DMSO-d6) δ12.17 (s, 1H), 8.64 (s, 1H), 8.05 (d, J = 7.2Hz, 1H), 7.41 (d, J = 16.0Hz, 1H), 7.26 (t, J = 9.3Hz, 2H), 6.41 (d, J = 16.2Hz, 1H) ， 4.66 (dd, J=14.0, 6.8Hz, 1H), 3.26-3.19 (m, 2H), 2.86 (dd, J=16.1, 6.6Hz, 2H); LCMSm / z 318[M+H] +

[0332] Step 3: (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0333]

[0334] To a mixture of (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid 1 (40 mg, 0.126 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (52.8 mg, 0.151 mmol), DIPEA (64 μL, 0.378 mmol) and DMF (2.5 mL) was added HBTU (57.4 mg, 0.151 mmol), and the mixture was stirred at room temperature for 2 hr. After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound (42.7 mg, 61.4%) as a yellow solid.

[0335] LCMS m / z 552[M+H] +

[0336] Step 4: (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0337]

[0338] By the same method as in Example 3, using (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)acryloyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (40 mg, 0.073 mmol), K2CO3 (20.0 mg, 0.145 mmol) and MeOH (0.36 mL) to obtain the title compound as a white solid (27.2 mg, 85.7%).

[0339] 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 2H), 7.98 (s, 1H), 7.70 (s, 1H), 7.34 (s, 1H), 7. 27 (dd, J=16.7, 7.6Hz, 2H), 6.91 (dd, J=16.0, 9.6Hz, 1H), 4.65 (dd, J=13.6, 6.8H z, 1H), 4.08 (s, 1H), 3.81 (dd, J=12.6.9.8Hz, 2H), 3.65 (dd, J=24.1, 15.4Hz, 2H ), 3.48 (s, 2H), 3.22 (dd, J=15.2, 7.5Hz, 2H), 2.86 (dd, J=15.4.4.6Hz, 2H); LCMS m / z 438[M+H] +

[0340] Example 10. 1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one

[0341] Step 1: Ethyl 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoate

[0342]

[0343] To a mixture of ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (0.3 g, 0.869 mmol) and EA / MeOH / THF (14 mL / 28 mL / 14 mL) was added Pd(OH)2 (0.146 g, 1.04 mmol), and the mixture was stirred under an atmosphere of H2 overnight (rt). The reaction mixture was filtered through a pad of celite and concentrated, and the resulting residue was purified by column chromatography (EtOAc / Hex) to give the title compound (0.115 g, 38.2%) as a white solid.

[0344] 1 H NMR (400MHz, DMSO-d6) δ8.17 (s, 2H), 7.31 (d, J=6.7Hz, 1H), 7.24 (t, J=9.2Hz, 2H), 4.61-4.52 (m, 1H), 4.02 (q, J=7.1Hz, 2 LCMS m / z 348[M+H] +

[0345] Step 2: 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid

[0346]

[0347] By the same method as in step 2 of Example 9, using ethyl 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoate (113 mg, 0.325 mmol), LiOH (39 mg, 1.63 mmol), DW (0.7 mL) and MeOH / THF (0.7 mL / 7 mL), the title compound (75.6 mg, 72.8%) was obtained as a white solid.

[0348] 1 H NMR (400MHz, DMSO-d6) δ12.12 (bs, 1H), 8.17 (s, 2H), 7.30 (d, J=6.6Hz, 1H), 7.24 (t, J=9.3Hz, 2H), 4.61-4.51 (m, 1 LCMS m / z 320[M+H] +

[0349] Step 3: (4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0350]

[0351] By the same method as in Step 3 of Example 9, using 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid (16 mg, 0.050 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (21 mg, 0.060 mmol), DIPEA (26 μL, 0.150 mmol), HBTU (22.8 mg, 0.060 mmol) and DMF (1 mL), the title compound (24 mg, 86.5%) was obtained as a yellow solid.

[0352] LCMS m / z 554[M+H] +

[0353] Step 4: 1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one

[0354]

[0355] By the same method as in Example 3, using (4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (20 mg, 0.036 mmol), K2CO3 (10 mg, 0.072 mmol) and MeOH (0.18 mL) to obtain the title compound as a yellow solid (8.7 mg, 54.8%).

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.19 (d, J=1.4Hz, 2H), 7.72 (s, 1H), 7.29-7.22 (m, 2H), 4.56 (dd, J=13.9, 7.4Hz, 1H), 3.86-3.70 (m, 1H), 3.58-3.39 (m, 3H), 3.28 (d, J=7.8Hz, 1H), 3.21-3.13 (m, 2H), 2.81 (dd, J=15.9, 6.4Hz, 2H), 2. 61 (t, J=7.2Hz, 2H), 2.23 (dd, J=31.5, 6.1Hz, 2H), 2.06-1.84 (m, 2H); LCMS m / z 440[M+H] +

[0357] Example 11. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0358] Step 1: 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0359]

[0360] The title compound was prepared by the same method as in Preparation Example 3, except that 2-(3,5-dichlorophenyl)ethan-1-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0361] 1 H NMR (400MHz, DMSO-d6) δ12.40 (broad, 1H), 8.62 (d, J=9.6Hz, 2H), 8.07 (t, J=5.7Hz, 1H), 7.4 2 (s, 1H), 7.31 (d, J=1.6Hz, 2H), 3.58 (dd, J=12.8, 6.6Hz, 2H), 2.87 (t, J=6.8Hz, 2H); LCMS m / z 352[M+H] +

[0362] Step 2: (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0363]

[0364] By the same method as in step 1 of Example 1, using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr. at 40 °C for 3 hours at 5 °C.

[0137] The product was stirred at 40 °C for 24 hours at 5 °C for 3 hours at 5 °C.

[0138] The product was stirred at 40 °C for 3 hours at 5 °C for 4 hours at 5 °C.

[0139] The product was stirred at 40 °C for 24 hours at 5 °C for 3 hours at 5 °C.

[0139] The product was stirred at 40 °C for 3 hours at 5 °C for 4 hours at 5 °C.

[0365] LCMS m / z 530[M+H]+

[0366] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0367]

[0368] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (34.7 mg, 0.059 mmol), K2CO3 (16.4 mg, 0.12 mmol) and MeOH (2 mL) were added to obtain the title compound as a white solid (11.8 mg, 42.2%).

[0369] 1 H NMR (400MHz, DMSO-d6) δ8.70 (d, J=7.4Hz, 2H), 7.98 (t, J=5.7Hz, 1H), 7.82 (wide, 1H), 7.43 (s, 1H), 7.32 (d, J=1.6Hz ,2H), 3.97-3.88(m, 1H), 3.74-3.54(m, 6H), 2.88(t, J=6.8Hz, 2H), 2.47-2.35(m, 1H), 2.25-2.10(m, 1H); LCMSm / z 472[M+H] +

[0370] Example 12. (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0371] Step 1: 5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0372]

[0373] The title compound was prepared by the same method as in Preparation Example 3, except that 5-methoxy-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0374] 1 H NMR (400MHz, DMSO-d6) δ8.65 (d, J=16.3Hz, 2H), 8.30 (d, J=7.0Hz, 1H), 7.10 (d, J=8.2Hz, 1H), 6.81 (s, 1H), 6.71 (dd, LCMS m / z 326[M+H] +

[0375] Step 2: (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0376]

[0377] By the same method as in step 1 of Example 1, using 5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] C.-14-nitropropane-2-yl)-1H-1,2,3-triazol-1-yl]methyl pivalate (26 mg, 0.080 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (34 mg, 0.096 mmol), DIPEA (68 μL, 0.096 mmol), BOP reagent (42 mg, 0.096 mmol) and DMF (1 mL) to obtain the title compound (17 mg, 38%) as a white solid.

[0378] 1H NMR (400MHz, DMSO-d6) δ8.74 (d, J=12.3Hz, 2H), 8.26-8.17 (m, 2H), 7.11 (d, J=8. 1Hz, 1H), 6.81 (s, 1H), 6.72 (d, J=8.2Hz, 1H), 6.28 (s, 2H), 4.73-4.62 (m, 1H), 3. 98-3.89 (m, 1H), 3.76-3.67 (m, 4H), 3.66-3.56 (m, 3H), 3.21 (td, J=16.3, 7.5Hz, 2H), 2.93-2.80(m, 2H), 2.46-2.37(m, 1H), 2.22-2.14(m, 1H), 1.12(s, 9H); LCMS m / z 560[M+H] +

[0379] Example 13. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0380]

[0381] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (11 mg, 0.020 mmol), K2CO3 (5.0 mg, 0.39 mmol) and MeOH (1 mL) to obtain the title compound as a white solid (2.7 mg, 31%).

[0382] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=15.3Hz, 2H), 8.22 (d, J=7.0Hz, 1H), 7.81 (s, 1H), 7.11 (d, J=8.3Hz, 1H), 6.81 (s, 1H), 6.72 (d, J=8.2Hz, 1H LCMS m / z 446[M+H] +

[0383] Example 14. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine

[0384] Step 1: 5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0385]

[0386] The title compound was prepared by the same method as Preparation Example 3, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine, and ethyl 5-chloropyrimidine-5-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0387] LCMS m / z 332[M+H] +

[0388] Step 2: (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0389]

[0390] By the same method as in step 1 of Example 1, using 5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-

[0136] The mixture was stirred at 40 °C for 2 h: 2 h: 10 min. Add oxadiazole-2(3H)-one (24 mg, 0.07 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (32 mg, 0.09 mmol), DIPEA (62 μL, 0.36 mmol), BOP reagent (39 mg, 0.087 mmol) and DMF (2 mL) to obtain the title compound (28.8 mg, 69.9%) as a brown solid.

[0391] LCMS m / z 566[M+H] +

[0392] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine

[0393]

[0394] By the same method as in step 2 of Example 1, using (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (27.5 mg, 0.049 mmol), K2CO3 (13.4 mg, 0.097 mmol) and MeOH (2 mL) were added to obtain the title compound as a white solid (3.95 mg, 18%).

[0395] 1 H NMR (400MHz, CD3OD) δ8.59 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.11 (t, J = 8.8Hz, 2H), 4.82-4.74 (m, 1H), 4.09-4.01 (m , 1H), 3.86-3.68 (m, 4H), 3.41-3.34 (m, 2H), 2.90 (dd, J=15.9, 5.4Hz, 2H), 2.56-2.46 (m, 1H), 2.36-2.25 (m, 1H); LCMS m / z 452[M+H] +

[0396] Example 15. Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylate

[0397]

[0398] To 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- To a solution of oxadiazole-2(3H)-one (60 mg, 0.181 mmol) in DMF (0.9 mL) was added methyl 3-pyrrolidinecarboxylate hydrochloride (36.0 mg, 0.217 mmol), followed by DIPEA (92 μL, 0.543 mmol) at 0°C. After stirring at the same temperature for 30 minutes, BOP reagent (96.1 mg, 0.217 mmol) was added, and the mixture was stirred at room temperature overnight. DW was added to the reaction mixture, extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (45.4 mg, 56.7%) as a white solid.

[0399] 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 2H), 8.24 (d, J = 6.4Hz, 1H), 7.27 (t, J = 9.1Hz, 2H), 4.68 (d, J = 6.6Hz, 1H), 3.75-3 .59 (m, 5H), 3.52 (s, 2H), 3.24 (dd, J=16.0, 7.6Hz, 2H), 2.87 (dd, J=16.0, 6.4Hz, 2H), 2.20 (d, J=32.5Hz, 2H).LCMS m / z 443[M+H] +

[0400] Example 16. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0401] Step 1: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0402]

[0403] The title compound was prepared by the same method as in Preparation Example 3, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine, and ethyl 2-chloro-4-methylpyrimidine-5-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0404] 1H NMR (400 MHz, DMSO-d6) δ 12.30 (broad, 1H), 8.58-8.47 (m, 1H), 8.28-8.15 (m, 1H), 7.28 (t, J = 9.2 Hz, 6H), 4.71 (s, 4H), 3.29-3.19 (m, 2H), 2.88 (dd, J = 15.9, 6.6 Hz, 2H), 2.54 (s, 3H); LCMS m / z 346 [M+H] +

[0405] Step 2: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0406]

[0407] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-

[0136] The mixture was stirred at 40 °C for 2 h: 2 h: 10 min, 0.25 min, 0.45 % tOH-HCl (0.2% HCl) (50% HCl), 2% HCl (pH 7.5), 1% HCl (pH 8.5), 0.6% HCl (pH 8.5), 2% HCl (pH 7.5), 1% HCl (pH 8.5), 2% HCl (pH 7.5), 1% HCl (pH 8.5), 2% HCl (pH 7.5), 1% HCl (pH 8.5), 1% HCl (pH 8.5), 2 ...

[0408] LCMS m / z 580[M+H] +

[0409] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0410]

[0411] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (29.5 mg, 0.051 mmol), K2CO3 (14.1 mg, 0.10 mmol) and MeOH (2 mL) were added to obtain the title compound (17 mg, 71.8%) as a white solid.

[0412] 1 H NMR (400MHz, DMSO-d6) δ8.62 (broad, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.28 (t, J = 9.3Hz, 2H), 4.71 (s, 1H), 3.98-3.88 (m, 1H), 3.75-3.5 5 (m, 4H), 3.25 (dd, J=15.9, 7.2Hz, 2H), 2.88 (dd, J=15.9, 6.7Hz, 2H), 2.57 (s, 3H), 2.46-2.35 (m, 1H), 2.24-2.10 (m, 1H); LCMSm / z 466[M+H] +

[0413] Example 17. 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-4-yl oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0414] Step 1: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidin-2-amine

[0415]

[0416] A mixture of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (0.5 g, 2.96 mmol), 2-chloro-5-vinylpyrimidine (0.831 g, 5.91 mmol), DIPEA (10.1 mL, 59.1 mmol) and n-BuOH (5.9 mL) was reacted in a microwave (160° C., 1 hour). After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (EA / Hex) to obtain the title compound (0.322 g, 39.7%) as a brown solid.

[0417] 1H NMR (400MHz, DMSO-d6) δ8.44 (s, 2H), 7.65 (d, J=6.6Hz, 1H), 7.25 (t, J=9.3Hz, 2H), 6.52 (dd, J=17.8, 11.3Hz, 1H), 5.70 (d, LCMS m / z274[M+H] +

[0418] Step 2: 5-(3-bromo-4,5-dihydroiso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0419]

[0420] 1,1-Dibromoformaldehyde oxime (0.356 g, 1.76 mmol) was dissolved in DMF (2.9 mL) and cooled to -10 ° C. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidine-2-amine (0.320 g, 1.17 mmol) and KHCO (0.293 g, 2.93 mmol) in DW (2.9 mL) were slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. DW was added to the reaction mixture, extracted with EtOAC, and the organic layer was dried over MgSO, filtered and concentrated. The obtained residue was purified by column chromatography (EtOAc / Hex) to obtain the title compound (0.294 g, 63.5%) as a brown solid.

[0421] 1 H NMR (400MHz, DMSO-d6) δ8.35 (s, 2H), 7.76 (d, J = 6.9Hz, 1H), 7.25 (t, J = 9.2Hz, 2H), 5.54 (t, J = 10.6Hz, 1H), 4.62 (d, J = 7.0Hz, 1H) , 3.60 (dd, J=17.3, 10.8Hz, 1H), 3.47 (dd, J=17.3, 10.5Hz, 1H), 3.20 (dd, J=15.9, 7.1Hz, 2H), 2.83 (dd, J=12.5, 4.1Hz, 2H); LCMS m / z 396[M+H] +

[0422] Step 3: 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-4-yl oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0423]

[0424] 5-(3-bromo-4,5-dihydroiso A mixture of 4-(4-(6-difluoro-2-nitro-1H-indene-2-yl)pyrimidin-2-amine (55 mg, 0.139 mmol), 4-(pyrrolidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate (39.4 mg, 0.167 mmol), Na2CO3 (36.7 mg, 0.348 mmol) and t-BuOH (1.4 mL) was reacted in a microwave (160° C., 2 h). The reaction mixture was filtered, washed with 10% MeOH / DCM solution, and the filtrate was concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound (15.8 mg, 25.1%) as an orange solid.

[0425] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 2H), 7.53 (s, 1H), 7.00 (t, J=8.7Hz, 2H), 5.75 (t, J=6. 3Hz, 1H), 5.39 (t, J=8.8Hz, 1H), 4.81 (dd, J=12.6, 5.7Hz, 1H), 3.77 (dd, J=15.6, 6.6H z, 1H), 3.67-3.50 (m, 3H), 3.43-3.29 (m, 3H), 3.06 (dd, J=14.9, 8.1Hz, 1H), 2.83 (dd, J=16.1, 5.0Hz, 2H), 2.40 (dd, J=12.4, 5.8Hz, 1H), 2.17 (dd, J=13.2, 7.1Hz, 1H); LCMS m / z453[M+H] +

[0426] Example 18. 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0427]

[0428] 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-4-yl To the reaction mixture was added 4-(4-(4-(4-(4-(4-(4-(4-nitro-2-yl)-2-nitro-1-oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (10 mg, 0.022 mmol), I2 (8.4 mg, 0.033 mmol), imidazole (4.5 mg, 0.066 mmol) and toluene (1.1 mL) at 110 °C for 3 hours. EtOAc and 10% Na2S2O4 solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (4.2 mg, 42.2%) as a white solid.

[0429] 1 H NMR (400MHz, DMSO-d6) δ 8.68 (s, 2H), 8.13 (d, J = 6.7Hz, 1H), 7.27 (t, J = 9.3Hz, 2H), 6.51 (s, 1H), 4.67 (dd, J = 13.8, 7.0Hz, 1H), 3.68 (d, J = 8.4Hz, 1 LCMS m / z 4511M+H] +

[0430] Example 19. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0431] Step 1: 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0432]

[0433] The title compound was prepared by the same method as in Preparation Example 3, except that 5-bromo-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0434] 1 H NMR (400MHz, DMSO-d6) δ12.46 (s, 1H), 8.66 (d, J=13.9Hz, 2H), 8.33 (d, J=6.8Hz, 1H), 7.43 (s, 1H), 7.33 (d, J=8. 0Hz, 1H), 7.19 (d, J=8.1Hz, 1H), 4.73-4.63 (m, 1H), 3.28-3.20 (m, 2H), 2.90 (ddd, J=22.4, 16.2, 6.5Hz, 2H); LCMS m / z 374[M+H] +

[0435] Step 2: (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0436]

[0437] By the same method as in step 1 of Example 1, using 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] C.-14-nitropropane-2-yl)-1H-1,2,3-triazol-1-yl]methyl pivalate (37 mg, 0.1 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (45 mg, 0.13 mmol), DIPEA (87 μL, 0.5 mmol), BOP reagent (52 mg, 0.12 mmol) and DMF (2 mL) to obtain the title compound (50 mg, 82%) as a yellow solid.

[0438] LCMS m / z 608, 610 [M+H] +

[0439] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0440]

[0441] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (50 mg, 0.08 mmol), K2CO3 (22 mg, 0.16 mmol) and MeOH (1 mL) to obtain the title compound as a white solid (25 mg, 63%).

[0442] 1 H NMR (400MHz, CD3OD) δ8.71 (s, 2H), 8.23 ​​(d, J = 8.0Hz, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.0Hz, 2H), 7.18 (d, J = 8.0Hz, 2H), 4.68 LCMS m / z494.496[M+H] +

[0443] Example 20. (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0444] Step 1: (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid

[0445]

[0446] The title compound was prepared by the same method as in steps 1 and 2 of Example 9, except that 2,3-dihydro-1H-inden-2-amine was used instead of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine in step 1 of Example 9.

[0447] LCMS m / z 282[M+H] +

[0448] Step 2: (E)-(4-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0449]

[0450] (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (27 mg, 0.095 mmol) and (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (41.7 mg, 0.11 mmol) were dissolved in DMF (2 mL), DIPEA (49 μL, 0.28 mmol) and HBTU (43 mg, 0.11 mmol) were added, and the mixture was stirred at room temperature for 5 hours. DW was added to the reaction mixture, extracted with EtOAc, and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and the resulting residue was purified by column chromatography (0% to 100% EtOAc / Hex) to obtain the title compound (30.8 mg, 63%) as a white solid.

[0451] LCMS m / z 516[M+H] +

[0452] Step 3: (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0453]

[0454] By the same method as in Step 2 of Example 1, using (E)-(4-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (28.6 mg, 0.056 mmol), K2CO3 (15.3 mg, 0.11 mmol) and MeOH (2 mL) to obtain the title compound as a white solid (11.4 mg, yield 51.2%).

[0455] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 7.97 (dd, J = 6.4, 3.4 Hz, 1H), 7.78 (broad, 1H), 7.35 (dd, J = 15.5, 3.6 Hz, 1H), 7.26-7.07 (m, 4H), 6.92 (dd, J = 15.5, 9.0 Hz, 1H), 4.72-4.60 (m, 1H), 4.18-4.04(m, 1H), 3.92-3.77(m, 1H), 3.75-3.56(m, 2H), 3.56-3.40(m, 2H), 3.25(dd, J=1 6.0, 7.8Hz, 2H), 2.91 (dd, J=15.7, 4.7Hz, 2H), 2.41-2.22 (m, 1H), 2.15-1.94 (m, 1H); LCMS m / z 402[M+H] +

[0456] Example 21. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0457] Step 1: 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0458]

[0459] The title compound was prepared by the same method as in Preparation Example 3, except that (3,5-difluorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0460] LCMS m / z 306[M+H] +

[0461] Step 2: (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0462]

[0463] By the same method as in step 1 of Example 1, using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] 2 hours at room temperature for 24 hours at room temperature

[0138] 2 hours at room temperature for 24 hours at room temperature

[0139] 3 hours at room temperature

[0139] 3 hours at room temperature

[0139] 4 ...

[0464] LCMS m / z 540[M+H] +

[0465] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0466]

[0467] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (31.8 mg, 0.059 mmol), K2CO3 (16.3 mg, 0.12 mmol) and MeOH (2 mL) to obtain the title compound as a white solid (16.7 mg, 66.7%).

[0468] 1 H NMR (400MHz, DMSO-d6) δ8.73 (broad, 2H), 8.45 (t, J=6.4Hz, 1H), 7.81 (s, 1H), 7.09 (t, J=9.3Hz, 1H), 7.02 (d, J=6.9 Hz, 2H), 4.58 (d, J=6.2Hz, 2H), 3.98-3.87 (m, 1H), 3.75-3.54 (m, 4H), 2.45-2.34 (m, 1H), 2.23-2.08 (m, 1H); LCMS m / z 426[M+H] +

[0469] Example 22. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylic acid

[0470]

[0471] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1-oxadiazole-2-yl)pyrrolidine-3-carboxylate (39.4 mg, 0.089 mmol) was dissolved in THF (0.45 mL), 1N NaOH (223 μL, 0.223 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After THF was concentrated and removed, EA was added, and the mixture was stirred for 1 hour. The resulting solid was filtered to obtain the title compound (36 mg, 94.4%) as a white solid.

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 2H), 8.21 (d, J=6.5Hz, 1H), 7.27 (t, J=9.2Hz, 2H), 4.68 (dd, J=13.1, 5.9Hz, 1H), 3.68-3.60 (m, 1H) , 3.47-3.39 (m, 2H), 3.24 (dd, J=16.2, 7.8Hz, 2H), 2.87 (dd, J=16.1, 6.2Hz, 2H), 2.65 (d, J=6.5Hz, 1H), 2.03 (d, J=55.0Hz, 3H); LCMS m / z 429[M+H] +

[0473] Example 23. 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0474] Step 1: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carbohydrazide

[0475]

[0476] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylate (53.5 mg, 0.12 mmol) was dissolved in EtOH (3 mL), hydrazine monohydrate (0.2 mL, 2.4 mmol) was added, and the mixture was stirred at 85° C. overnight. DW was added to the reaction mixture, and the mixture was stirred at 0° C. for 2 hours. The obtained solid was filtered and dried to obtain the title compound (43.8 mg, 81.9%) as a white solid.

[0477] LCMS m / z 443[M+H] +

[0478] Step 2: 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0479]

[0480] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1-oxadiazole-2-yl)pyrrolidine-3-carbohydrazide (43.8 mg, 0.099 mmol) was dissolved in THF (2 mL), and TEA (14 μL, 0.099 mmol) and CDI (19.3 mg, 0.12 mmol) were slowly added at 0°C, and the mixture was stirred at the same temperature for 20 minutes, and then at room temperature for 20 minutes. The reaction mixture was concentrated, DW was added, extracted with EtOAc, and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and the resulting residue was purified by column chromatography (0% to 10% MeOH / DCM) to obtain the title compound (26.4 mg, 56.9%) as a white solid.

[0481] 1H NMR (400MHz, DMSO-d6) δ12.22 (s, 1H), 8.74 (broad, 2H), 8.27 (d, J = 6.7Hz, 1H), 7.29 (t, J = 9.3Hz, 2H), 4.76-4.63 (m, 1H), 3.86-3.77 (m, 1H), 3. 76-3.69 (m, 1H), 3.69-3.56 (m, 3H), 3.26 (dd, J=16.0, 7.5Hz, 2H), 2.90 (dd, J=16.1, 6.5Hz, 2H), 2.41-2.30 (m, 1H), 2.30-2.18 (m, 1H); LCMS m / z 469[M+H] +

[0482] Example 24. Methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetate

[0483]

[0484] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (60 mg, 0.181 mmol), methyl 2-pyrrolidin-3-yl acetate hydrochloride (39.0 mg, 0.217 mmol), DIPEA (92 μL, 0.543 mmol), BOP reagent (96.1 mg, 0.217 mmol) and DMF (0.9 mL) were added to obtain the title compound (22.5 mg, 27.2%) as a yellow solid.

[0485] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 2H), 8.23 ​​(d, J=6.8Hz, 1H), 7.27 (t, J=9.2Hz, 2H), 4.68 (dd, J=13.3, 6.6Hz, 1H), 3.72-3.65 (m, 1H), 3.58 (d, J=16.2Hz , 4H), 3.44 (d, J=8.8Hz, 1H), 3.24 (dd, J=16.4, 7.4Hz, 3H), 3.16-3.09 (m, 1H ), 2.87 (dd, J=15.9, 6.2Hz, 2H), 2.72-2.53 (m, 2H), 2.23-2.03 (m, 2H); LCMS m / z 457[M+H] +

[0486] Example 25. 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetic acid

[0487]

[0488] By the same method as in Example 22, using methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetate (10 mg, 0.022 mmol), 1 N NaOH (223 μL, 0.223 mmol) and THF (0.11 mL) to obtain the title compound as a white solid (8 mg, 82.5%).

[0489] 1 H NMR (400MHz, D2O) δ8.54 (s, 2H), 6.99 (t, J=9.4Hz, 2H), 3.59 (s, 1H), 3.44 (d, J=37.6Hz, 3H), 3.16 (dd, J=17. 6, 7.5Hz, 2H), 3.07-3.02 (m, 1H), 2.76 (d, J=16.1Hz, 2H), 2.60-2.48 (m, 2H), 2.20 (s, 2H), 2.07 (s, 1H); LCMS m / z 443[M+H] +

[0490] Example 26. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-ol

[0491]

[0492] By the same method as in Step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazol-2(3H)-one (0.3 g, 0.906 mmol), 3-hydroxypyrrolidine HCl (0.134 g, 1.09 mmol), DIPEA (462 μL, 2.72 mmol), BOP reagent (0.481 g, 1.09 mmol) and DMF (4.5 mL) to obtain the title compound (0.235 g, 64.8%) as an off-white solid.

[0493] 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 2H), 8.23 ​​(d, J = 6.9Hz, 1H), 7.27 (t, J = 9.3Hz, 2H), 5.08 (d, J = 3.6Hz, 1H), 4.68 (dd, J = 13.9, 7.0Hz, 1H), 4. 38 (s, 1H), 3.58-3.51 (m, 3H), 3.35 (d, J=10.9Hz, 1H), 3.24 (dd, J=16.2, 7.4Hz, 2H), 2.88 (dd, J=16.1, 6.4Hz, 2H), 2.04-1.86 (m, 2H); LCMS m / z 401[M+H] +

[0494] Example 27. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl methanesulfonate

[0495]

[0496] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-ol (0.0191 g, 0.477 mmol) and TEA (100 μL, 0.716 mmol) were dissolved in DCM (1.2 mL), MsCl (41 μL, 0.525 mmol) was added at 0°C, and the mixture was stirred at room temperature for 8 hours. DW was added to the reaction mixture, extracted with DCM, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound (86 mg, 37.7%) as an off-white solid.

[0497] 1H NMR (400MHz, DMSO-d6) δ8.72 (s, 2H), 8.25 (d, J = 6.7Hz, 1H), 7.27 (t, J = 9.3Hz, 2H), 5.41 (s, 1H), 4.68 (dd, J = 14.0, 6.9Hz, 1H), 3.83-3.71 LCMS m / z 479[M+H] +

[0498] Example 28. 5-(5-(3-(1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0499]

[0500] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1-O-oxadiazole-2-yl)pyrrolidin-3-yl methanesulfonate (35 mg, 0.073 mmol) and 1,2,4-triazole (6.1 mg, 0.088 mmol) were dissolved in DMF (0.73 mL), NaH (57% to 63% oil dispersion) (3.5 mg, 0.088 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to 0° C., MeOH was added to terminate the reaction, DW was added, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated, and the resulting residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (32.3 mg, 97.8%) as a white solid.

[0501] 1H NMR (400MHz, DMSO-d6) δ8.73 (s, 2H), 8.65 (s, 1H), 8.24 (d, J = 6.6Hz, 1H), 7.99 (s, 1H), 7.27 (t, J = 9.2Hz, 2H), 5.32-5.24 (m, 1H), 4.68 (dd, J = 13.9, 7 .2Hz, 1H), 3.98 (dd, J=11.0, 6.4Hz, 1H), 3.86-3.62 (m, 4H), 3.24 (dd, J=16.1, 7.3Hz, 2H), 3.15 (d, J=5.3Hz, 1H), 2.87 (dd, J=16.1, 6.3Hz, 2H); LCMS m / z 452[M+H] +

[0502] Example 29. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0503]

[0504] By the same method as in Example 28, using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- In the mixture of oxadiazole-2-yl)pyrrolidin-3-yl methanesulfonate (35 mg, 0.073 mmol), 3-methyl-1H-1,2,4-triazole (7.3 mg, 0.088 mmol), NaH (57% to 63% oil dispersion) (3.5 mg, 0.088 mmol) and DMF (0.73 mL), the title compound was obtained as a white solid (31.4 mg, 92.2%).

[0505] 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 2H), 8.48 (s, 1H), 8.25 (d, J = 7.0Hz, 1H), 7.27 (t, J = 9.2Hz, 2H), 5.20 (d, J = 28.4Hz, 2H), 4.68 (dd, J = 14.3, 7 .4Hz, lH), 3.95 (s, 1H), 3.70 (ddd, J=14.1, 12.3, 5.9Hz, 4H), 3.24 (dd, J=16.0, 7.6Hz, 2H), 2.88 (dd, J=16.0, 6.5Hz, 2H), 2.22 (s, 3H); LCMS m / z 466[M+H] +

[0506] Example 30. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0507] Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0508]

[0509] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The title compound was obtained as an off-white solid (25.5 mg, 63.8%) by mixing oxadiazole-2(3H)-one (23 mg, 0.069 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (31 mg, 0.08 mmol), DIPEA (59 μL, 0.35 mmol), BOP reagent (37 mg, 0.08 mmol) and DMF (2 mL).

[0510] LCMS m / z 580[M+H] +

[0511] Step 2: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0512]

[0513] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (25.5 mg, 0.044 mmol), K2CO3 (12.2 mg, 0.088 mmol) and MeOH (2 mL) to obtain the title compound as a white solid (17.8 mg, 86.9%).

[0514] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (broad, 2H), 8.25 (d, J = 6.9 Hz, 2H), 7.79 (s, 1H), 7.29 (t, J = 9.2 Hz, 3H), 4.77-4.64 (m, 1H), 3.95-3.84 (m, 1H), 3.72-3.62 (m, 1H), 3.62-3.49 (m, 2H), 3.26 (dd, J = 16.0, 7.6 Hz, 3H), 2.89 (dd, J = 16.1, 6.4 Hz, 3H), 2.44-2.31 (m, 1H), 2.20-2.06 (m, 2H), 1.45 (s, 3H); LCMS m / z 466 [M+H] +

[0515] Example 31. N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0516] Step 1: (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0517]

[0518] By the same method as in step 1 of Example 1, using 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The title compound (38.3 mg, 84.9%) was obtained as an off-white solid by mixing oxadiazole-2(3H)-one (24.5 mg, 0.083 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (38 mg, 0.10 mmol), DIPEA (71 μL, 0.41 mmol), BOP reagent (44 mg, 0.10 mmol) and DMF (2 mL).

[0519] LCMS m / z 544[M+H] +

[0520] Step 2: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0521]

[0522] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (38.3 mg, 0.07 mmol), K2CO3 (19.5 mg, 0.14 mmol) and MeOH (2 mL) were added to obtain the title compound as a white solid (15.6 mg, 51.7%).

[0523] 1 H NMR (400MHz, DMSO-d6) δ8.71 (broad, 2H), 8.23 ​​(d, J = 6.8Hz, 1H), 7.79 (s, 1H), 7.23-7.07 (m, 4H), 4.77-4.61 (m, 1H), 3.88 (d, J = 9.7Hz, 1H), 3. 76-3.62 (m, 1H), 3.62-3.48 (m, 2H), 3.27 (dd, J=15.8, 7.6Hz, 2H), 2.93 (dd, J=15.8, 6.9Hz, 2H), 2.44-2.31 (m, 1H), 2.21-2.06 (m, 1H); LCMS m / z 430[M+H] +

[0524] Example 32. N-(3,5-dichlorophenethyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0525] Step 1: (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0526]

[0527] By the same method as in step 1 of Example 1, using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- The title compound (29.6 mg, 68.1%) was obtained as a white solid by mixing oxadiazole-2(3H)-one (25.5 mg, 0.072 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (33 mg, 0.086 mmol), DIPEA (62 μL, 0.36 mmol), BOP reagent (38 mg, 0.086 mmol) and DMF (2 mL).

[0528] LCMS m / z 600[M+H] +

[0529] Step 2: N-(3,5-dichlorophenethyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- Preparation of oxadiazole-2-yl)pyrimidin-2-amine

[0530]

[0531] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (29.6 mg, 0.05 mmol), K2CO3 (13.6 mg, 0.099 mmol) and MeOH (2 mL) were added to obtain the title compound as a white solid (15.4 mg, 64.2%).

[0532] 1 H NMR (400MHz, DMSO-d6) δ8.69 (d, J=6.6Hz, 3H), 7.97 (t, J=5.8Hz, 2H), 7.85 (wide, 1H), 7.42 (s, 1H), 7.32 (s, 2H), 3.86 (d, J=9.7 LCMS m / z486[M+H] +

[0533] Example 33. N-(3,5-difluorobenzyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0534] Step 1: (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0535]

[0536] By the same method as in step 1 of Example 1, using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-

[0147] The title compound (25.7 mg, 68.4%) was obtained as a white solid by mixing oxadiazole-2(3H)-one (21 mg, 0.068 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (31 mg, 0.082 mmol), DIPEA (58 μL, 0.34 mmol), BOP reagent (36 mg, 0.082 mmol) and DMF (2 mL).

[0537] LCMS m / z 554[M+H] +

[0538] Step 2: N-(3,5-difluorobenzyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0539]

[0540] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (25.7 mg, 0.046 mmol), K2CO3 (13 mg, 0.093 mmol) and MeOH (2 mL) were added to obtain the title compound as an off-white solid (16.2 mg, 79.5%).

[0541] 1 H NMR (400MHz, DMSO-d6) δ 8.73 (s, 2H), 8.45 (t, J = 6.4Hz, 1H), 7.79 (wide, 1H), 7.09 (t, J = 9.1Hz, 1H), 7.02 (d, J = 6.5Hz, 2H), 4.58 (d, J =6.3Hz, 2H), 3.87 (d, J = 9.5Hz, 1H), 3.74-3.62 (m, 1H), 3.61-3.42 (m, 2H), 2.44-2.31 (m, 1H), 2.19-2.06 (m, 1H), 1.45 (s, 3H); LCMS m / z 440[M+H] +

[0542] Example 34. (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0543] Step 1: (E)-(4-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0544]

[0545] By the same method as in step 2 of Example 20, using (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (21.1 mg, 0.075 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (34.2 mg, 0.09 mmol), DIPEA (38 μL, 0.22 mmol), HBTU (34 mg, 0.090 mmol) and DMF (2 mL), the title compound (29.7 mg, 75%) was obtained as a white solid.

[0546] Step 2: (E)-3-(2-((2,3-hydrogen-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0547]

[0548] By the same method as in step 2 of Example 1, using (E)-(4-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (29.7 mg, 0.056 mmol), K2CO3 (15.5 mg, 0.11 mmol) and MeOH (2 mL), the title compound (8.6 mg, 36.9%) was obtained as a light brown solid.

[0549] 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 2H), 7.98 (d, J=7.0Hz, 1H), 7.33 (dd, J=15.6, 2.9Hz, 1H ), 7.27-7.08 (m, 4H), 6.90 (dd, J=20.5, 15.9Hz, 1H), 4.73-4.56 (m, 1H), 4.01 (d, J=8.2H z, 1H), 3.86-3.75 (m, 1H), 3.74-3.63 (m, 1H), 3.61-3.51 (m, 1H), 3.51-3.41 (m, 1H), 3.2 5 (dd, J=15.7, 7.5Hz, 6H), 2.91 (dd, J=15.7, 6.6Hz, 2H), 1.40 (d, J=7.9Hz, 3H); LCMSm / z 416[M+H] +

[0550] Example 35. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0551] Step 1: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynylpyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0552]

[0553] By the same method as in Step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (70 mg, 0.211 mmol), 3-ethynylpyrrolidine, 2,2,2-trifluoroacetate (49 mg, 0.254 mmol), DIPEA (108 μL, 0.634 mmol), BOP reagent (112 mg, 0.254 mmol) and DMF (1.1 mL) were added to afford the title compound (59.5 mg, 68.9%) as an orange solid.

[0554] 1 H NMR (400MHz, DMSO-d6) δ8.83-8.71 (m, 2H), 8.30 (d, J=6.7Hz, 1H), 7.32 (t, J=9.2 Hz, 2H), 4.73 (dd, J=13.6, 6.8Hz, 1H), 3.82-3.77 (m, 1H), 3.63 (s, 1H), 3.55 (t, J= 8.6Hz, 1H), 3.48-3.42 (m, 1H), 3.37 (s, 2H), 3.29 (dd, J=16.1, 7.5Hz.2H), 2.92 ( dd, J=15.9, 6.5Hz, 2H), 2.30 (d, J=6.9Hz, 1H), 2.04 (dd, J=12.2, 7.5Hz, 1H); LCMS m / z 409[M+H] +

[0555] Step 2: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0556]

[0557] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynylpyrrolidin-1-yl)-1,3,4- 1-oxadiazole-2-yl)pyrimidin-2-amine (20 mg, 0.049 mmol) was dissolved in MeOH (45 μL), then azidomethane (66 μL), ascorbic acid (1.7 mg, 0.010 mmol) in DW (12 μL) and CuSO4-5H2O (1.0 mg, 0.004 mmol) in DW (12 μL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the resulting residue was purified by column chromatography (MeOH / DCM) to give the title compound (5 mg, 21.9%) as a yellow solid.

[0558] 1 H NMR (400 MHz, CD 33 OD) δ8.77 (s, 2H), 7.89 (s, 1H), 7.12 (t, J=9.0Hz, 2H), 4.38 (s, 2H), 4.25 (dd, J=9. 4, 6.2Hz, 2H), 3.73 (dd, J=21.0, 7.3Hz, 4H), 3.36 (s, 5H), 2.97-2.89 (m, 2H); LCMS m / z 466[M+H] +

[0559] Example 36. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0560] Step 1: 5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0561]

[0562] The title compound was prepared by the same method as in Preparation Example 3, except that 5-fluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0563] LCMS m / z 314[M+H] +

[0564] Step 2: (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0565]

[0566] By the same method as in step 1 of Example 1, using 5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The mixture was stirred at 40 °C for 2 h: 2 h: 10 min, 30 min, 45 min, 80 min, 10 min.

[0137] The mixture was stirred at 40 °C for 2 h: 10 min, 30 min, 45 min, 80 min, 10 min.

[0138] The mixture was stirred at 40 °C for 2 h: 10 min, 30 min, 45 min, 80 min, 10 min. [0139 ...

[0567] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 2H), 7.66 (s, 1H), 7.16 (dd, J=7.9, 5.4Hz, 1H), 6 .93 (d, J=8.4Hz, 1H), 6.87 (t, J=8.2Hz, 1H), 6.21 (s, 2H), 5.68 (d, J=7.5Hz, 1H) .4.95-4.82(m, 1H), 4.05(s, 1H), 3.85-3.66(m, 4H), 3.45-3.31(m, 2H), 2.87(t d, J=16.0, 4.9Hz, 2H), 2.57-2.43(m, 1H), 2.41-2.26(m, 1H), 1.19(s, 9H); LCMS m / z 548[M+H] +

[0568] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0569]

[0570] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (17.3 mg, 0.032 mmol), K2CO3 (8.8 mg, 0.064 mmol) and MeOH (0.73 mL) to obtain the title compound as a yellow solid (13.5 mg, 99%).

[0571] 1 H NMR (400MHz, DMSO-d6) 68.73 (s, 2H), 8.24 (d, J=6.6Hz, 1H), 7.80 (br s, 1H), 7.28-7.19 (m, 1H), 7.06 (d, J=8.8Hz, 1H), 6.96 (t, J=9.0Hz, 1H), 4.70 (dd, J=14.3, 6.9Hz, 1H), 3.93 (t, J= 8.0Hz, 1H), 3.74-3.55(m, 4H), 3.31-3.20(m, 2H), 2.99-2.82(m, 2H), 2.45-2.35(m, 1H), 2.24-2.10(m, 1H); LCMS m / z 434[M+H] +

[0572] Example 37. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0573] Step 1: 5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0574]

[0575] The title compound was prepared by the same method as in Preparation Example 3, except that 5-chloro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0576] 1H NMR(400MHz,DMSO-d6)δ12.44(br s, 1H), 8.66 (d, J=17.0Hz, 2H), 8.34 (d, J=6.9Hz, 1H), 7.29 (s, 1H), 7.22 (dd, J= 18.6, 8.0Hz, 2H), 4.74-4.63(m, 1H), 3.30-3.21(m, 2H), 2.98-2.84(m, 2H); LCMS m / z 330[M+H] +

[0577] Step 2: (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0578]

[0579] By the same method as in step 1 of Example 1, using 5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The mixture was added with oxadiazole-2(3H)-one (21.4 mg, 0.065 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (32 mg, 0.09 mmol), DIPEA (57.5 μL, 0.34 mmol), BOP reagent (34.5 mg, 0.08 mmol) and DMF (1.3 mL) to obtain the title compound (7.5 mg, 20%) as a white solid.

[0580] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 2H), 7.66 (s, 1H), 7.22 (s, 1H), 7.16 (s, 2H), 6.21 (s, 2H), 5.69 (d, J=7.6Hz, 1H), 4.92-4.82 (m, 1H), 4.05 (s , 1H), 3.84-3.67(m, 4H), 3.44-3.32(m, 2H), 2.88(ddd,J=16.4, 11.3, 5.2Hz, 2H), 2.56-2.45(m, 1H), 2.39-2.27(m, 1H), 1.19(s, 9H); LCMS m / z564[M+H] +

[0581] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0582]

[0583] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (7 mg, 0.012 mmol), K2CO3 (3.3 mg, 0.024 mmol) and MeOH (0.45 mL) to obtain the title compound as a white solid (5 mg, 89%).

[0584] 1 H NMR (400MHz, DMSO-d6) 68.73 (s, 2H), 8.24 (d, J=6.6Hz, 1H), 7.80 (br s, 1H), 7.29 (s, 1H), 7.22 (dd, J=19.3, 7.8Hz, 2H), 4.68 (q, J=6.8Hz, 1H), 3.92 (dd, J=9.0, 7.7Hz, 1H), 3.75 LCMS m / z 450[M+H] +

[0585] Example 38. 5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0586] Step 1: Preparation of 4-(pyrrolidin-3-yl)-1H-imidazole, 2,2,2-trifluoroacetate

[0587]

[0588] By the same method as in Step 2 of Preparation Example 1, using tert-butyl 3-(1H-imidazol-4-yl)pyrrolidine-1-carboxylate (50 mg, 0.21 mmol), TFA (2 mL) and DCM (4 mL), the title compound was obtained (quantitatively) and used in the next reaction without purification (23 mg).

[0589] LCMS m / z 138 [M+H] +

[0590] Step 2: 5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0591]

[0592] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazol-2(3H)-one (30 mg, 0.09 mmol), 4-(pyrrolidin-3-yl)-1H-imidazole, 2,2,2-trifluoroacetate (23 mg, 0.1 mmol), BOP reagent (49 mg, 0.11 mmol), DIPEA (213 μL, 1.22 mmol) and DMF (1 mL) to obtain the title compound (3 mg, 7%) as a white solid.

[0593] 1 H NMR (400MHz, CD3OD) δ8.78 (s, 2H), 7.70 (s, 1H), 7.14 (t, J=8.0Hz, 2H), 4.87-4.84 (m, 1H), 3.79-3.64 (m, 4H), 3.38-3.36(m, 2H), 3.26-3.24(m, 1H), 2.97-2.92(m, 2H), 2.44-2.40(m, 1H), 2.28-2.24(m, 1H); LCMS m / z 451[M+H] +

[0594] Example 39. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0595]

[0596] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the mixture of oxadiazol-2(3H)-one (30 mg, 0.091 mmol), 4-(azetidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate (24.1 mg, 0.109 mmol), DIPEA (46 μL, 0.272 mmol), BOP reagent (48.1 mg, 0.109 mmol) and DMF (0.5 mL) was added to give the title compound (21.3 mg, 53.8%) as a yellow solid.

[0597] 1 H NMR (400MHz, DMSO-d6) δ8.71 (d, J=10.0Hz, 2H), 8.28 (d, J=6.6Hz, 1H), 7.91 (s, 1H), 7.27 (t, J=9.4Hz, 2H), 4.69 (d d, J=13.7, 6.8Hz, 1H), 4.50 (s, 2H), 4.21 (s, 3H), 3.24 (dd, J=15.9, 7.6Hz, 2H), 2.88 (dd, J=16.1, 6.7Hz, 2H); LCMS m / z 438[M+H] +

[0598] Example 40. (E)-1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0599] Step 1: (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0600]

[0601] By the same method as in Step 3 of Example 9, using (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (60 mg, 0.189 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (76.1 mg, 0.227 mmol), DIPEA (96 μL, 0.567 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, HBTU (86.1 mg, 0.227 mmol) and DMF (3.4 mL), the title compound (86.1 mg, 84.7%) was obtained as a white solid.

[0602] 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 2H), 8.24 (s, 1H), 8.00 (d, J=6.5Hz, 1H), 7. 27 (dd, J=23.0, 12.7Hz, 3H), 6.66 (d, J=15.8Hz, 1H), 6.28 (s, 2H), 4.66-4.6 2 (m, 1H), 4.31 (t, J=6.9Hz, 2H), 3.99 (t, J=5.6Hz, 2H), 3.22 (dd.J=16.1, 7. 7Hz, 2H), 3.14-3.11 (m, 1H), 2.86 (dd, J=16.2, 6.8Hz, 2H), 1.11 (s, 9H); LCMS m / z 538[M+H] +

[0603] Step 2: (E)-1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one

[0604]

[0605] By the same method as in Example 3, using (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)acryloyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (80 mg, 0.149 mmol), K2CO3 (41.1 mg, 0.298 mmol) and MeOH (0.7 mL), the title compound (32 mg, 50.8%) was obtained as a yellow solid.

[0606] 1H NMR (400MHz, DMSO-d6) δ 8.66 (s, 2H), 8.00 (d, J = 7.0Hz, 1H), 7.87 (s, 1H), 7.27 (dd, J = 22.4, 12.6Hz, 3H), 6.66 (d, J = 15.7Hz, 1H), 4.65 (dd, J = 1 4.6, 7.0Hz, 1H), 4.33-4.26 (m, 2H), 4.04-3.94 (m, 2H), 3.22 (dd, J=16.0, 7.2Hz, 2H), 3.15 (d, J=5.1Hz, 1H), 2.86 (dd, J=16.3, 6.4Hz, 2H); LCMS m / z 424[M+H] +

[0607] Example 41. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0608] Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0609]

[0610] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0147] The product was prepared by mixing oxadiazole-2(3H)-one (0.1 g, 0.302 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (0.122 g, 0.362 mmol), DIPEA (154 μL, 0.906 mmol), BOP reagent (0.160 g, 0.362 mmol) and DMF (1.5 mL) to obtain the title compound (47.8 mg, 28.7%) as a white solid.

[0611] 1H NMR (400MHz, DMSO-d6) δ8.71 (s, 2H), 8.29-8.28 (m, 1H), 7.27 (t, J = 9.2Hz, 2H), 6.28 (s, 2H), 4.69 (dd, J = 14.3, 7.1Hz, 1H) , 4.50 (s, 2H), 4.22 (d, J = 3.3Hz, 3H), 3.24 (dd, J = 15.9, 7.8Hz, 2H), 2.88 (dd, J = 16.1, 6.7Hz, 2H), 1.14-1.08 (m, 9H); LCMS m / z 552[M+H] +

[0612] Step 2: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0613]

[0614] (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1H-1,2,3-triazol-1-yl)methyl pivalate (45 mg, 0.082 mmol) and MeOTf (11 μL, 0.098 mmol) were dissolved in a small amount of DCM and stirred at room temperature overnight. MeOH (0.41 mL) was added to the reaction mixture, followed by KCO (22.6 mg, 0.163 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and concentrated, and the obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound (3.4 mg, 8.9%) as a yellow solid.

[0615] 1 H NMR (400MHz, DMSO-d6) δ8.70 (d, J=11.5Hz, 2H), 8.31-8.24 (m, 1H), 7.88 (s, 1H), 7.31-7.22 (m, 2H), 4.69 (dd, J=13.5, 6.7Hz, 1H), 4.54(dt, J=7.5, 3.8Hz, 2H), 4.28-4.19(m, 2H), 3.94-3.81(m, 3H), 3.27-3.21(m, 2H), 3.15-3.08(m, 1H), 2.92-2.83(m, 2H); LCMS m / z 452[M+H]+

[0616] Example 42. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0617] Step 1: (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0618]

[0619] By the same method as in step 1 of Example 1, using 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0147] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr. at 40 °C for 3 hours at 5 °C.

[0148] The product was stirred at 40 °C for 24 hours at 5 °C for 3 hours at 5 °C for 3 hours at 5 °C.

[0149] The product was stirred at 40 °C for 24 hours at 5 °C for 3 hours at 5 °C.

[0149] The product was stirred at 40 °C for 3 hours at 5 °C for 3 hours at 5 °C.

[0149] The product was stirred at 40 °C for 3 hours at 5 °C for 4 hours at 5 °C.

[0620] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 2H), 7.76 (s, 1H), 7.26-7.16 (m, 4H), 6.23 (s, 2H), 5.78 (d, J=7.8Hz, 1H), 4.92-4.84 (m, 1H), 4.60 (t, J =8.3Hz, 2H), 4.41 (t, J = 7.6Hz, 2H), 4.27-4.20 (m, 1H), 3.42 (dd, J = 15.9, 6.9Hz, 2H), 2.91 (dd, J = 15.9, 5.1Hz, 2H), 1.20 (s, 9H); LCMS m / z 516[M+H] +

[0621] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0622]

[0623] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (39 mg, 0.076 mmol), K2CO3 (21 mg, 0.15 mmol) and MeOH (1.5 mL) were added to obtain the title compound as a white solid (19.5 mg, 63.6%).

[0624] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=16.6Hz, 2H), 8.27 (d, J=6.9Hz, 1H), 7.93 (s, 1H), 7.29-7.07 (m, 4H), 4.73-4.64 (m 1H), 4.52 (s, 2H), 4.23 (s, 3H), 3.27 (dd, J=15.9, 7.5Hz, 2H), 2.93 (dd, J=15.7, 6.8Hz, 2H); LCMS m / z 402[M+H] +

[0625] Example 43. 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisocyanate oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0626] Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisoxazine oxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0627]

[0628] By the same method as in step 3 of Example 17, using 5-(3-bromo-4,5-dihydroisoxazine To the mixture was added 4-(4-((4-((((-(((-((-((-((-((-((-((-((-((-((-((-1H-triazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)-pivalate)-2-amine))-5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (0.150 g, 0.380 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (0.153 g, 0.455 mmol), Na2CO3 (0.101 g, 0949 mmol) and t-BuOH (3.4 mL)) to obtain the title compound as a yellow solid (43.8 mg, 20.9%).

[0629] 1 H NMR (400MHz, DMSO-d6) δ8.32 (s, 2H), 8.22 (s, 1H), 7.62 (d, J = 7.4Hz, 1H), 7.25 (s, 2H), 6.28 (s, 2H), 5.27 (d, J = 19.1Hz, 2H), 4 .65-4.59 (m, 2H), 4.20 (dd, J=12.1, 4.7Hz, 2H), 3.95 (d, J=6.8Hz, 1H), 3.19 (s, 4H), 2.83 (d, J=9.6Hz, 2H), 1.11 (s, 9H); LCMS m / z553[M+H] +

[0630] Step 2: 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisoxadiazole oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0631]

[0632] By the same method as in Example 3, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisocyanate oxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (15 mg, 0.027 mmol), K2CO3 (7.5 mg, 0.054 mmol) and MeOH (0.14 mL) to obtain the title compound as a white solid (10.8 mg, 90.7%).

[0633] 1H NMR (400MHz, DMSO-d6) δ8.32 (s, 2H), 7.77 (s, 1H), 7.62 (d, J=6.8Hz, 1H), 7.25 (t, J=9.3Hz, 2H), 5.27 (t, J=9.1Hz, 1H), 4.61 (dd, J=14.1, 7.2Hz, 1H), 4.20 (t, J=7.7Hz, 2H), 4.03 (dd, J=12.0, 4.9Hz, 2H), 3.93 (d, J=5.8Hz, 2H), 3.20 (d, J=8 .4Hz, 2H), 3.02 (dd, J=15.9, 9.6Hz, 1H), 2.83 (dd, J=15.8, 6.5Hz, 2H); LCMSm / z 439[M+H] +

[0634] Example 44. 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one

[0635] Step 1: (4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0636]

[0637] By the same method as in step 3 of Example 9, using 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid (52 mg, 0.163 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (65.5 mg, 0.195 mmol), DIPEA (83 μL, 0.489 mmol), HBTU (74.4 mg, 0.195 mmol) and DMF (3.3 mL), the title compound (60 mg, 68.3%) was obtained as a yellow solid.

[0638] LCMS m / z 540[M+H] +

[0639] Step 2: 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one

[0640]

[0641] By the same method as in Example 3, using (4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (40 mg, 0.074 mmol), K2CO3 (20.5 mg, 0.148 mmol) and MeOH (0.4 mL) to obtain the title compound as a yellow solid (18.4 mg, 58.3%).

[0642] 1 H NMR (400MHz, DMSO-d6) δ8.17 (s, 2H), 7.28 (d, J=6.9Hz, 1H), 7.24 (t, J=9.4Hz , 2H), 4.57 (dd, J=14.0, 6.9Hz, 1H), 4.44 (t, J=8.4Hz, 1H), 4.20 (t, J=8.5Hz, 1 H), 4.10 (d, J=6.3Hz, 1H), 3.96-3.84 (m, 2H), 3.19 (dd, J=16.3, 7.6Hz, 2H), 2. 81 (dd, J=15.6, 6.7Hz, 2H), 2.59 (t, J=7.5Hz, 2H), 2.32 (t, J=7.3Hz, 2H); LCMS m / z 426[M+H] +

[0643] Example 45. 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0644] Step 1: (4-(1-(5-(2-(((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)iso oxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0645]

[0646] By the same method as in Example 18, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisocyanate Toluene (2.3 mL) was added 4-(4-(2-nitro-1H-1,2,3-triazol-1-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (25 mg, 0.045 mmol), I2 (17.2 mg, 0.068 mmol), imidazole (9.2 mg, 0.136 mmol) and toluene (2.3 mL) to obtain the title compound (6.5 mg, 26.1%) as a white solid.

[0647] 1 H NMR (400MHz, CD3OD) δ8.66 (s, 2H), 8.10 (s, 1H), 7.10 (t, J=9.0Hz, 2H), 6.30 (s, 2H), 6.29 (s, 1H), 4.83-4.77 (m, 3H), 4 .39 (t, J=7.5Hz, 2H), 4.19 (dd, J=13.6, 7.7Hz, 1H), 4.14-4.10 (m, 2H), 2.91 (dd, J=15.8, 6.1Hz, 2H), 1.18 (s, 8H); LCMS m / z 551[M+H] +

[0648] Step 2: 5-(3-(3-((1H-1,2,3-triazol-4-yl)azetidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0649]

[0650] By the same method as in Example 3, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)iso oxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (6.5 mg, 0.012 mmol), K2CO3 (3.3 mg, 0.024 mmol) and MeOH (0.1 mL) afforded the title compound as a white solid (0.8 mg, 15.5%).

[0651] 1H NMR (400MHz, CD3OD) δ8.66 (s, 2H), 7.80 (s, 1H), 7.11 (t, J=9.0Hz, 2H), 6.29 (s, 1H), 4.81 (dd, J=13.8, 7.3Hz, 3H ), 4.40 (t, J=7.7Hz, 2H), 4.22 (dt, J=15.6, 7.8Hz, 1H), 4.11 (t, J=6.6Hz, 2H), 2.91 (dd, J=15.8, 6.1Hz, 2H); LCMS m / z 437[M+H] +

[0652] Example 46. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-sulfonamide

[0653]

[0654] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- A solution of oxadiazol-2(3H)-one (60 mg, 0.181 mmol), azetidine-3-sulfonamide hydrochloride (37.5 mg, 0.217 mmol), DIPEA (92 μL, 0.543 mmol), BOP reagent (96.1 mg, 0.217 mmol) and DMF (0.9 mL) was added to obtain the title compound (31 mg, 38.3%) as a white solid.

[0655] 1 H NMR (400MHz, DMSO-d6) δ8.72 (d, J=13.8Hz, 2H), 8.29 (d, J=6.8Hz, 1H), 7.30-7.24 (m, 4H), 4.68 (dd, J=13.9, 6.9Hz, 1H), 4.44 (d, J=7.6Hz, 2H), 4.30-4.24 (m, 3H), 3.24 (dd, J=16.0, 7.5Hz, 2H), 2.88 (dd, J=16.0, 6.5Hz, 2H); LCMSm / z 450[M+H] +

[0656] Example 47. Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylate

[0657]

[0658] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (60 mg, 0.18 mmol), methyl 3-pyrrolidinecarboxylate hydrochloride (33 mg, 0.22 mmol), DIPEA (92 μL, 0.54 mmol), BOP reagent (96 mg, 0.22 mmol) and DMF (0.9 mL) were added to obtain the title compound (46 mg, 59%) as a white solid.

[0659] 1 H NMR (400MHz, CDCl3) δ8.77 (s, 2H), 7.02 (t, J=8.8Hz, 2H), 5.67 (d, J=7.4Hz, 1H), 4.93-4.84 (m, 1H), 4.41 (s, 2H) , 4.40 (s, 2H), 3.79 (s, 3H), 3.71-3.63 (m, 1H), 3.36 (dd, J=16.3, 7.0Hz, 2H), 2.85 (dd, J=16.0.5.4Hz, 2H); LCMS m / z 429[M+H] +

[0660] Example 48. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0661] Step 1: (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0662]

[0663] By the same method as in step 1 of Example 1, using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-

[0137] The product of the reaction mixture was added to the mixture of oxadiazole-2(3H)-one (39.7 mg, 0.13 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (55 mg, 0.16 mmol), DIPEA (111 μL, 0.65 mmol), BOP reagent (69.3 mg, 0.16 mmol) and DMF (1.3 mL) to obtain the title compound (48.9 mg, 71.6%) as a white solid.

[0664] 1 H NMR (400MHz, CD3OD) δ8.74 (d, J=1.5Hz, 2H), 8.13 (s, 1H), 6.94 (d, J=6.7Hz, 2H), 6.79 (t, J=9.2Hz, 1H), 6. 30 (s, 2H), 4.65 (s, 2H), 4.61 (t, J=8.2Hz, 2H), 4.36 (t, J=6.4Hz, 2H), 4.32-4.24 (m, 1H), 1.17 (s, 9H); LCMS m / z 526[M+H] +

[0665] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0666]

[0667] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (39 mg, 0.095 mmol), K2CO3 (26.2 mg, 0.19 mmol) and MeOH (2 mL) to obtain the title compound as a white solid (31.7 mg, 81.3%).

[0668] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (broad, 2H), 8.49 (t, J = 6.3 Hz, 1H), 7.89 (s, 1H), 7.09 (t, J = 9.3 Hz, 1H), 7.02 (d, J = 6.9 Hz, 2H), 4.58 (d, J = 6.2 Hz, 2H), 4.51 (m, 2H), 4.22 (m, 3H); LCMS m / z 412 [M+H] +

[0669] Example 49. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-ol

[0670]

[0671] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazol-2(3H)-one (60 mg, 0.181 mmol), azetidin-3-ol, 2,2,2-trifluoroacetate (37.0 mg, 0.217 mmol), DIPEA (92 μL, 0.543 mmol), BOP reagent (96.1 mg, 0.217 mmol) and DMF (0.9 mL) to obtain the title compound (25 mg, 35.7%) as a white solid.

[0672] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 2H), 8.26 (d, J = 6.9Hz, 1H), 7.27 (t, J = 9.3Hz, 2H), 5.84 (d, J = 6.6Hz, 1H), 4.68 (dd, J = 13.6.7.0Hz, 1H), 4.61 (d, J=6.8Hz, 1H), 4.33-4.27 (m, 2H), 3.89 (dd, J=8.6.4.9Hz, 2H), 3.24 (dd, J=16.0.7.6Hz, 2H), 2.87 (dd, J=16.0, 6.4Hz, 2H); LCMS m / z 387[M+H] +

[0673] Example 50. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylic acid

[0674]

[0675] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1-oxadiazole-2-yl)azetidine-3-carboxylate (34 mg, 0.08 mmol) was dissolved in THF (0.40 mL), 1N NaOH (0.2 mL, 0.20 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 1N HCl was added to the reaction mixture to adjust the pH to 2, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (32 mg, 97%) as a white solid.

[0676] 1 H NMR (400MHz, DMSO-d6) δ12.80 (s, 1H), 8.71 (s, 2H), 8.29 (d, J=6.8Hz, 1H), 7.29 (t, J=9.2Hz, 2H), 4.75-4.64 (m, 1H), 4.32 LCMS m / z 415[M+H] +

[0677] Example 51. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0678] Step 1: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-methylazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0679]

[0680] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (70.7 mg, 0.21 mmol), 3-ethynyl-3-methylazetidine, 2,2,2-trifluoroacetate (53.6 mg, 0.26 mmol), DIPEA (182 μL, 1.07 mmol), BOP reagent (113.3 mg, 0.26 mmol) and DMF (2 mL) to obtain the title compound (60.0 mg, 68.8%) as a yellow solid.

[0681] LCMS m / z 409[M+H] +

[0682] Step 2: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0683]

[0684] By the same method as in Step 1 of Preparation Example 2, using N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-methylazetidin-1-yl)-1,3,4-

[0137] The reaction mixture was stirred for 2 h. The mixture was stirred for 2 h. The title compound was obtained as an off-white solid (5.15 mg, 21.2% yield).

[0685] 1 H NMR (400 MHz, CD3OD) δ 8.74 (broad, 2H), 7.84 (broad, 1H), 7.10 (t, J = 9.0 Hz, 2H), 4.84-4.78 (m, 1H), 4.49 (d, J = 7.7 Hz, 2H), 4.23 (d, J = 7.8 Hz, 2H), 3.34 (d, J = 7.3 Hz, 2H), 2.92 (dd, J = 15.9, 6.1 Hz, 2H), 1.81 (s, 3H); LCMS m / z 452 [M+H] +

[0686] Example 52. Methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetate

[0687]

[0688] 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Diazole -2 (3H) -one (60mg, 0.18mmol) was dissolved in DMF (0.9mL), methyl 2- (azetidine -3- bases) acetate hydrochloride (36mg, 0.22mmol) was added, and the mixture was cooled to 0 ° C. Then, DIPEA (92 μL, 0.54mmol) was added, and the mixture was stirred for 30 minutes, after which BOP reagent (96mg, 0.22mmol) was added, and the mixture was stirred at room temperature for 3 hours. DW was added to the reaction mixture, and the resulting solid was filtered and washed with DW and hexane. The filtered solid was dried to obtain the title compound (59mg, 74%) as a white solid without further purification.

[0689] 1 H NMR (400MHz, CDCl3) δ8.77 (s, 2H), 7.02 (t, J=8.8Hz, 2H), 5.63 (d, J=7.6Hz, 1H), 4.93-4.84 (m, 1H), 4.39 (t, J=8.3Hz, 2H), 3.93 (dd, J=8 .0, 5.8Hz, 2H), 3.71 (s, 3H), 3.36 (dd, J=15.8, 7.0Hz, 2H), 3.26-3.17 (m, 1H), 2.85 (dd, J=16.1, 5.3Hz, 2H), 2.75 (d, J=7.7Hz, 2H); LCMS m / z 443[M+H] +

[0690] Example 53. 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetic acid

[0691]

[0692] By the same method as in Example 50, using methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetate (39 mg, 0.09 mmol), 1 N NaOH (0.22 mL, 0.22 mmol) and THF (0.44 mL) to obtain the title compound as a white solid (23 mg, 61%).

[0693] 1H NMR (400MHz, DMSO-d6) δ12.24 (s, 1H), 8.71 (s, 2H), 8.28 (d, J = 6.7Hz, 1H), 7.29 (t, J = 9.3Hz, 2H), 4.75-4.65 (m, 1H), 4.23 (t, J = 8.1H LCMS m / z 429[M+H] +

[0694] Example 54. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine

[0695] Step 1: 5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0696]

[0697] The title compound was prepared by the same method as in Preparation Example 3, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine, and ethyl 6-chloronicotinate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0698] LCMS m / z 331[M+H] +

[0699] Step 2: (4-(1-(5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0700]

[0701] By the same method as in step 1 of Example 1, using 5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-

[0136] The title compound was obtained as an off-white solid (41.3 mg, 81.2%) by mixing oxadiazole-2(3H)-one (30.5 mg, 0.092 mmol), (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (39 mg, 0.11 mmol), DIPEA (158 μL, 0.92 mmol), BOP reagent (98 mg, 0.22 mmol) and DMF (3 mL).

[0702] 1 H NMR (400MHz, CDCl3) δ8.60 (d, J=1.8Hz, 1H), 7.96 (dd, J=8.8, 2.2Hz, 1H), 7.76 (s, 1 H), 7.02 (t, J=8.8Hz, 2H), 6.45 (d, J=8.7Hz, 1H), 6.23-6.22 (m, 2H), 5.08 (d, J=7.4 Hz, 1H), 4.78-4.68 (m, 1H), 4.59 (t, J=8.3Hz, 2H), 4.44-4.37 (m, 2H), 4.26-4.18 (m , 1H), 3.37 (dd, J=16.0, 6.9Hz, 2H), 2.85 (dd, J=16.0, 4.7Hz, 2H), 1.20 (s, 9H); LCMS m / z551[M+H] +

[0703] Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine

[0704]

[0705] By the same method as in step 2 of Example 1, using (4-(1-(5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (35.1 mg, 0.064 mmol), K2CO3 (18 mg, 0.13 mmol) and MeOH (1.3 mL) were added to obtain the title compound as a white solid (17.8 mg, 63.7%).

[0706] 1H NMR (400MHz, DMSO-d6) δ8.47 (d, J=2.0Hz, 2H), 7.86 (s, 1H), 7.78 (dd, J=8.8, 2.2Hz, 2H), 7.57 (d, J=6.5Hz, 2H), 7.31 (t, J=9.3Hz, 4H), 6. 60 (d, J=8.8Hz, 2H), 4.74-4.63 (m, 1H), 4.56-4.46 (m, 2H), 4.21 (s, 3H), 3.28 (dd, J=16.2, 7.3Hz, 2H), 2.82 (dd, J=16.1, 5.4Hz, 2H); LCMS m / z 437[M+H] +

[0707] Example 55. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl methanesulfonate

[0708]

[0709] By the same method as in Example 27, using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2-yl)azetidin-3-ol (21 mg, 0.054 mmol), MsCl (4.6 μL, 0.060 mmol), TEA (11 μL, 0.082 mmol) and DCM (0.14 mL) to obtain the title compound as a white solid (15 mg, 59.4%).

[0710] 1 H NMR (400MHz, DMSO-d6) δ8.71 (d, J=13.7Hz, 2H), 8.30 (d, J=6.7Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 5.45 (ddd, J=10.7, 6.7, 3.9Hz, 1H), 4.73-4 .63 (m, 1H), 4.57-4.50 (m, 2H), 4.26 (dd, J=9.7, 4.3Hz, 2H), 3.28 (s, 3H), 3.24 (dd, J=16.1, 7.7Hz, 2H), 2.87 (dd, J=16.1, 6.4Hz, 2H); LCMS m / z 465[M+H] +

[0711] Example 56. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0712] Step 1: 3-Ethynyl-3-fluoroazetidine, 2,2,2-trifluoroacetate

[0713]

[0714] By the same method as in Step 2 of Preparation Example 1, using tert-butyl 3-ethynyl-3-fluoroazetidine-1-carboxylate (199 mg, 1.0 mmol), TFA (3.3 mL) and DCM (10 mL), the title compound was obtained (quantitatively) and used in the next reaction without purification (196 mg).

[0715] Step 2: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0716]

[0717] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (232 mg, 0.7 mmol), 3-ethynyl-3-fluoroazetidine, 2,2,2-trifluoroacetate (196 mg, 1.0 mmol), BOP reagent (371 mg, 0.84 mmol), DIPEA (872 μL, 5.0 mmol) and DMF (5 mL) were added to obtain the title compound (200 mg, 69%) as a white solid.

[0718] 1 LCMS m / z 413[M+H] +

[0719] Step 3: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0720]

[0721] By the same method as in Step 1 of Preparation Example 2, using N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4-

[0137] In the mixture of oxadiazol-2-yl)pyrimidin-2-amine (100 mg, 0.24 mmol), TMSN3 (38 μL, 0.29 mmol), CuI (5 mg, 0.0265 mmol) and DMF (3 mL) / MeOH (0.3 mL) to obtain the title compound (10 mg, 9%) as a white solid.

[0722] 1 LCMS m / z 456[M+H] +

[0723] Example 57. 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carbonitrile

[0724]

[0725] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (100 mg, 0.30 mmol), azetidine-3-carbonitrile, 2,2,2-trifluoroacetate (98 mg, 0.55 mmol), DIPEA (257 μL, 1.51 mmol), BOP reagent (160 mg, 0.36 mmol) and DMF (3 mL) to obtain the title compound (53 mg, 44%) as a white solid.

[0726] 1H NMR (400MHz, DMSO-d6) δ8.72 (d, J=16.8Hz, 2H), 8.32 (d, J=6.7Hz, 1H), 7.29 (t, J=9.3Hz, 2H), 4.76-4.64 (m, 1H), 4.45 LCMS m / z 396[M+H] +

[0727] Example 58. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0728] Step 1: tert-Butyl 3-(1H-tetrazol-5-yl)azetidine-1-carboxylate

[0729]

[0730] Tert-butyl 3-cyanoazetidine-1-carboxylate (1.0 g, 5.5 mmol) was dissolved in DMF (30 mL), NaN (1.1 g, 18 mmol), NH4Cl (0.94 g, 18 mmol) were added and stirred overnight at 110 ° C. The reaction mixture was concentrated, distilled water was added, pH was adjusted to 1 to 2 with 1N HCl, and extracted with EtOAc (3 times). The organic layers were combined, dried over MgSO4, filtered and concentrated, and the residue obtained was purified by column chromatography (0% to 3% MeOH in DCM) to obtain the title compound (1.2 g, 97%) as a colored solid.

[0731] LCMS m / z 224[MH] -

[0732] Step 2: tert-butyl 3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidine-1-carboxylate

[0733]

[0734] Tert-butyl 3-(1H-tetrazolyl-5-yl)azetidine-1-carboxylate (30 mg, 0.13 mmol) was dissolved in DCM (2 mL), trifluoroacetic anhydride (28 μL, 0.20 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to give the title compound as a colorless oil (quantitatively), which was used in the next step without purification (39 mg).

[0735] 1 H NMR (400MHz, DMSO-d6) δ4.29-4.10 (m, 4H), 3.85 (s, 1H), 1.40 (s, 9H).

[0736] Step 3: 2-(azetidin-3-yl)-5-(trifluoromethyl)-1,3,4- Oxadiazole, 2,2,2-trifluoroacetate

[0737]

[0738] By the same method as in step 2 of Preparation Example 1, tert-butyl 3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidine-1-carboxylate (39 mg, 0.13 mmol), TFA (1 mL) and DCM (2 mL) to afford the title compound as a colorless oil (quantitatively), which was used in the next reaction without purification (41 mg).

[0739] Step 4: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0740]

[0741] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (37 mg, 0.11 mmol), 2-(azetidin-3-yl)-5-(trifluoromethyl)-1,3,4- Oxadiazole, 2,2,2-trifluoroacetate (39 mg, 0.13 mmol), DIPEA (94 μL, 0.56 mmol), BOP reagent (59 mg, 0.13 mmol) and DMF (2 mL) afforded the title compound as a white solid (35 mg, 62%).

[0742] 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J=13.6Hz, 2H), 8.31 (d, J=6.8Hz, 1H), 7.29 (t, J=9.2Hz, 2H), 4.76 -4.66 (m, 1H), 4.62-4.41 (m, 5H), 3.26 (dd, J=16.0, 7.5Hz, 2H), 2.89 (dd, J=16.0, 6.5Hz, 2H); LCMS m / z 507[M+H] +

[0743] Example 59. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0744] Step 1: (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0745]

[0746] By the same method as in step 1 of Example 1, using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The mixture was added with oxadiazole-2(3H)-one (36.7 mg, 0.1 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (44 mg, 0.13 mmol), DIPEA (89 μL, 0.52 mmol), BOP reagent (55.3 mg, 0.13 mmol) and DMF (1.5 mL) to obtain the title compound (43.4 mg, 72.8%) as a white solid.

[0747] 1H NMR (400MHz, CDCl3) δ8.78 (s, 2H), 7.76 (s, 1H), 7.24 (s, 1H), 7.13 (d, J = 1.6Hz, 2H), 6.23 (s, 2H), 5.62 (t, J = 6.0Hz, 1H), 4. 60 (t, J=8.3Hz, 2H), 4.42 (t, J=7.2Hz, 2H), 4.28-4.19 (m, 1H), 3.74 (q, J=6.8Hz, 2H), 2.94-2.87 (m, 2H), 1.20 (s, 9H); LCMS m / z 572[M+H] +

[0748] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0749]

[0750] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (33.5 mg, 0.059 mmol), K2CO3 (16 mg, 0.12 mmol) and MeOH (2 mL) to obtain the title compound as a white solid (17.8 mg, 63.7%).

[0751] 1 H NMR (400MHz, DMSO-d6) δ8.68 (d, J=9.2Hz, 2H), 8.01 (t, J=5.7Hz, 1H), 7.92 (s, 1H), 7.42 (s, 1H), 7.32 (d , J=1.4Hz, 2H), 4.56-4.48 (m, 2H), 4.28-4.18 (m, 3H), 3.58 (q, J=6.8Hz, 2H), 2.88 (t, J=6.8Hz, 2H); LCMS m / z 458[M+H] +

[0752] Example 60.5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine

[0753] Step 1: (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0754]

[0755] By the same method as in step 1 of Example 1, using 5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-

[0266] To the mixture of oxadiazole-2(3H)-one (32 mg, 0.097 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (41 mg, 0.12 mmol), DIPEA (82 μL, 0.48 mmol), BOP reagent (51.3 mg, 0.12 mmol) and DMF (1.5 mL) was added to give the title compound (49.5 mg, 93%) as a brown oil.

[0756] LCMS m / z 552[M+H] +

[0757] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine

[0758]

[0759] By the same method as in step 2 of Example 1, using (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (43.5 mg, 0.079 mmol), K2CO3 (22 mg, 0.16 mmol) and MeOH (1.5 mL) were added to afford the title compound as a brown solid (11.7 mg, 33.9%).

[0760] 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.99 (s, 1H), 7.94 (broad, 1H), 7.33 (t, J = 9.2 Hz, 2H), 4.72-4.61 (m, 1H), 4.58-4.46 (m, 2H), 4.22 (s, 3H), 3.28 (dd, J = 7.1 Hz, 2H), 2.84 (dd, J = 16.2, 4.9 Hz, 2H); LCMS m / z 438 [M+H] +

[0761] Example 61. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0762] Step 1: tert-butyl 3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidine-1-carboxylate

[0763]

[0764] By the same procedure as in Step 2 of Example 58, tert-butyl 3-(1H-tetrazol-5-yl)azetidine-1-carboxylate (100 mg, 0.44 mmol), 2,2-difluoroacetic anhydride (73 μL, 0.67 mmol) and DCM (5 mL) were used for the reaction, and the residue was purified by column chromatography (0% to 3% MeOH / DCM) to obtain the title compound (53 mg, 43%) as a colorless oil.

[0765] 1 H NMR (400MHz, DMSO-d6) δ7.47 (t, J=51.3Hz, 1H), 4.29-4.05 (m, 5H), 1.39 (s, 9H)

[0766] Step 2: 2-(azetidin-3-yl)-5-(difluoromethyl)-1,3,4- Oxadiazole, 2,2,2-trifluoroacetate

[0767]

[0768] By the same method as in step 2 of Preparation Example 1, using tert-butyl 3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidine-1-carboxylate (50 mg, 0.18 mmol), TFA (1 mL) and DCM (2 mL) to give the title compound as a colorless oil (quantitatively), which was used in the next reaction without purification (58 mg).

[0769] LCMS m / z 176[M+H] +

[0770] Step 3: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0771]

[0772] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazol-2(3H)-one (35 mg, 0.11 mmol), 2-(azetidin-3-yl)-5-(difluoromethyl)-1,3,4- Oxadiazole, 2,2,2-trifluoroacetate (35 mg, 0.13 mmol), DIPEA (91 μL, 0.53 mmol), BOP reagent (56 mg, 0.13 mmol) and DMF (1 mL) afforded the title compound as a white solid (39 mg, 75%).

[0773] 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J=14.9Hz, 2H), 8.31 (d, J=6.7Hz, 1H), 7.50 (t, J=51.3Hz, 1H), 7.29 (t, J=9.3Hz, 2H), 4.75-4.65 ( LCMS m / z 489[M+H] +

[0774] Example 62. (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0775]

[0776] By the same method as in step 1 of Example 1, using 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the solution of oxadiazole-2(3H)-one (68.0 mg, 0.18 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (100 mg, 0.28 mmol), DIPEA (158 μL, 0.93 mmol), BOP reagent (96.5 mg, 0.22 mmol) and DMF (3.60 mL) were added to obtain the title compound (83 mg, 77%) as a white solid.

[0777] 1 H NMR (400MHz, DMSO-d6) δ 8.80-8.65 (m, 2H), 8.32-8.24 (m, 2H), 7.43 (s, 1H), 7.33 (d, J = 7.7Hz, 1H), 7.19 (d, J = 8.3Hz, 1H), 6.30 (s, 2H) , 4.73-4.64 (m, 1H), 4.56-4.48 (m, 2H), 4.28-4.18 (m, 3H), 3.28-3.20 (m, 2H), 2.91 (ddd,J=22.4, 15.7, 6.5Hz, 2H), 1.13 (s, 9H); LCMS m / z 594[M+H] +

[0778] Example 63. (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0779]

[0780] By the same method as in step 1 of Example 1, using 5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the solution of oxadiazole-2(3H)-one (55.0 mg, 0.18 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (100 mg, 0.28 mmol), DIPEA (152 μL, 0.89 mmol), BOP reagent (93.0 mg, 0.21 mmol) and DMF (3.50 mL) were added to obtain the title compound (66 mg, 71%) as a white solid.

[0781] 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 2H), 8.30 (s, 1H), 8.29 (d, J=6.9Hz, 1H), 7.23 (dd, J=8.3, 5.4Hz, 1H), 7.06 (d, J=9.0Hz, 1H), 6.96 (t, J=8.7Hz , 1H), 6.30 (s, 2H), 4.75-4.66 (m, 1H), 4.52 (s, 2H), 4.24 (d, J = 3.3Hz, 3H), 3.24 (dd, J = 16.3, 7.3Hz, 2H), 2.98-2.83 (m, 2H), 1.13 (s, 9H); LCMS m / z 534[M+H] +

[0782] Example 64. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0783]

[0784] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (50.0 mg, 0.08 mmol), K2CO3 (23.0 mg, 0.17 mmol) and MeOH (1.68 mL) were added to obtain the title compound as a white solid (33 mg, 82%).

[0785] 1H NMR (400MHz, DMSO-d6) δ8.82-8.64 (m, 2H), 8.28 (d, J=6.8Hz, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.33 (d, J=7.7Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 4.73-4.64 (m, 1H), 4.52 (s, 2H), 4.22 (s, 3H), 3.23 (dd, J=16.0, 6.7Hz, 2H), 2.91 (ddd, J=22.1, 16.0, 6.3Hz, 2H); LCMSm / z 480[M+H] +

[0786] Example 65. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0787]

[0788] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- To the mixture of oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (44.8 mg, 0.08 mmol), K2CO3 (23.0 mg, 0.17 mmol) and MeOH (1.68 mL) was added to afford the title compound (30 mg, 86%) as a white solid.

[0789] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=13.3Hz, 2H), 8.29 (d, J=6.8Hz, 1H), 7.93 (s, 1H), 7.23 (dd, J=8.1, 5.8Hz, 1H), 7.06 (d, J=9.1Hz, 1H LCMS m / z 420[M+H] +

[0790] Example 66. 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0791] Step 1: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carbohydrazide

[0792]

[0793] By the same method as in step 1 of Example 23, using methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylate (62 mg, 0.14 mmol), hydrazine monohydrate (0.3 mL, 2.9 mmol) and EtOH (3 mL) to obtain the title compound as a white solid (44.9 mg, 72.4%).

[0794] LCMS m / z 429[M+H] +

[0795] Step 2: 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0796]

[0797] By the same method as in step 2 of Example 23, using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carbohydrazide (39 mg, 0.091 mmol), TEA (0.013 mL, 0.091 mmol), CDI (18 mg, 0.11 mmol) and THF (1.5 mL) to obtain the title compound as a white solid (11.4 mg, 27.5%).

[0798] 1H NMR (400MHz, DMSO-d6) δ12.30 (broad, 1H), 8.73 (d, J = 17.5Hz, 2H), 8.31 (d, J = 6.7Hz, 1H), 7.29 (t, J = 9.3Hz, 2H), 4.70 (m, 1H), 4.52-4.41 (m, 2H), 4.37-4.24 (m, 2H), 4.12-3.98 (m, 1H), 3.26 (dd, J=16.2, 7.5Hz, 2H), 2.89 (dd, J=16.0, 6.6Hz, 2H); LCMS m / z455[M+H] +

[0799] Example 67. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0800] Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0801]

[0802] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-

[0136] To the mixture of oxadiazole-2(3H)-one (39.2 mg, 0.11 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (48 mg, 0.14 mmol), DIPEA (97 μL, 0.57 mmol), BOP reagent (60.3 mg, 0.14 mmol) and DMF (2 mL) was added to give the title compound (34.8 mg, 54.2%) as a brown oil.

[0803] 1H NMR (400MHz, CDCl3) δ8.61 (broad, 1H), 7.76 (s, 1H), 7.02 (t, J=8.8Hz, 2H), 6.23 (s, 2H), 5.61 (d, J=7.8Hz, 1H), 4.96-4.85 (m, 1H), 4.59 (t, J= 8.3Hz, 2H), 4.41 (t, J=7.2Hz, 2H), 4.28-4.19 (m, 1H), 3.36 (dd, J=16.1, 7.0Hz, 2H), 2.84 (dd, J=15.9, 5.3Hz, 2H), 2.69 (s, 3H), 1.20 (s, 9H)

[0804] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0805]

[0806] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (30.6 mg, 0.054 mmol), K2CO3 (15 mg, 0.11 mmol) and MeOH (2 mL) to obtain the title compound as a light brown solid (11.7 mg, 33.9%).

[0807] 1 H NMR (400MHz, DMSO-d6) δ8.59 (d, J=18.0Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.28 (t, J=9.3Hz, 2H), 4.71 (s , 1H), 4.52 (s, 2H), 4.23 (s, 3H), 3.30-3.19 (m, 2H), 2.88 (dd, J=16.0, 6.7Hz, 2H), 2.65-2.53 (m, 3H); LCMS m / z 452[M+H] +

[0808] Example 68. 5-(5-(3-(1H-tetrazolyl-5-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0809]

[0810] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- 1-oxadiazole-2-yl)azetidine-3-carbonitrile (101 mg, 0.25 mmol) was dissolved in DMF (3 mL), NaN (53 mg, 0.81 mmol), NH Cl (29 mg, 0.81 mmol) were added, and the mixture was stirred at 80° C. overnight. After the reaction mixture was concentrated, the obtained residue was purified by column chromatography (0% to 20% MeOH in DCM) to give the title compound (7 mg, 6.3%) as a white solid.

[0811] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 5H), 8.30 (d, J=6.7Hz, 2H), 7.28 (t, J=9.2Hz, 5H), 4.73-4.66 (m, 3H), 4.62 -4.55(m, 4H), 4.49-4.43(m, 2H), 4.39-4.31(m, 4H), 3.27-3.21(m, 5H), 2.88(dd, J=16.1, 6.6Hz, 5H); LCMS m / z 439[M+H] +

[0812] Example 69. N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0813] Step 1: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-methylazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0814]

[0815] By the same method as in step 1 of Example 1, using 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] Oxadiazole-2(3H)-one (65 mg, 0.22 mmol), 3-ethynyl-3-methylazetidine, 2,2,2-trifluoroacetate (55 mg, crude), DIPEA (190 μL, 1.1 mmol), BOP reagent (116.7 mg, 0.26 mmol) and DMF (2 mL) were added to obtain the title compound (78.0 mg, 95.3%) as an off-white solid.

[0816] LCMS m / z 373[M+H] +

[0817] Step 2: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0818]

[0819] By the same method as in Step 1 of Preparation Example 2, using N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-methylazetidin-1-yl)-1,3,4-

[0137] The reaction mixture was mixed with oxadiazol-2-yl)pyrimidin-2-amine (67 mg, 0.18 mmol), TMSN3 (25 mg, 0.22 mmol), CuI (1.7 mg, 0.01 mmol) and DMF / MeOH (5.4 mL / 0.6 mL) to obtain the title compound (10.7 mg, 14.3%) as a white solid.

[0820] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=18.1Hz, 2H), 8.27 (d, J=6.9Hz, 1H), 7.86 (s, 1H), 7.28-7.10 (m, 4H), 4.74-4.64 (m, 1H) , 4.41-4.29 (m, 2H), 4.15 (d, J=7.6Hz, 2H), 3.27 (dd, J=15.9.7.6Hz, 2H), 2.93 (dd, J=15.8, 6.8Hz, 2H), 1.72 (s, 3H); LCMS m / z 416[M+H] +

[0821] Example 70. (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0822]

[0823] By the same method as in step 1 of Example 1, using 5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazole-2(3H)-one (30 mg, 0.092 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (35 mg, 0.092 mmol), DIPEA (78 μL, 0.46 mmol), BOP reagent (49 mg, 0.11 mmol) and DMF (1 mL) to obtain the title compound (34 mg, 68%) as an off-white solid.

[0824] 1 H NMR (400MHz, DMSO-d6) δ8.72 (d, J=18.9Hz, 2H), 8.30 (s, 1H), 8.26 (d, J=6.9Hz, 1H), 7.11 (d, J=8.3Hz, 1H), 6.81 (s, 1H), 6.71 (d, J=8.3Hz, 1H), 6.30 (s ， 2H), 4.71-4.62(m, 1H), 4.52(s, 2H), 4.28-4.19(m, 3H), 3.71(s, 3H), 3.26-3.16(m, 2H), 2.92-2.80(m, 2H), 1.12(s, 9H); LCMS m / z 546[M+H] +

[0825] Example 71. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0826]

[0827] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (28 mg, 0.051 mmol), K2CO3 (14 mg, 0.10 mmol) and MeOH (1 mL) to obtain the title compound as a white solid (15 mg, 68%).

[0828] 1 H NMR (400MHz, DMSO-d6) δ8.72 (d, J=17.1Hz, 2H), 8.25 (d, J=6.9Hz, 1H), 7.93 (s, 1H), 7.10 (d, J=8.2Hz, 1H), 6.81 (s, 1H), 6.71 LCMS m / z 432[M+H] +

[0829] Example 72. (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0830]

[0831] By the same method as in step 1 of Example 1, using 5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0137] C.-144

[0138] The product was stirred at 40 °C for 24 hours at room temperature for 1 hr.

[0139] C.-144

[0139] C.-144

[0138] Methylparaben (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (96 mg, 0.27 mmol), DIPEA (146 μL, 0.86 mmol), BOP reagent (89 mg, 0.20 mmol) and DMF (3.4 mL) to obtain the title compound (23 mg, 26%) as a white solid.

[0832] 1H NMR (400MHz, DMSO-d6) δ8.75 (s, 2H), 8.40-8.33 (m, 2H), 8.31 (s, 1H), 7.92 (s, 1H), 6.30 (s, 2H), 4.87-4.77 (m, 1H), 4.57-4.46 (m, 2H), 4.29-4.17 (m, 3H), 3.43 (dd, J=17.4, 7.9Hz, 2H), 3.05 (dd, J=17.2, 5.5Hz, 2H), 1.13 (s, 9H); LCMS m / z 518[M+H] +

[0833] Example 73. (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0834]

[0835] By the same method as in step 1 of Example 1, using 5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0266] The product was stirred at 40 °C for 24 hours at room temperature for 1 000 rpm for 24 hours.

[0267] The product was stirred at 40 °C for 24 hours at room temperature for 1 000 rpm for 24 hours.

[0268] The product was stirred at 40 °C for 24 hours at room temperature for 1 000 rpm for 24 hours.

[0269] The product was stirred at 40 °C for 24 hours at room temperature for 1 000 rpm for 24 hours.

[0269] The product was stirred at 40 °C for 24 hours at room temperature for 1 000 rpm for 24 hours.

[0836] 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 2H), 8.37-8.25 (m, 3H), 7.61 (d, J=7.5Hz, 1H), 7.15 (dd, J=7.4, 5.0Hz, 1H), 6.30 (s, 2H), 4.78 LCMS m / z517[M+H] +

[0837] Example 74. N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-amine

[0838]

[0839] By the same method as in step 3 of Example 7, using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (18 mg, 0.035 mmol), K2CO3 (9.6 mg, 0.07 mmol) and MeOH (0.7 mL) were added to obtain the title compound as a white solid (9 mg, 64%).

[0840] 1 H NMR (400MHz, DMSO-d6) δ8.75 (s, 2H), 8.45-8.28 (m, 3H), 7.92 (s, 1H), 4.87-4.77 (m, 1H), 4.58-4 .47 (m, 2H), 4.29-4.17 (m, 3H), 3.43 (dd, J=17.3, 8.0Hz, 2H), 3.05 (dd, J=17.3.5.5Hz, 2H); LCMS m / z 404[M+H] +

[0841] Example 75. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0842] Step 1: tert-Butyl 3-(prop-1-yn-1-yl)azetidine-1-carboxylate

[0843]

[0844] Tert-butyl 3-ethynyl azetidine-1-carboxylate (500mg, 2.76mmol) is dissolved in THF (8mL), and N2 is cooled to -78 ℃ under atmosphere, n-BuLi (2.5M in hexane, 1.10mL, 2.78mmol) is slowly dripped in 10 minutes and stirred for 30 minutes.After being warmed to room temperature, CH is slowly dripped in 5 minutes3I (259 μ L, 4.14mmol) is stirred for 5 hours.DW is added in reaction mixture and extracted with EtOAc, and organic layer is dried through Na2SO4, filtered and concentrated.The residue obtained is purified by column chromatography (0% to 3%MeOH / DCM) to obtain the compound (500mg, 93%) indicated as yellow oil.

[0845] LCMS m / z 196[M+H] +

[0846] Step 2: tert-Butyl 3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0847]

[0848] Tert-butyl 3-(prop-1-yn-1-yl)azetidine-1-carboxylate (195 mg, 1.0 mmol), TMSN3 (200 μL, 1.55 mmol) were added to the reaction vessel and allowed to react in a microwave reactor (200 ° C., 2 hours). The reaction mixture was purified by column chromatography (0% to 5% MeOH in DCM) to obtain the title compound as a brown oil. (19 mg, 8%).

[0849] 1 H NMR (400MHz, CDCl3) δ4.33-4.28(m, 2H), 4.18-4.14(m, 2H), 3.85-3.79(m, 1H), 2.28(s, 3H), 1.45(s, 9H)

[0850] Step 3: 4-(azetidin-3-yl)-5-methyl-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0851]

[0852] By the same method as in Step 2 of Preparation Example 1, using tert-butyl 3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (19 mg, 0.079 mmol), TFA (350 μL) and DCM (1 mL), the title compound was obtained (quantitatively), which was used in the next step reaction without purification (19 mg).

[0853] Step 4: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0854]

[0855] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazol-2(3H)-one (26 mg, 0.079 mmol), 4-(azetidin-3-yl)-5-methyl-1H-1,2,3-triazole, 2,2,2-trifluoroacetate (19 mg, 0.079 mmol), BOP reagent (58 mg, 0.13 mmol), DIPEA (77 μL, 0.43 mmol) and DMF (1 mL) to obtain the title compound (7 mg, 20%) as a brown solid.

[0856] 1 H NMR (400MHz, CD3OD) δ8.72 (s, 2H), 7.09 (t, J = 8.0Hz, 2H), 4.85-4.78 (m, 1H), 4.60 (t, J = 8.0Hz, 2H) , 4.39 (t, J=8.0Hz, 2H), 4.26-4.23 (m, 1H), 3.34-3.28 (m, 2H), 2.94-2.88 (m, 2H) 2.29 (s, 3H); LCMS m / z 452[M+H] +

[0857] Example 76. 5-(5-(3-(1H-imidazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0858]

[0859] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazol-2(3H)-one (30 mg, 0.09 mmol), 4-(azetidin-3-yl)-1H-imidazole, 2,2,2-trifluoroacetate (20 mg, 0.09 mmol), BOP reagent (73 mg, 0.16 mmol), DIPEA (96 μL, 0.54 mmol) and DMF (1 mL) to obtain the title compound (3.5 mg, 9%) as a white solid.

[0860] 1 H NMR (400 MHz, CD 33 OD) δ 8.74 (s, 2H), 7.71 (s, 1H), 7.13-7.08 (m, 3H), 4.86-4.83 (m, 1H), 4.54 (t, J=8. 0Hz, 2H), 4.31(t, J=8.0Hz, 2H), 4.17-4.13(m, 1H), 3.35-3.30(m, 2H), 2.94-2.89(m ， 2H); LCMS m / z 437 [M+H] +

[0861] Example 77. N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine

[0862]

[0863] By the same method as in step 3 of Example 7, using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0137] The product was prepared by mixing 1H-1,2,3-triazol-1-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (42 mg, 0.081 mmol), K2CO3 (22.5 mg, 0.16 mmol) and MeOH (1.6 mL) to obtain the title compound (21 mg, 64%) as a white solid.

[0864] 1H NMR (400MHz, DMSO-d6) δ8.74 (s, 2H), 8.37-8.25 (m, 2H), 7.92 (s, 1H), 7.61 (d, J=7.3Hz, 1H), 7.21-7 .08(m, 1H), 4.79-4.66(m, 1H), 4.52(s, 2H), 4.23(s, 3H), 3.48-3.19(m, 2H), 3.06-2.88(m, 2H); LCMS m / z 403[M+H] +

[0865] Example 78. (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one

[0866] Step 1: (4-(3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0867]

[0868] The title compound was prepared by the same method as in Preparation Example 5, except that tert-butyl 3-ethynyl-3-methylazetidine-1-carboxylate was used instead of tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate.

[0869] LCMS m / z 253[M+H] +

[0870] Step 2: (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0871]

[0872] By the same method as in step 2 of Example 20, using (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (33 mg, 0.10 mmol), (4-(3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (45 mg, 0.12 mmol), DIPEA (53 μL, 0.31 mmol), HBTU (47 mg, 0.12 mmol) and DMF (1.5 mL), the title compound (51.7 mg, 90.9%) was obtained as a white solid.

[0873] LCMS m / z 552[M+H] +

[0874] Step 3: (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one

[0875]

[0876] By the same method as in step 2 of Example 1, using (E)-(4-(1-(3-(2-((5,6-difluoro-2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (45.7 mg, 0.083 mmol), K2CO3 (23 mg, 0.17 mmol) and MeOH (1.6 mL), the title compound (16.9 mg, 46.6%) was obtained as a white solid.

[0877] 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 2H), 8.01 (d, J = 6.7Hz, 1H), 7.90 (wide, 1H), 7 .36-7.23(m, 3H), 6.67(d, J=15.8Hz, 1H), 4.71-4.61(m, 1H), 4.46(d, J=7.6H z, 1H), 4.24 (d, J = 8.2Hz, 1H), 4.14 (d, J = 9.4Hz, 1H), 3.92 (d, J = 9.2Hz, 1H), 3 .24 (dd, J=16.1, 7.6Hz, 2H), 2.87 (dd, J=16.0, 6.5Hz, 2H), 1.63 (s, 3H); LCMS m / z 438[M+H] +

[0878] Example 79. 5-(5-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0879]

[0880] By the same method as in Example 28, using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- In the mixture of oxadiazole-2-yl)azetidin-3-yl methanesulfonate (30 mg, 0.065 mmol), 1,2,4-triazole (5.4 mg, 0.078 mmol), NaH (57% to 63% oil dispersion) (3.1 mg, 0.078 mmol) and DMF (0.6 mL), the title compound was obtained as a white solid (6.6 mg, 23.4%).

[0881] 1 H NMR (400MHz, DMSO-d6) δ8.78-8.68 (m, 2H), 8.68 (s, 1H), 8.29 (d, J=7.7Hz, 1H), 8.10 (s, 1H), 7.27 (t, J=9.4Hz, 2H), 5.63-5.55 (m, 1 LCMS m / z 438[M+H] +

[0882] Example 80. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0883]

[0884] By the same method as in Example 28, using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- In the mixture of oxadiazole-2-yl)azetidin-3-yl methanesulfonate (30 mg, 0.065 mmol), 3-methyl-1H-1,2,4-triazole (6.4 mg, 0.078 mmol), NaH (57% to 63% oil dispersion) (3.1 mg, 0.078 mmol) and DMF (0.6 mL), the title compound was obtained as a white solid (8.6 mg, 29.5%).

[0885] 1 H NMR (400MHz, DMSO-d6) δ8.77-8.68 (m, 2H), 8.50 (s, 1H), 8.32-8.25 (m, 1H), 7.31-7.23 (m, 2H), 5.51 (s, 1H), 4.73-4.66 ( LCMS m / z 452[M+H] +

[0886] Example 81. N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-morpholinoazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0887]

[0888] By the same method as in step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the solution of oxadiazol-2(3H)-one (40 mg, 0.121 mmol), 4-(azetidin-3-yl)morpholine hydrochloride (25.9 mg, 0.145 mmol), DIPEA (64 μL, 0.362 mmol), BOP reagent (64.1 mg, 0.145 mmol) and DMF (0.6 mL) was added to give the title compound (45.8 mg, 83.3%) as a white solid.

[0889] 1H NMR (400MHz, DMSO-d6) δ8.69 (s, 2H), 8.27 (d, J=6.3Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 4.68 (d, J=6.5Hz, 1H), 4.15 (t, J=7.7 Hz, 2H), 4.03-3.94 (m, 2H), 3.58 (s, 3H), 3.29-3.21 (m, 3H), 2.87 (dd, J=16.1, 6.4Hz, 2H), 2.52 (s, 2H), 2.33 (s, 3H); LCMS m / z 456[M+H] +

[0890] Example 82. (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one

[0891] Step 1: (E)-(4-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0892]

[0893] By the same method as in step 2 of Example 20, using (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (36.8 mg, 0.13 mmol), (4-(3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (36.8 mg, 0.13 mmol), DIPEA (67 μL, 0.31 mmol), HBTU (60 mg, 0.16 mmol) and DMF (1.5 mL), the title compound (45.7 mg, 67.8%) was obtained as a pale pink solid.

[0894] LCMS m / z 516[M+H] +

[0895] Step 2: (E)-3-(2-((2,3-hydrogen-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one

[0896]

[0897] By the same method as in step 2 of Example 1, using (E)-(4-(1-(3-(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)acryloyl)-3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (40.4 mg, 0.078 mmol), K2CO3 (63 mg, 0.16 mmol) and MeOH (2 mL), the title compound (13.1 mg, 41.7%) was obtained as a white solid.

[0898] 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 2H), 8.00 (d, J=6.8Hz, 1H), 7.33 (d, J=15.8Hz , 1H), 7.25-7.11 (m, 4H), 6.67 (d, J=15.8Hz, 1H), 4.70-4.60 (m, 1H), 4.46 (d, J= 8.5Hz, 1H), 4.25 (d, J=8.3Hz, 1H), 4.14 (d, J=9.4Hz, 1H), 3.92 (d, J=9.5Hz, 1H) , 3.25 (dd, J=15.9, 7.5Hz, 2H), 2.91 (dd, J=15.8.6.9Hz, 2H), 1.65 (s, 3H); LCMS m / z 402[M+H] +

[0899] Example 83. N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0900] Step 1: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0901]

[0902] By the same method as in step 1 of Example 1, using 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The title compound (100 mg, 78%) was obtained as a white solid by mixing oxadiazol-2(3H)-one (100 mg, 0.34 mmol), 3-ethynyl-3-fluoroazetidine, 2,2,2-trifluoroacetate (93 mg, 0.47 mmol), BOP reagent (180 mg, 0.41 mmol), DIPEA (423 μL, 2.43 mmol) and DMF (3 mL).

[0903] 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 2H), 7.20-7.19 (m, 2H), 7.14-7.12 (m, 2H), 4. 69-4.64(m, 1H), 4-58-4.46(m, 4H), 3.28-3.22(m, 2H), 2.93-2.88(m, 2H); LCMS m / z 377[M+H] +

[0904] Step 2: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0905]

[0906] By the same method as in Step 1 of Preparation Example 2, using N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4-

[0137] The reaction mixture was mixed with oxadiazol-2-yl)pyrimidin-2-amine (55 mg, 0.15 mmol), TMSN3 (25 μL, 0.19 mmol), CuI (3.3 mg, 0.018 mmol) and DMF (2 mL) / MeOH (0.2 mL) to obtain the title compound (10 mg, 16%) as a white solid.

[0907] 1 H LCMS m / z 420[M+H] +

[0908] Example 84. (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0909] Step 1: 5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0910]

[0911] The title compound was prepared by the same method as in Preparation Example 3, except that 6,7-dihydro-5H-cyclopenta[c]pyridin-6-amine dihydrochloride was used instead of 2,3-dihydro-1H-inden-2-amine.

[0912] 1 H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H), 8.67 (d, J = 13.9Hz, 2H), 8.44 (s, 1H), 8.39-8.32 (m, 2H), 7.28 (d, J=4.7Hz, 1H), 4.76-4.68 (m, 1H), 3.31-3.27 (m, 2H), 2.96 (dd, J=16.5, 6.0Hz, 2H); LCMS m / z 297[M+H] +

[0913] Step 2: (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0914]

[0915] By the same method as in step 1 of Example 1, using 5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-

[0266] The title compound was obtained as an off-white solid (4.0 mg, 23%) by mixing oxadiazol-2(3H)-one (10 mg, 0.034 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (11 mg, 0.034 mmol), DIPEA (22 μL, 0.17 mmol), BOP reagent (18 mg, 0.041 mmol) and DMF (1 mL).

[0916] 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J=17.8Hz, 2H), 8.44 (s ， 1H), 8.36-8.28(m, 3H), 7.28(s, 1H), 6.30(s, 2H), 4.75-4.69(m, 1H), 4.54-4.49(m, 2H), 4.28-4.21(m, 3H), 3.30-3.27(m, 2H), 2.96(dd, J=16.2, 6.6Hz, 2H), 1.13(s, 9H); LCMSm / z 517[M+H] +

[0917] Example 85. N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-amine

[0918]

[0919] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (3.7 mg, 0.0076 mmol), K2CO3 (2 mg, 0.014 mmol) and MeOH (1 mL) to obtain the title compound as an off-white solid (2.9 mg, 99%).

[0920] 1H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 8.44 (s, 1H), 8.33 (dd, J=14.9, 5.9Hz, 2H), 7.93 (s, 1H), 7.29 (d, J= 4.6Hz, 1H), 4.76-4.67 (m, 1H), 4.53 (s, 2H), 4.23 (s, 3H), 3.30 (s, 2H), 2.96 (dd, J=16.6, 5.9Hz, 2H); LCMS m / z 403[M+H] +

[0921] Example 86. (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0922]

[0923] By the same method as in step 1 of Example 1, using 5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-

[0136] To the reaction mixture was added oxadiazole-2(3H)-one (25 mg, 0.080 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (27 mg, 0.080 mmol), DIPEA (68 μL, 0.40 mmol), BOP reagent (43 mg, 0.096 mmol) and DMF (1 mL) to obtain the title compound (24 mg, 56%) as a yellow solid.

[0924] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 2H), 8.38 (t, J=6.2Hz, 1H), 8.30 (s, 1H), 6.88 (s, 1H), 6.85-6 .78(m, 2H), 6.30(s, 2H), 5.97(s, 2H), 4.52-4.45(m, 4H), 4.26-4.21(m, 3H), 1.13(s, 9H); LCMS m / z 534[M+H] +

[0925] Example 87. 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

[0926]

[0927] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (19 mg, 0.035 mmol), K2CO3 (10 mg, 0.071 mmol) and MeOH (1 mL) were added to obtain the title compound as a white solid (8.7 mg, 59%).

[0928] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 2H), 8.39 (t, J=6.2Hz, 1H), 7.92 (s, 1H), 6.88 (s, 1H), 6. 85-6.78 (m, 2H), 5.97 (s, 2H), 4.54-4.50 (m, 2H), 4.47 (d, J=6.3Hz, 2H), 4.22 (s, 3H); LCMS m / z 420[M+H] +

[0929] Example 88.5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

[0930] Step 1: Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate

[0931]

[0932] The title compound was prepared by the same method as in Step 1 of Preparation 3, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0933] LCMS m / z 320[M+H] +

[0934] Step 2: Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidine-5-carboxylate

[0935]

[0936] Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (50 mg, 0.157 mmol) was dissolved in DMF (1.6 mL), and NaH (57% to 63% oil dispersion) (9.4 mg, 0.235 mmol) was added at 0°C and stirred for 30 minutes. Then, MeI (15 μL, 0.235 mmol) was added at the same temperature and stirred at room temperature for 1 hour. DW was added to the reaction mixture, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (EtoAc / Hex) to obtain the title compound (22 mg, 42.1%) as a white solid.

[0937] 1 H NMR (400MHz, DMSO-d6) δ8.79 (s, 2H), 7.30 (t, J=9.3Hz, 2H), 5.78 (dt, J=15.3.7.7Hz, 1H), 4.26 ( q, J=7.1Hz, 2H), 3.14 (dd, J=16.4, 8.3Hz, 2H), 3.02 (q, J=7.0Hz, 5H), 1.28 (t, J=7.1Hz, 3H); LCMS m / z 334[M+H] +

[0938] Step 3: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0939]

[0940] The title compound was prepared by the same method as steps 2 and 3 of Preparation 3, except that ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidine-5-carboxylate was used instead of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate.

[0941] LCMS m / z 346[M+H] +

[0942] Step 4: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

[0943]

[0944] By the same method as in Step 1 of Example 1, using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4-

[0147] The title compound was obtained as a yellow solid (3.1 mg, 36.5%) by mixing oxadiazol-2(3H)-one (6.5 mg, 0.019 mmol), 4-(azetidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate (5 mg, 0.023 mmol), DIPEA (9.6 μL, 0.056 mmol), BOP reagent (10 mg, 0.023 mmol) and DMF (0.09 mL).

[0945] 1 H NMR (400MHz, DMSO-d6) δ8.77 (s, 2H), 7.31 (t, J=9.3Hz, 2H), 5.78-5.72 (m, 1H), 4.51 (s, 2H), 4. 21 (s, 2H), 3.28 (s, 2H), 3.14 (dd, J=16.3, 9.1Hz, 2H), 3.05 (d, J=7.0Hz, 2H), 3.00 (s, 3H); LCMS m / z 452[M+H] +

[0946] Example 89. N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0947] Step 1: N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0948]

[0949] By the same method as in step 1 of Example 1, using 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The title compound (50 mg, 73%) was obtained as a white solid by mixing oxadiazol-2(3H)-one (55 mg, 0.15 mmol), 3-ethynyl-3-fluoroazetidine, 2,2,2-trifluoroacetate (44 mg, 0.22 mmol), BOP reagent (79 mg, 0.18 mmol), DIPEA (186 μL, 0.17 mmol) and DMF (2 mL).

[0950] 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 2H), 7.41 (s, 1H), 7.32 (d, J=8.0Hz, 1H), 7.18 (d, J=8.0H z, 1H), 4.69-4.64 (m, 1H), 4.58-4.46 (m, 4H), 3.26-3.19 (m, 2H), 2.89-2.87 (m, 2H); LCMS m / z 455, 457[M+H] +

[0951] Step 2: N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine

[0952]

[0953] By the same method as in Step 1 of Preparation Example 2, using N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-ethynyl-3-fluoroazetidin-1-yl)-1,3,4-

[0137] In the mixture of oxadiazol-2-yl)pyrimidin-2-amine (90 mg, 0.2 mmol), TMSN3 (36 μL, 0.28 mmol), CuI (4.8 mg, 0.018 mmol) and DMF (3 mL) / MeOH (0.3 mL) to obtain the title compound (1.3 mg, 1.3%) as a white solid.

[0954] 1 H NMR (400MHz, CD3OD) δ8.76 (s, 2H), 8.04 (s, 1H), 7.38 (s, 1H), 7.22-7.20 (m, 2H), 7.30 (d, J=8. 0Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 4.88-4.61 (m, 5H), 3.38-3.30 (m, 2H), 2.93-2.89 (m, 2H); LCMS m / z 498,500[M+H] +

[0955] Example 90. 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazol-2-yl)butan-1-one

[0956] Step 1: Methyl 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazole-2-yl)butyrate

[0957]

[0958] Methyl 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (32.8 mg, 0.120 mmol), 4-(5-oxo-4,5-dihydro-1,3,4- oxadiazole-2-yl)butyrate (18.6 mg, 0.100 mmol), BOP reagent (53 mg, 0.120 mmol) and DIPEA (51 μL, 0.300 mmol) were dissolved in DMF (0.5 mL) and stirred at room temperature for 4 hours. DW was added to the reaction mixture, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound (8.5 mg, 25.2%) as a brown solid.

[0959] 1 H NMR (400MHz, CD3OD) δ7.11 (t, J=9.0Hz, 2H), 4.45-4.35 (m, 1H), 3.65 (d, J=2.2Hz, 3H), 2.91 (dd, J=16.1, 5.2Hz, 2H), 2.75 (t ， J=7.3Hz, 2H), 2.44(t, J=7.2Hz, 2H), 2.06-1.85(m, 4H).LCMS m / z 338[M+H] +

[0960] Step 2: 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazole-2-yl)butanoic acid

[0961]

[0962] Methyl 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- 1-diazole-2-yl) butyrate (3.0 mg, 0.025 mmol) was dissolved in MeOH / THF (0.45 mL / 0.05 mL), and a solution of LiOH (3.0 mg, 0.126 mmol) in distilled water (0.05 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, distilled water was added, and the mixture was acidified to pH 1 to 2 with 3N HCl. The mixture was extracted with EtOAc, washed with distilled water, dried over Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography (MeOH / DCM) to obtain the title compound (8.0 mg, 98.2%) as a white solid.

[0963] 1 H NMR (400MHz, CD3OD) δ7.11 (t, J=9.0Hz, 2H), 4.40 (dd, J=11.8, 6.0Hz.1H), 2.91 (dd, J= 16.1, 5.0Hz, 2H), 2.76 (t, J=7.3Hz, 2H), 2.37 (t, J=7.1Hz, 2H), 2.10-1.80 (m, 4H); LCMS m / z 324[M+H] +

[0964] Step 3: 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazol-2-yl)butan-1-one

[0965]

[0966] By the same method as in step 3 of Example 9, using 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- To the mixture was added 4-(oxadiazole-2-yl)butanoic acid (8 mg, 0.025 mmol), 4-(azetidin-3-yl)-1H-1,2,3-triazole dihydrochloride (4.8 mg, 0.030 mmol), DIPEA (13 μL, 0.074 mmol), HBTU (11.3 mg, 0.030 mmol) and DMF (0.49 mL) to obtain the title compound (1.0 mg, 9.4%) as a colorless oil.

[0967] 1H NMR (400MHz, CD3OD) δ7.28 (s, 1H), 7.11 (t, J=9.2Hz, 2H), 4.43-4.29 (m, 3H), 4.04 (d, J=6.1Hz, 2H), 3.76-3.68 (m, 1H), 3 .22 (d, J=7.6Hz, 2H), 2.92 (dd, J=16.0, 4.8Hz, 2H), 2.77 (t, J=7.2Hz, 2H), 2.28 (t, J=7.1Hz, 2H), 2.05-1.99 (m, 2H); LCMS m / z430[M+H] +

[0968] Example 91.5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0969] Step 1: (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0970]

[0971] By the same method as in step 1 of Example 1, using 5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-

[0136] The mixture was stirred for 2-30 min at 4 °C for 1 h. The mixture was stirred for 2-30 min. To the mixture was added oxadiazole-2(3H)-one (35 mg, 0.11 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (60.5 mg, crude), DIPEA (92 μL, 0.54 mmol), BOP reagent (56.3 mg, 0.13 mmol) and DMF (2 mL) to obtain the title compound (54 mg, 93%) as an off-white solid.

[0972] 1H NMR (400MHz, DMSO-d6) δ8.73 (d, J=15.6Hz, 2H), 8.35-8.23 (m, 2H), 7.29 (s, 1H), 7.22 (dd, J=18.9, 8.0Hz, 2H), 6.30 (s, 2H ), 4.69 (dd, J=14.1, 6.9Hz, 1H), 4.52 (s, 2H), 4.31-4.17 (m, 3H), 3.30-3.21 (m, 2H), 2.98-2.85 (m, 2H), 1.12 (s, 9H); LCMS m / z 550[M+H] +

[0973] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0974]

[0975] By the same method as in step 2 of Example 1, using (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (50 mg, 0.09 mmol), K2CO3 (25 mg, 0.18 mmol) and MeOH (1.82 mL) were added to afford the title compound as a white solid (25 mg, 63%).

[0976] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=15.2Hz, 2H), 8.29 (d, J=6.3Hz, 1H), 7.92 (s, 1H), 7.29 (s, 1H), 7.22 (dd, J=19. 7, 7.9Hz, 2H), 4.69 (dd, J=13.9.7.0Hz, 1H), 4.52 (s, 2H), 4.23 (s, 3H), 3.30-3.22 (m, 2H), 2.99-2.84 (m, 2H); LCMS m / z 436[M+H] +

[0977] Example 92. 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine

[0978] Step 1: 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- 2-oxadiazol-2(3H)-one

[0979]

[0980] The title compound was prepared by the same method as in Preparation 3, except that 2-(4-chlorophenyl)ethylamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0981] 1 H NMR (400MHz, DMSO-d6) δ12.15 (bs, 1H), 8.60 (d, J = 15.6Hz, 2H), 8.04 (t, J = 5.7Hz, 1H), 7.28 (dd, J=32.0, 8.3Hz, 4H), 3.53 (dd, J=13.4, 6.7Hz, 2H), 2.83 (t, J=7.1Hz, 2H); LCMS m / z 318[M+H] +

[0982] Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine

[0983]

[0984] By the same method as in step 1 of Example 1, using 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- Oxadiazole-2(3H)-one (60 mg, 0.189 mmol), 4-(pyrrolidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate (53.3 mg, 0.227 mmol), DIPEA (161 μmL, 0.567 mmol), BOP reagent (100 mg, 0.227 mmol) and DMF (3.8 mL) were added to obtain the title compound (49.5 mg, 60%) as a white solid.

[0985] 1H NMR (400MHz, DMSO-d6) δ8.68 (d, J=13.4Hz, 2H), 7.94 (t, J=5.7Hz, 1H), 7.39 (s, 1H), 7.33-7.23 (m, 4H ), 3.94-3.87 (m, 1H), 3.66 (d, J = 8.3Hz, 2H), 3.55 (dd, J = 16.4, 8.8Hz, 6H), 2.83 (t, J = 7.4Hz, 2H); LCMS m / z 438[M+H] +

[0986] Example 93.5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine

[0987]

[0988] By the same method as in step 1 of Example 1, using 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4- To the mixture of oxadiazole-2(3H)-one (60 mg, 0.189 mmol), 4-(azetidin-3-yl)-1H-1,2,3-triazole dihydrochloride (44.6 mg, 0.227 mmol), DIPEA (161 μL, 0.567 mmol), BOP reagent (100 mg, 0.227 mmol) and DMF (3.8 mL) was added to give the title compound (43 mg, 53.7%) as a yellow solid.

[0989] 1 H NMR (400MHz, DMSO-d6) δ8.67 (d, J=16.6Hz, 2H), 7.98 (t, J=5.7Hz, 1H), 7.90 (s, 1H), 7.28 (dd, J=30.5, 8.5Hz, 4H), 4.50 (s, 2H), 4.20 (s, 3H), 3.53 (dd, J=13.0, 6.5Hz, 2H), 2.84 (dd, J=14.4, 6.9Hz, 2H); LCMS m / z 424[M+H] +

[0990] Test Example 1. Evaluation of inhibitory activity against human autotaxin protein

[0991] (1) Experimental methods

[0992] The solution of each compound synthesized (80 μM, 100% dimethyl sulfoxide) was diluted 5 times with dimethyl sulfoxide to prepare 6 concentrations. The compound of each concentration was diluted 2 times with 1× test buffer (50mM Tris-Cl (pH 8.0), 5mM KCl, 1mM CaCl2, 1mM MgCl2, 140mM NaCl, deionized water, 1mg / mL BSA), and 1 μL (1.25% dimethyl sulfoxide) of the diluted mixture was distributed to each well of a 96-well transparent round bottom plate. 9 μL 1× test buffer was added, and 20 μL 240nM human autocrine motility factor protein (buffer: 50mM Tris-HCl, pH 8.0, with 150mM sodium chloride and 20% glycerol) was added. 10 μL of sonicated 360 μM 18:1 LysoPC (diluted with 1× assay buffer) was added. The reaction was carried out in a shaking incubator at 37°C for 2 hours, and a secondary reaction mixture (Choline Assay Kit, KA1662) was prepared (65 μL 1× Assay Buffer: 1 μL Choline Oxidase: 1 μL Dye Probe). 60 μL of the secondary reaction mixture was added to the plate for the reaction and incubated in a shaker for 30 minutes. The absorbance value was measured at a wavelength of 570 nm using a SpectraMax iD3 microplate reader. The formula: (1-absorbance value 测试组 / Absorbance value 对照组 )×100 to calculate the percentage inhibitory activity value (% inhibition).

[0993] (2) Results

[0994] The activity inhibition rates measured as above are shown in Table 1 below.

[0995] [Table 1]

[0996]

[0997]

[0998]

[0999] All the synthesized compounds of Examples 1 to 93 exhibited excellent inhibitory activities against human autotaxin protein.

[1000] The foregoing description of the present invention is for illustrative purposes only, and it will be apparent to those skilled in the art that the present invention disclosed herein may be modified without departing from the spirit of the present invention or the essential features of the present invention. It should therefore be understood that the above embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention in any way. For example, each component described in a single form may also be implemented in a distributed manner, and similarly, the components described as distributed may also be implemented in a combined form.

[1001] The scope of the present invention is indicated by the attached patent claims. The meaning and scope of the patent claims and all modifications or variations derived from their equivalents are considered to fall within the scope of the present invention.

Claims

1. A heterocyclic compound represented by the following formula 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein: <Formula 1> In the above formula, X is an aryl group; A fused bicyclic ring in which an aryl ring is fused to a non-aromatic cycloalkyl ring; a fused bicyclic ring in which an aryl ring is fused to a non-aromatic heterocyclic ring having 1 to 3 Os; a fused bicyclic ring in which a heteroaryl ring having 1 to 3 Ns is fused to a non-aromatic cycloalkyl ring, wherein X is fused to a non-aromatic heterocyclic ring having 1 to 3 Ns ... x substituted or unsubstituted, R x C 1-4 Alkoxy or halogen, p is an integer from 0 to 2, R N is hydrogen or C 1-4 alkyl, A is a 5- or 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O, wherein A is R a substituted or unsubstituted, R a C 1-4 alkyl, L is -(CH2) 1-5 CO-; -(CHCH) 1-2 CO-; or a 5-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from N and O, Y Ring R y Replaced or unsubstituted, R y C 1-4 Alkyl or halogen, m is 0 or 1, B is cyano; OH; COOH; CH2COOH; sulfonyl; sulfonate (-O-SO2-); or a 5- to 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from N and O, wherein B is R b or oxo (O) substituted or unsubstituted, Where R b C 1-4 Alkyl, C 1-4 Haloalkyl, amino, or C 1-4 Alkyl pivalate.

2. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that X is selected from phenyl, indanyl, benzodioxolyl, dihydro-cyclopentylpyrazinyl, and dihydro-cyclopentylpyridinyl.

3. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that R x is selected from the group consisting of methoxy, F, Cl and Br.

4. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that R N It is hydrogen or methyl.

5. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that A is selected from pyridine, pyrimidine, pyrazine and Oxadiazole.

6. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that R a It is methyl.

7. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that L is selected from -(CH2)2CO-, -(CH2)3CO-, -(CH)2CO-, dihydroisocyanate Azolyl, iso Azolyl and Oxazolyl.

8. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that R y Methyl or F.

9. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that B is selected from OH, cyano, carboxyl, carboxymethyl, sulfonyl, sulfonate, imidazole, triazole, tetrazolyl, Oxazolyl, Oxadiazoles and morpholinos.

10. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that R b Selected from methyl, difluoromethyl, trifluoromethyl, amino and methyl pivalate.

11. The heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to claim 1, characterized in that The heterocyclic compound is selected from: [1] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [2] (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [3] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [4] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [5] (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [6] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, [7] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine, [8] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine, [9] (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [10] 1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [11] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine, [12] (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [13] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [14] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine, [15] methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylate, [16] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine, [17] 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-4-yl oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [18] 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [19] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [20] (E)-1-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [21] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine, [22] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidine-3-carboxylic acid, [23] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)-1,3,4- oxadiazol-2(3H)-one, [24] methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetate, [25] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl)acetic acid, [26] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-ol, [27] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)pyrrolidin-3-yl methanesulfonate, [28] 5-(5-(3-(1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [29] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [30] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [31] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [32] N-(3,5-dichlorophenethyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [33] N-(3,5-difluorobenzyl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [34] (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)prop-2-en-1-one, [35] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [36] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [37] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [38] 5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [39] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [40] (E)-1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [41] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [42] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [43] 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisocyanate oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [44] 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [45] 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)iso oxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [46] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-sulfonamide, [47] methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylate, [48] ​​5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine, [49] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-ol, [50] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carboxylic acid, [51] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [52] methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetate, [53] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)acetic acid, [54] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine, [55] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl methanesulfonate, [56] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [57] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidine-3-carbonitrile, [58] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [59] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine, [60] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine, [61] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4- oxadiazole-2-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [62] (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [63] (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [64] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [65] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [66] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1,3,4- oxadiazol-2(3H)-one, [67] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine, [68] 5-(5-(3-(1H-tetrazolyl-5-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [69] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [70] (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [71] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(5-methoxy-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [72] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [73] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [74] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine, [75] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [76] 5-(5-(3-(1H-imidazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [77] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine, [78] (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one, [79] 5-(5-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [80] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(3-methyl-1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [81] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-morpholinoazetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [82] (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-(3-methyl-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)prop-2-en-1-one, [83] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [84] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopentyl[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [85] N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-amine, [86] (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4- oxadiazole-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, [87] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, [88] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine, [89] N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-fluoro-3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)pyrimidin-2-amine, [90] 1-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- oxadiazol-2-yl)butan-1-one, [91] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazole-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [92] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine, and [93] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4- oxadiazol-2-yl)-N-(4-chlorophenethyl)pyrimidin-2-amine.

12. A pharmaceutical composition for preventing or treating a disease associated with autotaxin activity, comprising the heterocyclic compound according to any one of claims 1 to 11, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

13. The pharmaceutical composition according to claim 12, characterized in that The disease associated with autotaxin activity is selected from fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

14. A pharmaceutical composition comprising the heterocyclic compound, its hydrate, its solvate or its pharmaceutically acceptable salt according to any one of claims 1 to 11, characterized in that Selected from the following: fibrotic diseases selected from idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, skin fibrosis, glomerulosclerosis, myocardial fibrosis and vascular fibrosis; inflammatory diseases selected from rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma; autoimmune diseases selected from multiple sclerosis and scleroderma; respiratory diseases selected from asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS); selected from arteriosclerosis , myocardial infarction, arterial and pulmonary hypertension, arrhythmia, stroke and other vascular damage; metabolic diseases selected from obesity and diabetes; cancers and cancer metastases selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion; ocular diseases selected from proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury and glaucoma; cholestatic and other forms of chronic pruritus; and acute or chronic organ transplant rejection. 15 . A pharmaceutical composition comprising the heterocyclic compound according to claim 1 , a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

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