Novel heterocyclic compounds and pharmaceutical compositions for autotaxin inhibition containing the 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 an autotaxin activity-related disease containing the same as an active ingredient. The heterocyclic compound according to the present invention exhibits excellent inhibitory activity against autotaxin, and is useful for the treatment and prevention of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic forms and other forms of chronic pruritus, and acute or chronic organ transplant rejection reactions, which are autotaxin-inhibiting related diseases.

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound, and more particularly, to a novel heterocyclic compound and a pharmaceutical composition for inhibiting autotaxin containing the same.

Background Art

[0002] Autotaxin (ATX) is a secretory enzyme important for the production of lysophosphatidic acid (LPA), a lipid signaling molecule, and is also referred to as ectonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity that converts lysophosphatidylcholine (LPC) to LPA. Therefore, the LPA levels in plasma and ascites are associated 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 associated with the physiological and pathophysiological effects of various diseases including neurological effects, blood vessel development, cardiovascular physiology, tissue regeneration, immune system effects, chronic inflammation, tumor metastasis and progression, organ fibrosis and obesity, and / or other metabolic diseases (e.g., type 2 diabetes).

[0004] Therefore, an increase in ATX activity and LPA levels, altered expression of LPA receptors, and altered responses to LPA may be associated with the initiation, progression, and / or outcome of various pathophysiological diseases related to the ATX / LPA signaling process. 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 such diseases, it is necessary to reduce the levels of LPA and / or autotaxin (ATX) that induces it.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The problem to be solved by the present invention is to provide a novel-structured autotaxin inhibitory compound that exhibits excellent inhibitory activity against autotaxin.

[0006] Another problem to be solved by the present invention is to provide a pharmaceutical composition for autotaxin inhibition containing the autotaxin inhibitory compound having the novel structure.

[0007] Another problem to be solved by the present invention is to provide a method for inhibiting autotaxin, and thereby treating and preventing diseases, using the autotaxin inhibitory compound having the novel structure.

[0008] Another problem to be solved by the present invention is to provide the use of the autotaxin inhibitory compound having the novel structure for autotaxin inhibition and thereby for treating diseases.

[0009] The problems to be solved by the present invention are not limited to the above-described problems, and other technical problems will be clearly understood by those having ordinary knowledge in the technical field to which the present invention pertains from the following description of the invention.

Means for Solving the Problems

[0010] To solve the above problems, one aspect of the present invention provides a heterocyclic compound represented by the following Chemical Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0011]

Chemical Formula

[0012] In Chemical Formula 1, X is aryl; a bicyclic fused ring in which an aryl ring and a non-aromatic cycloalkyl ring are fused; a bicyclic fused ring in which an aryl ring and a non-aromatic heterocyclic ring having 1 to 3 O atoms are fused; a bicyclic fused ring in which a heteroaryl ring having 1 to 3 N atoms and a non-aromatic cycloalkyl ring are fused, and the X is substituted or unsubstituted with a single or plural independent R x and is unsubstituted or substituted with, the R x is 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-membered or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N and O, and the A is substituted or unsubstituted with R a and is unsubstituted or substituted with, the R a is 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 the group consisting of N and O, the Y ring is substituted or unsubstituted with R y and is unsubstituted or substituted with, the R y is C 1-4 alkyl or halogen, m is 0 or 1, B is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of cyano; OH; COOH; CH2COOH; sulfonyl; sulfonate (-O-SO2-); or N and O, and said B is R b optionally substituted with or without R said R b is C 1-4 alkyl, C 1-4 haloalkyl, amino, or C 1-4 alkyl pivalate.

[0013] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating an autotaxin activity-related disease, comprising the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient.

[0014] Still another aspect of the present invention provides a method for inhibiting autotaxin and treating or preventing diseases thereby, using the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt.

[0015] Still another aspect of the present invention provides the use of the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt for inhibiting autotaxin and treating or preventing diseases thereby.

[0016] Still another aspect of the present invention provides a pharmaceutical composition comprising the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt and a pharmaceutically acceptable additive.

Advantages of the Invention

[0017] It has been clarified that the heterocyclic compound having a novel structure according to one aspect of the present invention exhibits excellent inhibitory activity against autotaxin.

[0018] Accordingly, the novel heterocyclic compound with a new structure according to one aspect of the present invention can be usefully used for the treatment and prevention of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic forms and other forms of chronic pruritus, and acute or chronic organ transplant rejection reactions, which are diseases related to the inhibition of autotaxin.

[0019] It should be understood that the effects of the present invention are not limited to the above-mentioned effects, and include all effects that can be inferred from the configuration of the invention described in the description or claims of the present invention.

Embodiments for Carrying Out the Invention

[0020] In the present specification, autotaxin (ATX) is a secretory enzyme that plays an important role in the production of lysophosphatidic acid (LPA), and is also referred to as ectonucleotide pyrophosphatase / phosphodiesterase 2 (ENPP2). Autotaxin exhibits lysophospholipase D activity that converts lysophosphatidylcholine (LPC) to LPA. Therefore, the LPA levels in plasma and ascites are related to ATX activity.

[0021] The present invention provides a heterocyclic compound represented by the following Chemical Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0022]

Chemical Formula

[0023] In Chemical Formula 1, X is aryl; a bicyclic fused ring in which an aryl ring and a non-aromatic cycloalkyl ring are fused; a bicyclic fused ring in which an aryl ring and a non-aromatic heterocyclic ring having 1 to 3 O atoms are fused; a bicyclic fused ring in which a heteroaryl ring having 1 to 3 N atoms and a non-aromatic cycloalkyl ring are fused, and the X is substituted or unsubstituted with a single or plural independent R x and, the R x is C1-4 is 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 having 1 to 3 heteroatoms selected from the group consisting of N and O, and said A is substituted or unsubstituted with R a and, said R a is 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 the group consisting of N and O, said Y ring is substituted or unsubstituted with R y and, said R y is C 1-4 alkyl or halogen, m is 0 or 1, B is cyano; OH; COOH; CH2COOH; sulfonyl; sulfonate (-O-SO2-); or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of N and O, and said B is substituted or unsubstituted with R b or oxo (O), said R b is C 1-4 alkyl, C 1-4 haloalkyl, amino, or C 1-4 alkyl pivalate.

[0024] In one embodiment, said X can be one selected from the group consisting of phenyl, dihydroindenyl, benzodioxolyl, dihydro-cyclopentapyradinyl, and dihydro-cyclopentapyridinyl.

[0025] In one embodiment, said R xmay be one selected from the group consisting of methoxy, F, Cl, and Br.

[0026] In one embodiment, said R N may be hydrogen or methyl.

[0027] In one embodiment, said A may be one selected from the group consisting of pyridine, pyrimidine, pyrazine, and oxadiazole.

[0028] In one embodiment, said R a may be methyl.

[0029] In one embodiment, said L may be one selected from the group consisting of -(CH2)2CO-, -(CH2)3CO-, -(CH)2CO-, dihydroisoxazolyl, isoxazolyl, and oxadiazolyl.

[0030] In one embodiment, said R y may be methyl or F.

[0031] In one embodiment, said B may be one selected from the group consisting of OH, cyano, carboxyl, carboxymethyl, sulfonyl, sulfonate, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxadiazolone, and morpholino.

[0032] In one embodiment, said R b may be one selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, amino, and methyl pivalate.

[0033] Specific examples of the heterocyclic compound according to the present invention are as follows.

[0034] [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-oxadiazol-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-oxadiazol-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-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)pyrrolidine-3-carboxylate,

[16] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-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-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)isoxazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)pyrrolidin-3-yl methanesulfonate,

[28] 5-(5-(3-(1H-1,2,4-Triazol-1-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-dihydroisoxazol-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)isoxazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)azetidin-3-yl)acetic acid,

[54] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-2-yl)azetidin-3-ylmethanesulfonate,

[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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[68] 5-(5-(3-(1H-tetrazol-5-yl)azetidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-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-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate,

[73] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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.

[0035] In this specification, when defining the compound of Chemical Formula 1, unless otherwise specifically mentioned, the following definitions apply.

[0036] The term "alkyl" is a straight-chain or branched-chain saturated hydrocarbon having C1-C 10 Alkyl is preferred. For example, the alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0037] The term "alkylene" refers to a divalent functional group derived from an alkyl group, preferably containing 1 to 10 carbon atoms, but not limited thereto. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0038] The term "cycloalkyl" is a partially or fully saturated single or fused cyclic hydrocarbon having C3-C 10 -Cycloalkyl is preferred. For example, it includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, etc.

[0039] The term "hydroxy" is defined as -OH, and the term "alkoxy" means an alkyloxy radical in which the hydrogen atom of the hydroxy group is substituted with 1 to 10 alkyls, unless otherwise defined.

[0040] The term "halogen" or "halo" means fluorine / fluoro (F), chlorine (Cl), bromine (Br) or iodine (I).

[0041] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy substituted with one or more halogen atoms.

[0042] The term "heteroatom" means N, O or S.

[0043] The term "aryl" means an aromatic hydrocarbon and includes a carbocyclic aromatic ring or a polycyclic aromatic ring system in which a heteroaryl ring is fused to one or more other rings. Desirably, C5-C 12 aryl, more desirably C5-C 10 aryl. For example, the aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc.

[0044] The term "heteroaryl" or "aromatic heterocycle" means a 3- to 12-membered, more desirably 5- to 10-membered aromatic hydrocarbon that contains one or more heteroatoms selected from N, O, and S as ring atoms and forms a single or fused ring that can be fused with benzo or C3-C8 cycloalkyl. For example, the heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, etc. Further, heteroaryl includes a group in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocycle, for example, dihydrocyclopentapyradinyl, etc.

[0045] A non-aromatic heterocyclic ring is a non-aromatic carbocyclic ring containing one or more heteroatoms such as nitrogen, oxygen or sulfur within the ring. The ring is 5, 6, 7 or 8 membered and / or may be fused to other rings such as cycloalkyl or aromatic rings. Examples of such compounds include 3-1H-benzimidazol-2-one, 3-1-alkyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolidinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidyl, benzoic acid, benzotriazol-1-yl, benzopyrrolidine, benzopiperidine, benzoxolane, benzothiolane, and benzothiane, etc.

[0046] Arylalkyl, alkylaryl and heteroarylalkyl mean groups formed by the bonding of aryl and alkyl as defined above, or heteroaryl and alkyl, and include, for example, but are not limited to, benzyl, thiophenemethyl, pyrimidinemethyl, etc.

[0047] The compound represented by Chemical Formula 1 according to the present invention can be produced and used in the form of a prodrug, hydrate, solvate and pharmaceutically acceptable salt in order to enhance in vivo absorption or increase solubility. Therefore, the prodrug, hydrate, solvate and pharmaceutically acceptable salt also belong to the scope of the present invention. In addition, the compound represented by Chemical Formula 1 has a chiral carbon, and its stereoisomers exist, and such stereoisomers are also included within the scope of the present invention.

[0048] The term "prodrug" means a substance that is transformed into a parent drug in vivo. Prodrugs are sometimes used because in some cases they are easier to administer than the parent drug. For example, these can achieve bioavailability by oral administration, whereas the parent drug may not. Also, prodrugs can have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug can be a hydrolyzable ester in vivo of a compound according to the invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug can be a short peptide (polyamino acid) bonded to an acid group that is converted by substance metabolism so that the peptide exposes an active site.

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

[0050] The term "solvate" means a compound of the invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Desirable solvents here include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0051] The term "isomer" means a compound of the invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or stereochemically different. Such isomers include structural isomers such as tautomers, and stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), etc. All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0052] The term "pharmaceutically acceptable salt" means a salt form of a compound that does not induce severe irritation in the organism to which the compound is administered and does not damage the biological activity and physical properties of the compound. The pharmaceutically acceptable salts include acid addition salts formed with acids containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid, etc., and sulfonic acids like 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 like lysine, arginine, guanidine, etc., and organic salts like dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of Formula 1 according to the present invention can be converted into its salt by ordinary methods.

[0053] In addition, the present invention provides a method for producing the compound of Formula 1. The synthesis methods of Examples 1 to 93 are exemplified as the production methods of the compound of Formula 1 of the present invention, but the synthesis methods of Examples 1 to 93 do not limit the method for producing the compound of Formula 1 according to the present invention. It is self-evident that the synthesis methods of Examples 1 to 93 are only illustrative and can be easily modified by an ordinary technician with a specific substituent.

[0054] The present invention also provides a pharmaceutical composition for preventing or treating autotaxin activity-related diseases, comprising the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient.

[0055] The present invention also provides a method for inhibiting autotaxin and treating or preventing a disease thereby, by administering the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt to a patient in need thereof.

[0056] The present invention also provides the use of the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt for inhibiting autotaxin and treating or preventing a disease thereby.

[0057] As a result of measuring the autotaxin protein inhibitory activity against the heterocyclic compound of the present invention, it was confirmed that excellent autotaxin inhibitory activity was exhibited even at a very low level of compound concentration (nM level), and it can be used for the treatment and prevention of autotaxin activity-related diseases.

[0058] In one embodiment, the autotaxin activity-related disease may be selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, ocular diseases, cholestatic forms and other forms of chronic pruritus, and acute or chronic organ transplant rejection reactions.

[0059] The fibrotic diseases include, without limitation, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, skin fibrosis, glomerulosclerosis, myocardial and vascular fibrosis.

[0060] The inflammatory diseases include, without limitation, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma.

[0061] The autoimmune diseases include, without limitation, multiple sclerosis and scleroderma.

[0062] The respiratory diseases include, without limitation, asbestosis and Acute Respiratory Distress Syndrome (ARDS).

[0063] The cardiovascular diseases include, without limitation, arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia, stroke, and other vascular injuries.

[0064] The metabolic diseases include, without limitation, obesity and diabetes.

[0065] The cancers and cancer metastases include, without limitation, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatoma, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion.

[0066] The eye diseases include, without limitation, 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.

[0067] The present invention also provides a pharmaceutical composition or dosage form comprising the heterocyclic compound, its hydrate, its solvate, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable additive.

[0068] The additive may include pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and may be formulated into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral dosage forms such as topical solutions, topical suspensions, topical emulsions, gels (such as ointments), inhalants, sprays, injections, etc. by conventional methods. The dosage forms may be formulated in various forms, for example, single-dose or multiple-dose dosage forms.

[0069] The pharmaceutical composition of the present invention may contain 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.

[0070] The pharmaceutical composition of the present invention can be administered to mammals such as livestock and humans by various routes, for example, orally, dermally, subcutaneously, intramuscularly, intravenously, intraperitoneally, intrarectally, by injection into the intrauterine dura or intracerebrovascular, or by topical administration. Therefore, the composition of the present invention can be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of oral tablets, 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 dried corn starch can be used as diluents. If an oral aqueous suspension is required, the active ingredient can be combined with an emulsifier and / or a suspending agent. If necessary, specific sweeteners and / or flavoring agents can be added. In the case of intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution is suitably adjusted and buffered. In the case of intravenous administration, the total concentration of the solute is adjusted so that the formulation is isotonic. The composition according to the present invention can be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline at pH 7.4. The solution can be introduced into the bloodstream in the muscle of the patient by local injection.

[0071] The dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the degree of the disease, the form of the active ingredient, the administration route and duration, and can be appropriately adjusted for each patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg per day, preferably 0.01 to 100 mg / kg, and the administration can be once a day or divided into several times a day. Further, the pharmaceutical composition of the present invention can contain the active ingredient at 0.001 to 90% by weight based on the total weight of the composition.

[0072] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes, for example, orally, dermally, intraperitoneally, rectally, or by intravenous, intramuscular, subcutaneous, intrauterine dural, or intracerebroventricular injection.

[0073] Hereinafter, the present invention will be described in more detail with reference to production examples, examples, and test examples. However, the following production examples, examples, and test examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0074] <Production Example 1> Production of (4-(Pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate Step : Production of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0075]

Chemical formula

[0076] After dissolving azidomethyl pivalate (0.2 g, 1.27 mmol) and tert-butyl 3-ethynyl-1-pyrrolidinecarboxylate (0.249 g, 1.27 mmol) in THF (2.5 mL) / DW (2.5 mL), CuOAc (15.6 mg, 0.127 mmol) and NaOAc (0.313 g, 3.82 mmol) were sequentially added, and then stirred at room temperature overnight. DW was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as a colorless oil (0.23 g, 50.4%).

[0077] 11H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 6.20 (s, 2H), 3.84 - 3.78 (m, 1H), 3.52 (dd, J = 15.6, 7.8 Hz, 2H), 3.46 - 3.37 (m, 2H), 2.31 (s, 2H), 1.46 (s, 9H), 1.19 (s, 9H) Step 2: Preparation of (4-(Pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0078]

Chemical Structure

[0079] 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 the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a yellow oil (quantitative), which was used in the next reaction without purification (180 mg).

[0080] 1 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 6.20 (s, 2H), 3.75 (s, 2H), 2.52 (s, 5H), 1.19 (s, 9H) <Production Example 2> Preparation of 4-(Pyrrolidin-3-yl)-1H-1,2,3-triazole trifluoroacetic acid Step 1: tert-Butyl 3-(1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0081]

Chemical Structure

[0082] 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 a mixture of DMF / MeOH (5.1 mL / 0.67 mL) were stirred at 80 °C overnight. After concentrating the reaction mixture, DW was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and the residue obtained was purified by column chromatography (MeOH / DCM) to obtain the title compound as a pale green oil (0.154 g, 42.0%).

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 3.91 - 3.77 (m, 1H), 3.65 - 3.35 (m, 4H), 2.37 - 2.04 (m, 2H), 1.47 (s, 9H) Step 2: Preparation of 4-(pyrrolidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0084]

Chemical formula

[0085] 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 obtain the title compound as a yellow oil (quantitative) and used in the next reaction without purification (148 mg).

[0086] <Production Example 3> Preparation of 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one Step 1: Preparation of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate

[0087] [Chem.]

[0088] 2,3-Dihydro-1H-inden-2-amine (1 g, 7.5 mmol) was dissolved in anhydrous 1,4-dioxane (25 mL), and then DIPEA (N,N-diisopropylethylamine) (2.6 mL, 15 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (1.26 g, 6.76 mmol) were sequentially added, followed by stirring at 100 °C for 3 hours. After the reaction mixture was cooled to room temperature, DW (20 mL) was added and stirred for 2 hours. The resulting solid was filtered, washed with DW and dioxane, and then dried in vacuo to obtain the title compound (1.5 g, yield 70.5%) as a white solid.

[0089] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.72 (s, 1H), 8.46 (d, J = 6.9 Hz, 1H), 7.32 - 7.04 (m, 4H), 4.75 - 4.67 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.27 (dd, J = 15.8, 7.6 Hz, 2H), 2.92 (dd, J = 15.8, 6.8 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); LCMS m / z 284 [M+H] + Step 2: Preparation of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide

[0090] [Chem.]

[0091] 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) were stirred at 80 °C overnight. After cooling to room temperature, DW was added and the mixture was stirred at 0 °C for 2 h. The resulting solid was filtered and dried in vacuo to obtain the title compound as a white solid (0.4 g, 84.6%).

[0092] LCMS m / z 270 [M+H] + Step 3: Preparation of 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0093]

Chemical Structure

[0094] 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. Then, 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 min and at room temperature for 20 min. After concentrating the reaction mixture, EtOAc was added and the mixture was stirred at room temperature for 1 h. The resulting solid was filtered, washed once with cold EtOAc, and dried in vacuo to obtain the title compound as a white solid (0.33 g, 86%).

[0095] 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] + <Production Example 4> Production of 5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one Step 1: Ethyl 2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidine-5-carboxylate

[0096]

Chemical Structure

[0097] 6,7-Dihydro-5H-cyclopenta[b]pyridin-6-amine dihydrochloride (346 mg, 1.67 mmol) was dissolved in anhydrous dioxane (5.6 mL), and DIPEA (0.85 mL, 5.01 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (280 mg, 1.50 mmol) were added, followed by stirring at 100 °C for 4 hours. DW (20 mL) was added to the reaction mixture, and the mixture was 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 - 33% EtOAc / Hex → 3% MeOH / DCM) to obtain the title compound as a brown solid (125 mg, 29%).

[0098] 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 32.9 Hz, 2H), 8.39 (d, J = 4.9 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.09 (dd, J = 7.2, 5.3 Hz, 1H), 5.89 (d, J = 7.1 Hz, 1H), 4.98 - 4.85 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H), 3.58 - 3.39 (m, 2H), 2.98 (ddd, J = 36.1, 16.5, 5.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H) Step 2: 2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidine-5-carbohydrazide

[0099]

Chem.

[0100] 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 then stirred at 100 °C for 22 h. After concentrating the reaction mixture, DCM was added to solidify it. The resulting solid was filtered and then dried to obtain the title compound as a pale orange solid. (81 mg, 71%) LCMS m / z 272 [M+H] + Step 3: 5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0101]

Chem.

[0102] 2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidine-5-carbohydrazide (80 mg, 0.30 mmol) was dissolved in acetonitrile (1.6 mL), then TEA (43.3 μL, 0.31 mmol) and CDI (63 mg, 0.39 mmol) were added at 0 °C and stirred at the same temperature for 15 min, and then stirred at room temperature for 6 h. After concentrating the reaction mixture, the obtained residue was purified by column chromatography (0 - 2% MeOH / DCM) to obtain the title compound as a beautiful solid (83 mg, 94%).

[0103] 11H NMR (400 MHz, DMSO-d6) δ12.12 (br s, 1H), 8.66 (d, J = 15.9 Hz, 2H), 8.36 (d, J = 6.8 Hz, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 7.4, 5.2 Hz, 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] + <Production Example 5>Production of (4-(3-Methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate Step 1: Production of tert-Butyl 3-methyl-3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)pyrrolidine-1-carboxylate

[0104] [Chemical formula]

[0105] After dissolving azidomethyl pivalate (101 mg, 0.65 mmol) and tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (135 mg, 0.65 mmol) in t-BuOH (1.2 mL) / DW (1.2 mL), 10% aqueous (aq.) CuSO4·5H2O solution (0.5 mL, 0.19 mmol) and sodium ascorbate (38 mg, 0.19 mmol) were sequentially added, and the mixture was stirred at room temperature overnight. DW was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine. After drying the organic layer over MgSO4, the residue obtained by filtration and concentration was purified by column chromatography (0 - 2% MeOH / DCM) to obtain the title compound as a colorless oil (244 mg, 99%).

[0106] 11H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 6.20 (s, 2H), 3.68 (t, J = 9.8 Hz, 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) Step 2: Preparation of (4-(3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0107]

Chemical Structure

[0108] The title compound was obtained as a pale pink oil (quantitative) 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) in the same manner as in Step 2 of Production Example 1, and was used in the next reaction without purification (326 mg).

[0109] LCMS m / z 267 [M+H] + <Production Example 6> Preparation of 4-(azetidin-3-yl)-1H-1,2,3-triazole, 2,2,2-trifluoroacetate Step 1: Preparation of tert-butyl 3-(1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0110]

Chemical Structure

[0111] The title compound was obtained as a colorless oil (29.2 mg, 59.0%) 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) in the same manner as in Step 1 of Production Example 2.

[0112] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 4.19 (s, 2H), 3.88 (s, 3H), 1.37 (s, 9H) Step 2: Production of 4-(azetidin-3-yl)-1H-1,2,3-triazole 2,2,2-trifluoroacetate

[0113]

Chemical formula

[0114] The title compound was obtained as a yellow oil (quantitative) 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) in the same manner as in Step 2 of Production Example 2, and was used in the next reaction without purification (24 mg).

[0115] <Production Example 7> Production of 4-(azetidin-3-yl)-1H-1,2,3-triazole dihydrochloride

[0116]

Chemical formula

[0117] 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 then a 4M HCl dioxane solution (60 mL) was slowly added thereto on a water bath, followed by stirring at room temperature for 4 hours. The resulting solid was filtered, washed with cold DCM, and then the solid was dissolved in MeOH and concentrated. Subsequently, it was concentrated by azeotropy with toluene three times to obtain the title compound as an off-white solid (11.4 g, 97.5%).

[0118] 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (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). <Production Example 8> Production of (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate Step 1: Production of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0119]

Chemical Structure

[0120] 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), THF (3.8 mL) / DW (3.8 mL), the title compound was obtained as a white solid in the same manner as in Step 1 of Production Example 1 (0.361 g, 55.9%).

[0121] 11H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.22 (s, 2H), 4.32 (t, J = 8.6 Hz, 2H), 4.13 - 4.02 (m, 2H), 3.94 - 3.87 (m, 1H), 1.45 (s, 9H), 1.20 (s, 9H) Step 2: (4-(Azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0122]

Chem.

[0123] The title compound was obtained quantitatively (0.355 g, 1.05 mmol) of tert-butyl 3-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate using the same method as in Step 2 of Production Example 1, TFA (3.5 mL), and DCM (10.5 mL), and used in the next reaction without purification (282 mg).

[0124] <Example 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 Step 1: (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0125]

Chem.

[0126] 5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 then DIPEA (69 μL, 0.4 mmol) and BOP reagent (42.7 mg, 0.097 mmol) were added sequentially. After stirring overnight at room temperature, DW was added to the reaction mixture and extracted with EtOAc, and the organic layer was washed with brine. After drying the organic layer over MgSO4, it was filtered and concentrated, and the residue obtained was purified by column chromatography (0 - 10% MeOH / DCM) to obtain the title compound as a white solid (34.5 mg, 80.9%).

[0127] LCMS m / z 530 [M+H] + Step 2: 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

[0128]

Chem.

[0129] (4-(1-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), and then K2CO3 (17.3 mg, 0.13 mmol) was added. The mixture was stirred at room temperature for 1 hour. After adding DW to the reaction mixture, it was 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 - 10% MeOH / DCM) to obtain the title compound as a white solid (19 mg, 72.9%).

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 14.2 Hz, 2H), 8.24 (d, J = 6.8 Hz, 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, 7.6 Hz, 2H), 2.45 - 2.33 (dd, J = 15.9, 6.7 Hz, 2H), 2.24 - 2.11 (m, 1H), 2.16 (m, 1H); LCMS m / z 416 [M+H] + <Example 2>(4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate Step 1: 5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0131]

Chemical formula

[0132] The title compound was produced in the same manner as Production 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.

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.65 (d, J = 14.6 Hz, 2H), 8.33 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dq, J = 13.8, 6.9 Hz, 1H), 3.24 (dd, J = 16.1, 7.6 Hz, 2H), 2.87 (dd, J = 16.0, 6.4 Hz, 2H); LCMS m / z 332 [M+H] + Step 2: (4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0134]

Chemical formula

[0135] Using the same method as in Step 1 of Example 1, (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), the title compound was obtained as a white solid (69.8 mg, 40.8%).

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.23 (d, J = 6.9 Hz, 1H), 8.18 (s, 1H), 7.27 (t, J = 9.4 Hz, 2H), 6.26 (s, 2H), 4.68 (dd, J = 14.4, 7.4 Hz, 1H), 3.94 - 3.88 (m, 1H), 3.73 - 3.64 (m, 2H), 3.64 - 3.54 (m, 4H), 3.24 (d, J = 8.4 Hz, 2H), 2.88 (dd, J = 16.0, 6.5 Hz, 2H), 1.10 (s, 9H); LCMS m / z 566 [M+H] + <Example 3>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0137]

Chemical formula

[0138] ((4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), then K2CO3 (33.2 mg, 0.240 mmol) was added and stirred at room temperature for 2 h. After filtering the reaction mixture, the residue obtained by concentration was purified by column chromatography (MeOH / DCM) to obtain the title compound as a white solid (47.2 mg, 87.0%).

[0139] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.23 (d, J = 6.7 Hz, 1H), 7.79 (s, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dd, J = 13.9, 7.0 Hz, 1H), 3.94 - 3.87 (m, 1H), 3.58 (d, J = 9.0 Hz, 2H), 3.24 (d, J = 8.6 Hz, 2H), 2.87 (dd, J = 16.1, 6.5 Hz, 2H), 2.38 (dd, J = 12.4, 5.6 Hz, 2H), 2.20 - 2.06 (m, 2H); LCMS m / z 452 [M+H] + <Example 4>((4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pivalate

[0140]

Chemical formula

[0141] In the same manner as in Step 1 of Example 1, 5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (27.8 mg, 0.094 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (56 mg, crude), DIPEA (83 μL, 0.49 mmol), BOP reagent (49.8 mg, 0.113 mmol), and DMF (1.88 mL) were used to obtain the title compound as a yellow solid (28 mg, 56%).

[0142] 1 H NMR (400 MHz, DMSO-d6) δ8.75 (s, 2H), 8.29 (dd, J = 17.1, 5.7 Hz, 2H), 8.20 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.15 (dd, J = 7.3, 5.1 Hz, 1H), 6.28 (s, 2H), 4.79 - 4.66 (m, 1H), 3.93 (dd, J = 9.3, 7.5 Hz, 1H), 3.71 (dt, J = 14.1, 7.0 Hz, 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] + <Example 5>(4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate Step 1: 5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0143] [Chemical formula]

[0144] The title compound was prepared in the same manner as in Production Example 3, except that benzodioxol-5-ylmethanamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0145] 1 H NMR (400 MHz, DMSO-d6) δ12.42 (s, 1H), 8.64 (s, 2H), 8.45 (t, J = 6.3 Hz, 1H), 6.92 - 6.73 (m, 3H), 5.97 (s, 2H), 4.47 (d, J = 6.3 Hz, 2H); LCMS m / z 314 [M+H] + Step 2: (4-(1-(5-(2-((Benzodioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0146] [Chemical formula]

[0147] The title compound was obtained as a white solid (41 mg, 70%) using 5-(2-((benzodioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (34 mg, 0.11 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (45 mg, 0.13 mmol), DIPEA (91 μL, 0.54 mmol), BOP reagent (57 mg, 0.13 mmol), and DMF (1 mL) in the same manner as in Step 1 of Example 1.

[0148] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.34 (t, J = 6.3 Hz, 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 = 6.2 Hz, 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 / z 548 [M+H] + <Example 6>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

[0149]

Chem.

[0150] The title compound was obtained as a white solid (22 mg, 76%) using (4-(1-(5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0151] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.35 (t, J = 6.3 Hz, 1H), 7.81 (s, 1H), 6.89 (s, 1H), 6.85 - 6.77 (m, 2H), 5.97 (s, 2H), 4.46 (d, J = 6.2 Hz, 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] + <Example 7> N-(5-(5-(3-(1H-1,2,3-Triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine Step 1: 5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0152]

Chemical Structure

[0153] The title compound was prepared in the same manner as in Production Example 4, except that 6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine dihydrochloride was used instead of 6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine dihydrochloride.

[0154] 1H NMR (400 MHz, DMSO-d6) δ 12.03 (br s, 1H), 8.68 (s, 2H), 8.42 (d, J = 6.8 Hz, 1H), 8.36 (s, 2H), 4.88 - 4.76 (m, 1H), 3.46 - 3.41 (m, 2H), 3.05 (dd, J = 17.3, 5.5 Hz, 2H); LCMS m / z 298 [M+H] + Step 2: (4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0155]

Chem.

[0156] The title compound was obtained as a yellow solid (15 mg, 19%) using 5-(2-((6,7-dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (35.5 mg, 0.119 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (71 mg, 0.19 mmol), DIPEA (105 μL, 0.62 mmol), BOP reagent (63.4 mg, 0.14 mmol), and DMF (2.4 mL) in the same manner as in Step 1 of Example 1.

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.36 (s, 2H), 8.33 (d, J = 6.9 Hz, 1H), 8.20 (s, 1H), 6.28 (s, 2H), 4.88 - 4.74 (m, 1H), 3.93 (dd, J = 9.4, 7.0 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.66 - 3.54 (m, 3H), 3.43 (dd, J = 17.3, 7.9 Hz, 2H), 3.05 (dd, J = 17.3, 5.6 Hz, 2H), 2.44 - 2.35 (m, 1H), 2.24 - 2.13 (m, 1H), 1.12 (s, 9H); LCMS m / z 532 [M+H] + Step 3: N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine

[0158] [Chemical Structure]

[0159] (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 K2CO3 (6.6 mg, 0.047 mmol) was added. The mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the obtained residue was purified by column chromatography (0 - 8% MeOH / DCM) to obtain the title compound as a white solid (8 mg, 81%).

[0160] 1 H NMR (400 MHz, 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, 7.3 Hz, 1H), 3.77 - 3.52 (m, 4H), 3.43 (dd, J = 17.4, 8.0 Hz, 2H), 3.17 (d, J = 5.1 Hz, 1H), 3.05 (dd, J = 17.2, 5.6 Hz, 2H), 2.45 - 2.35 (m, 1H), 2.22 - 2.10 (m, 1H); LCMS m / z 418 [M+H] + <Example 8>N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine

[0161]

Chem.

[0162] The title compound was obtained as a white solid (9 mg, 50%) using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-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) in the same manner as in Step 3 of Example 7.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ8.75 (s, 2H), 8.30 (dd, J = 14.0, 5.8 Hz, 2H), 7.82 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.15 (dd, J = 7.4, 5.1 Hz, 1H), 4.80 - 4.65 (m, 1H), 3.93 (dd, J = 9.3, 7.4 Hz, 1H), 3.75 - 3.54 (m, 4H), 3.38 - 3.35 (m, 1H), 3.31 - 3.27 (m, J = 9.0 Hz, 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]+ (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 Step 1: Ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate

[0164]

Chemical formula

[0165] 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), and 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 concentrating the reaction mixture, the obtained residue was purified by column chromatography (EtOAc / Hex) to obtain the title compound as a brown solid (0.348 g, 54.4%).

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 2H), 8.09 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 16.1 Hz, 1H), 7.26 (t, J = 9.3 Hz, 2H), 6.51 (d, J = 16.1 Hz, 1H), 4.66 (dd, J = 13.8, 6.8 Hz, 1H), 4.15 (dd, J = 14.1, 7.0 Hz, 2H), 3.22 (dd, J = 16.1, 7.7 Hz, 2H), 2.86 (dd, J = 15.8, 6.3 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); LCMS m / z 346 [M+H] + Step 2: (E)-3-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid

[0167]

Chem.

[0168] A solution of LiOH (0.119 g, 4.99 mmol) in DW (2 mL) was added 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), and the mixture was stirred at room temperature overnight. After concentrating the reaction mixture, DW was added, the pH was adjusted to 1 - 2 with 3M HCl, and the mixture was 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 as an off-white solid (0.147 g, 46.4%).

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.64 (s, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 16.0 Hz, 1H), 7.26 (t, J = 9.3 Hz, 2H), 6.41 (d, J = 16.2 Hz, 1H), 4.66 (dd, J = 14.0, 6.8 Hz, 1H), 3.26 - 3.19 (m, 2H), 2.86 (dd, J = 16.1, 6.6 Hz, 2H); LCMS m / z 318 [M+H] + 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

[0170]

Chem.

[0171] (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 HBTU (57.4 mg, 0.151 mmol) were added to a mixture of DMF (2.5 mL), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, the obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as a yellow solid (42.7 mg, 61.4%).

[0172] LCMS m / z 552 [M+H] + 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

[0173]

Chem.

[0174] The title compound was obtained as an off-white solid (27.2 mg, 85.7%) using (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 (40 mg, 0.073 mmol), K2CO3 (20.0 mg, 0.145 mmol), and MeOH (0.36 mL) in the same manner as in Example 3.

[0175] 1 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 2H), 7.98 (s, 1H), 7.70 (s, 1H), 7.34 (s, 1H), 7.27 (dd, J = 16.7, 7.6 Hz, 2H), 6.91 (dd, J = 16.0, 9.6 Hz, 1H), 4.65 (dd, J = 13.6, 6.8 Hz, 1H), 4.08 (s, 1H), 3.81 (dd, J = 12.6, 9.8 Hz, 2H), 3.65 (dd, J = 24.1, 15.4 Hz, 2H), 3.48 (s, 2H), 3.22 (dd, J = 15.2, 7.5 Hz, 2H), 2.86 (dd, J = 15.4, 4.6 Hz, 2H); LCMS m / z 438 [M+H] + <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 Step 1: Ethyl 3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoate

[0176]

Chemical formula

[0177] 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.

[0178] 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.31 (d, J = 6.7 Hz, 1H), 7.24 (t, J = 9.2 Hz, 2H), 4.61 - 4.52 (m, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.18 (dd, J = 15.7, 7.4 Hz, 2H), 2.81 (dd, J = 16.1, 6.8 Hz, 2H), 2.59 (dt, J = 32.2, 7.2 Hz, 4H), 1.14 (t, J = 7.1 Hz, 3H); LCMS m / z 348 [M+H] + Step 2: 3-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid

[0179]

Chemical formula

[0180] The title compound was obtained as a white solid (75.6 mg, 72.8%) 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) in the same manner as in Step 2 of Example 9.

[0181] 11H NMR (400 MHz, DMSO-d6) δ 12.12 (bs, 1H), 8.17 (s, 2H), 7.30 (d, J = 6.6 Hz, 1H), 7.24 (t, J = 9.3 Hz, 2H), 4.61 - 4.51 (m, 1H), 3.19 (dd, J = 15.9, 7.7 Hz, 2H), 2.81 (dd, J = 15.9, 6.8 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 2.46 (d, J = 7.8 Hz, 2H); LCMS m / z 320 [M+H] + 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

[0182]

Chemical Structure

[0183] The title compound was obtained as a yellow solid (24 mg, 86.5%) 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) in the same manner as in Step 3 of Example 9.

[0184] LCMS m / z 554 [M+H] + 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

[0185]

Chem.

[0186] Using the same method as in Example 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 (20 mg, 0.036 mmol), K2CO3 (10 mg, 0.072 mmol), and MeOH (0.18 mL), the title compound was obtained as a yellow solid (8.7 mg, 54.8%).

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 1.4 Hz, 2H), 7.72 (s, 1H), 7.29 - 7.22 (m, 2H), 4.56 (dd, J = 13.9, 7.4 Hz, 1H), 3.86 - 3.70 (m, 1H), 3.58 - 3.39 (m, 3H), 3.28 (d, J = 7.8 Hz, 1H), 3.21 - 3.13 (m, 2H), 2.81 (dd, J = 15.9, 6.4 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.23 (dd, J = 31.5, 6.1 Hz, 2H), 2.06 - 1.84 (m, 2H); LCMS m / z 440 [M+H] + <Example 11>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine Step 1: 5-(2-((3,5-Dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0188]

Chem.

[0189] The title compound was prepared in the same manner as in Production Example 3, except that 2-(3,5-dichlorophenyl)ethane-1-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0190] 1 H NMR (400 MHz, DMSO-d6) δ12.40 (broad, 1H), 8.62 (d, J = 9.6 Hz, 2H), 8.07 (t, J = 5.7 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 1.6 Hz, 2H), 3.58 (dd, J = 12.8, 6.6 Hz, 2H), 2.87 (t, J = 6.8 Hz, 2H); LCMS m / z 352 [M+H] + Step 2: (4-(1-(5-(2-((3,5-Dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0191]

Chemical formula

[0192] The title compound was obtained as a white solid (36.8 mg, yield 86.2%) using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (25.6 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 (38.7 mg, 0.087 mmol), and DMF (2 mL) in the same manner as in Step 1 of Example 1.

[0193] LCMS m / z 530 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0194]

Chemical Structure

[0195] The title compound was obtained as a white solid (11.8 mg, 42.2%) using (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 7.4 Hz, 2H), 7.98 (t, J = 5.7 Hz, 1H), 7.82 (broad, 1H), 7.43 (s, 1H), 7.32 (d, J = 1.6 Hz, 2H), 3.97 - 3.88 (m, 1H), 3.74 - 3.54 (m, 6H), 2.88 (t, J = 6.8 Hz, 2H), 2.47 - 2.35 (m, 1H), 2.25 - 2.10 (m, 1H); LCMS m / z 472 [M+H] + <Example 12> (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate Step 1: 5-(2-((5-Methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0197]

Chem.

[0198] The title compound was prepared in the same manner as in Production Example 3, except that 5-methoxy-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0199] 1 H NMR (400 MHz, DMSO-d6) δ8.65 (d, J = 16.3 Hz, 2H), 8.30 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 6.71 (dd, J = 8.2, 2.2 Hz, 1H), 4.67 (dd, J = 14.3, 7.2 Hz, 1H), 3.71 (s, 3H), 3.21 (dd, J = 16.7, 9.0 Hz, 3H), 2.92 - 2.79 (m, 2H); LCMS m / z 326 [M+H] + Step 2: (4-(1-(5-(2-((5-Methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0200]

Chem.

[0201] The title compound was obtained as a white solid (17 mg, 38%) using 5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (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) in the same manner as in Step 1 of Example 1.

[0202] 1 H NMR (400 MHz, DMSO-d6) δ8.74 (d, J = 12.3 Hz, 2H), 8.26 - 8.17 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J = 8.2 Hz, 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, 7.5 Hz, 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] + <Example 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

[0203]

Chemical Structure

[0204] (4-(1-(5-(2-((5-Methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) were used in the same manner as in Step 2 of Example 1 to obtain the title compound as a white solid (2.7 mg, 31%).

[0205] 1 1H NMR (400 MHz, DMSO-d6) δ8.73 (d, J = 15.3 Hz, 2H), 8.22 (d, J = 7.0 Hz, 1H), 7.81 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.73 - 4.62 (m, 1H), 3.96 - 3.89 (m, 1H), 3.75 - 3.57 (m, 7H), 3.25 - 3.16 (m, 2H), 2.95 - 2.80 (m, 2H), 2.43 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H); LCMS m / z 446 [M+H] + <Example 14>5-(5-(3-(1H-1,2,3-Triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine Step 1: 5-(5-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2(3H)-one

[0206]

Chem.

[0207] The title compound was prepared in the same manner as in Production 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-chloropyrazine-2-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0208] LCMS m / z 332 [M+H] + Step 2: (4-(1-(5-(5-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0209]

Chemical formula

[0210] The title compound was obtained as a brown solid (28.8 mg, 69.9%) using 5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0211] LCMS m / z 566 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine

[0212]

Chem.

[0213] Using the same method as in Step 2 of Example 1, (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (3.95 mg, 18%).

[0214] 1 H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.11 (t, J = 8.8 Hz, 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, 5.4 Hz, 2H), 2.56 - 2.46 (m, 1H), 2.36 - 2.25 (m, 1H); LCMS m / z 452 [M+H] + <Example 15> Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carboxylate

[0215]

Chem.

[0216] To a solution of 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (60 mg, 0.181 mmol) in DMF (0.9 mL) was added methyl pyrrolidine-3-carboxylate hydrochloride (36.0 mg, 0.217 mmol), and then DIPEA (92 μL, 0.543 mmol) was added 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 and the mixture was extracted with EtOAc. 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 as a white solid (45.4 mg, 56.7%).

[0217] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.24 (d, J = 6.4 Hz, 1H), 7.27 (t, J = 9.1 Hz, 2H), 4.68 (d, J = 6.6 Hz, 1H), 3.75 - 3.59 (m, 5H), 3.52 (s, 2H), 3.24 (dd, J = 16.0, 7.6 Hz, 2H), 2.87 (dd, J = 16.0, 6.4 Hz, 2H), 2.20 (d, J = 32.5 Hz, 2H). LCMS m / z 443 [M+H] + <Example 16>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine Step 1: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0218]

Chemical Structure

[0219] The title compound was produced in the same manner as Production 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.

[0220] 1 H NMR (400 MHz, DMSO-d6) δ12.30 (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] + Step 2: (4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0221]

Chemical formula

[0222] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (25 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 (38 mg, 0.087 mmol), and DMF (2 mL), the title compound was obtained as a brown solid (30.9 mg, 73.7%).

[0223] LCMS m / z 580 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0224]

Chem.

[0225] Using the same method as in Step 2 of Example 1, (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (17 mg, 71.8%).

[0226] 11H NMR (400 MHz, DMSO-d6) δ 8.62 (broad, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.28 (t, J = 9.3 Hz, 2H), 4.71 (s, 1H), 3.98 - 3.88 (m, 1H), 3.75 - 3.55 (m, 4H), 3.25 (dd, J = 15.9, 7.2 Hz, 2H), 2.88 (dd, J = 15.9, 6.7 Hz, 2H), 2.57 (s, 3H), 2.46 - 2.35 (m, 1H), 2.24 - 2.10 (m, 1H); LCMS m / z 466 [M+H] + <Example 17>5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine <Step 1>: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidin-2-amine

[0227]

Chem.

[0228] 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 by microwave (160 °C, 1 h). After concentrating the reaction mixture, the obtained residue was purified by column chromatography (EA / Hex) to obtain the title compound as a brown solid (0.322 g, 39.7%).

[0229] 11H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 7.65 (d, J = 6.6 Hz, 1H), 7.25 (t, J = 9.3 Hz, 2H), 6.52 (dd, J = 17.8, 11.3 Hz, 1H), 5.70 (d, J = 17.4 Hz, 1H), 5.09 (d, J = 11.7 Hz, 1H), 4.67 - 4.57 (m, 1H), 3.21 (dd, J = 16.0, 7.5 Hz, 2H), 2.84 (dd, J = 15.8, 6.6 Hz, 2H); LCMS m / z 274 [M+H] + Step 2: 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0230]

Chem.

[0231] 1,1-Dibromoformaldoxime (0.356 g, 1.76 mmol) was dissolved in DMF (2.9 mL) and cooled to -10 °C. Then, a solution of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidin-2-amine (0.320 g, 1.17 mmol) and KHCO3 (0.293 g, 2.93 mmol) in DW (2.9 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. DW was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The obtained residue was purified by column chromatography (EtOAc / Hex) to obtain the title compound as a brown solid (0.294 g, 63.5%).

[0232] 11H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.76 (d, J = 6.9 Hz, 1H), 7.25 (t, J = 9.2 Hz, 2H), 5.54 (t, J = 10.6 Hz, 1H), 4.62 (d, J = 7.0 Hz, 1H), 3.60 (dd, J = 17.3, 10.8 Hz, 1H), 3.47 (dd, J = 17.3, 10.5 Hz, 1H), 3.20 (dd, J = 15.9, 7.1 Hz, 2H), 2.83 (dd, J = 12.5, 4.1 Hz, 2H); LCMS m / z 396 [M+H] + Step 3: 5-(3-(3-(1H-1,2,3-Triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0233]

Chem.

[0234] A mixture of 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-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 by microwave (160 °C, 2 h). The reaction mixture was filtered and washed with 10% MeOH / DCM solution, and then the filtrate was concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as an orange solid (15.8 mg, 25.1%).

[0235] 11H NMR (400 MHz, CDCl3) δ 8.36 (s, 2H), 7.53 (s, 1H), 7.00 (t, J = 8.7 Hz, 2H), 5.75 (t, J = 6.3 Hz, 1H), 5.39 (t, J = 8.8 Hz, 1H), 4.81 (dd, J = 12.6, 5.7 Hz, 1H), 3.77 (dd, J = 15.6, 6.6 Hz, 1H), 3.67 - 3.50 (m, 3H), 3.43 - 3.29 (m, 3H), 3.06 (dd, J = 14.9, 8.1 Hz, 1H), 2.83 (dd, J = 16.1, 5.0 Hz, 2H), 2.40 (dd, J = 12.4, 5.8 Hz, 1H), 2.17 (dd, J = 13.2, 7.1 Hz, 1H); LCMS m / z 453 [M+H] + <Example 18>5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0236]

Chemical formula

[0237] A mixture of 5-(3-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-4,5-dihydroisoxazol-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) was stirred at 110 °C for 3 h. EtOAc and 10% Na2S2O4 solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Then the organic layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound as a white solid (4.2 mg, 42.2%).

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 2H), 8.13 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 6.51 (s, 1H), 4.67 (dd, J = 13.8, 7.0 Hz, 1H), 3.68 (d, J = 8.4 Hz, 1H), 3.39 (dd, J = 15.0, 7.8 Hz, 2H), 3.23 (dd, J = 16.1, 7.5 Hz, 2H), 2.87 (dd, J = 16.1, 6.5 Hz, 2H), 2.35 (d, J = 6.3 Hz, 2H), 2.05 (d, J = 48.6 Hz, 2H); LCMS m / z 451 [M+H] + <Example 19>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0239]

Chem.

[0240] The title compound was prepared in the same manner as Production Example 3, except that 5-bromo-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0241] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.66 (d, J = 13.9 Hz, 2H), 8.33 (d, J = 6.8 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.73 - 4.63 (m, 1H), 3.28 - 3.20 (m, 2H), 2.90 (ddd, J = 22.4, 16.2, 6.5 Hz, 2H); LCMS m / z 374 [M+H] + Step 2: (4-(1-(5-(2-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0242]

Chem.

[0243] In the same manner as in Step 1 of Example 1, 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (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) were used to obtain the title compound as a yellow solid (50 mg, 82%).

[0244] LCMS m / z 608, 610 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0245]

Chem.

[0246] In the same manner as in Step 2 of Example 1, (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) were used to obtain the title compound as a white solid (25 mg, 63%).

[0247] 11H NMR (400 MHz, CD3OD) δ 8.71 (s, 2H), 8.23 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.68 - 4.63 (m, 1H), 3.91 - 3.88 (m, 1H), 3.69 - 3.59 (m, 4H), 3.28 - 3.18 (m, 2H), 2.94 - 2.83 (m, 2H), 2.39 - 2.37 (m, 1H), 2.16 - 2.14 (m, 1H); LCMS m / z 494, 496 [M+H] + <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 Step 1: (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid

[0248]

Chemical Structure

[0249] The title compound was prepared in the same manner 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.

[0250] LCMS m / z 282 [M+H] + 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

[0251] [Chemical formula]

[0252] (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), then 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. After adding DW to the reaction mixture, it was extracted with EtOAc and the organic layer was washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and the residue obtained was purified by column chromatography (0 - 100% EtOAc / Hex) to obtain the title compound as a white solid (30.8 mg, 63%).

[0253] LCMS m / z 516 [M+H] + 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

[0254] [Chemical formula]

[0255] The title compound was obtained as a white solid (11.4 mg, yield 51.2%) 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) in the same manner as in Step 2 of Example 1.

[0256] 1 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 = 16.0, 7.8 Hz, 2H), 2.91 (dd, J = 15.7, 4.7 Hz, 2H), 2.41 - 2.22 (m, 1H), 2.15 - 1.94 (m, 1H); LCMS m / z 402 [M+H] + <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 Step 1: 5-(2-((3,5-Difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0257]

Chemical formula

[0258] The title compound was prepared in the same manner as in Production Example 3, except that (3,5-difluorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0259] LCMS m / z 306 [M+H] + Step 2: (4-(1-(5-(2-((3,5-Difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0260]

Chem.

[0261] The title compound was obtained as a brown solid (33.6 mg, 90.9%) using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (20.9 mg, 0.07 mmol), (4-(pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate (30.1 mg, 0.082 mmol), DIPEA (58 μL, 0.34 mmol), BOP reagent (37 mg, 0.082 mmol), and DMF (2 mL) in the same manner as in Step 1 of Example 1.

[0262] LCMS m / z 540 [M+H] + 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

[0263]

Chem.

[0264] Using the same method as in Step 2 of Example 1, (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (16.7 mg, 66.7%).

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (broad, 2H), 8.45 (t, J = 6.4 Hz, 1H), 7.81 (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), 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] + <Example 22>1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carboxylic acid

[0266]

Chemical Structure

[0267] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carboxylate (39.4 mg, 0.089 mmol) was dissolved in THF (0.45 mL), then 1N NaOH (223 μL, 0.223 mmol) was added and stirred at room temperature for 1.5 h. After concentrating and removing THF, EA was added and stirred for 1 h. The resulting solid was filtered to obtain the title compound as a white solid (36 mg, 94.4%).

[0268] 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 2H), 8.21 (d, J = 6.5 Hz, 1H), 7.27 (t, J = 9.2 Hz, 2H), 4.68 (dd, J = 13.1, 5.9 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.47 - 3.39 (m, 2H), 3.24 (dd, J = 16.2, 7.8 Hz, 2H), 2.87 (dd, J = 16.1, 6.2 Hz, 2H), 2.65 (d, J = 6.5 Hz, 1H), 2.03 (d, J = 55.0 Hz, 3H); LCMS m / z 429 [M+H] + <Example 23>5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one Step 1: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carbohydrazide

[0269]

Chemical formula

[0270] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carboxylate (53.5 mg, 0.12 mmol) was dissolved in EtOH (3 mL), then hydrazine monohydrate (0.2 mL, 2.4 mmol) was added and stirred at 85 °C overnight. After adding DW to the reaction mixture, it was stirred at 0 °C for 2 h. The resulting solid was filtered and dried to obtain the title compound as a white solid (43.8 mg, 81.9%).

[0271] LCMS m / z 443 [M+H] + Step 2: 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1,3,4-oxadiazol-2(3H)-one

[0272]

Chemical formula

[0273] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidine-3-carbohydrazide (43.8 mg, 0.099 mmol) was dissolved in THF (2 mL), then TEA (14 μL, 0.099 mmol) and CDI (19.3 mg, 0.12 mmol) were slowly added at 0 °C and stirred at the same temperature for 20 min and at room temperature for 20 min. After concentrating the reaction mixture, DW was added and extracted with EtOAc, then the organic layer was washed with brine. After drying the organic layer over MgSO4, it was filtered and concentrated, and the residue obtained was purified by column chromatography (0 - 10% MeOH / DCM) to obtain the title compound as a white solid (26.4 mg, 56.9%).

[0274] 11H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.74 (broad, 2H), 8.27 (d, J = 6.7 Hz, 1H), 7.29 (t, J = 9.3 Hz, 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, 7.5 Hz, 2H), 2.90 (dd, J = 16.1, 6.5 Hz, 2H), 2.41 - 2.30 (m, 1H), 2.30 - 2.18 (m, 1H); LCMS m / z 469 [M+H] + <Example 24> Methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetate

[0275]

Chemical Structure

[0276] The title compound was obtained as a yellow solid (22.5 mg, 27.2%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (60 mg, 0.181 mmol), methyl 2-pyrrolidin-3-ylacetate 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) in the same manner as in Step 1 of Example 1.

[0277] 11H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 2H), 8.23 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 9.2 Hz, 2H), 4.68 (dd, J = 13.3, 6.6 Hz, 1H), 3.72 - 3.65 (m, 1H), 3.58 (d, J = 16.2 Hz, 4H), 3.44 (d, J = 8.8 Hz, 1H), 3.24 (dd, J = 16.4, 7.4 Hz, 3H), 3.16 - 3.09 (m, 1H), 2.87 (dd, J = 15.9, 6.2 Hz, 2H), 2.72 - 2.53 (m, 2H), 2.23 - 2.03 (m, 2H); LCMS m / z 457 [M+H] + <Example 25> 2-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetic acid

[0278]

Chemical formula

[0279] The title compound was obtained as a white solid (8 mg, 82.5%) using methyl 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetate (10 mg, 0.022 mmol), 1N NaOH (223 μL, 0.223 mmol), and THF (0.11 mL) in the same manner as in Example 22.

[0280] 11H NMR (400 MHz, D2O) δ 8.54 (s, 2H), 6.99 (t, J = 9.4 Hz, 2H), 3.59 (s, 1H), 3.44 (d, J = 37.6 Hz, 3H), 3.16 (dd, J = 17.6, 7.5 Hz, 2H), 3.07 - 3.02 (m, 1H), 2.76 (d, J = 16.1 Hz, 2H), 2.60 - 2.48 (m, 2H), 2.20 (s, 2H), 2.07 (s, 1H); LCMS m / z 443 [M+H] + <Example 26>1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-ol

[0281]

Chemical Structure

[0282] The title compound was obtained as an off-white solid (0.235 g, 64.8%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) in the same manner as in Step 1 of Example 1.

[0283] 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.23 (d, J = 6.9 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 5.08 (d, J = 3.6 Hz, 1H), 4.68 (dd, J = 13.9, 7.0 Hz, 1H), 4.38 (s, 1H), 3.58 - 3.51 (m, 3H), 3.35 (d, J = 10.9 Hz, 1H), 3.24 (dd, J = 16.2, 7.4 Hz, 2H), 2.88 (dd, J = 16.1, 6.4 Hz, 2H), 2.04 - 1.86 (m, 2H); LCMS m / z 401[M+H] + <Example 27> 1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl methanesulfonate

[0284]

Chemical Structure

[0285] 1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), and then MsCl (41 μL, 0.525 mmol) was added at 0 °C and stirred at room temperature for 8 hours. DW was added to the reaction mixture, and the mixture was extracted with DCM, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as an off-white solid (86 mg, 37.7%).

[0286] 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.25 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 5.41 (s, 1H), 4.68 (dd, J = 14.0, 6.9 Hz, 1H), 3.83 - 3.71 (m, 2H), 3.66 (d, J = 7.1 Hz, 1H), 3.61 - 3.50 (m, 1H), 3.27 (s, 3H), 3.25 - 3.20 (m, 2H), 2.88 (dd, J = 16.2, 6.5 Hz, 2H), 2.36 - 2.25 (m, 2H); LCMS m / z 479 [M+H] + <Example 28>5-(5-(3-(1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0287]

Chemical Structure

[0288] 1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl methanesulfonate (35 mg, 0.073 mmol), 1,2,4-triazole (6.1 mg, 0.088 mmol) were dissolved in DMF (0.73 mL), then NaH (57-63% oil dispersion) (3.5 mg, 0.088 mmol) was added and stirred at 60 °C overnight. After 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, concentrated, and the residue obtained was purified by column chromatography (MeOH / DCM) to obtain the title compound as a white solid (32.3 mg, 97.8%).

[0289] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.65 (s, 1H), 8.24 (d, J = 6.6 Hz, 1H), 7.99 (s, 1H), 7.27 (t, J = 9.2 Hz, 2H), 5.32 - 5.24 (m, 1H), 4.68 (dd, J = 13.9, 7.2 Hz, 1H), 3.98 (dd, J = 11.0, 6.4 Hz, 1H), 3.86 - 3.62 (m, 4H), 3.24 (dd, J = 16.1, 7.3 Hz, 2H), 3.15 (d, J = 5.3 Hz, 1H), 2.87 (dd, J = 16.1, 6.3 Hz, 2H); LCMS m / z 452[M+H] + <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

[0290]

Chemical formula

[0291] The title compound was obtained as a white solid (31.4 mg, 92.2%) using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-ylmethanesulfonate (35 mg, 0.073 mmol), 3-methyl-1H-1,2,4-triazole (7.3 mg, 0.088 mmol), NaH (57-63% oil dispersion) (3.5 mg, 0.088 mmol), and DMF (0.73 mL) in the same manner as in Example 28.

[0292] 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.48 (s, 1H), 8.25 (d, J = 7.0 Hz, 1H), 7.27 (t, J = 9.2 Hz, 2H), 5.20 (d, J = 28.4 Hz, 2H), 4.68 (dd, J = 14.3, 7.4 Hz, 1H), 3.95 (s, 1H), 3.70 (ddd, J = 14.1, 12.3, 5.9 Hz, 4H), 3.24 (dd, J = 16.0, 7.6 Hz, 2H), 2.88 (dd, J = 16.0, 6.5 Hz, 2H), 2.22 (s, 3H); LCMS m / z 466 [M+H] + <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 Step 1: (4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0293]

Chem.

[0294] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as an off-white solid (25.5 mg, 63.8%).

[0295] LCMS m / z 580 [M+H] + 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

[0296]

Chemical formula

[0297] Using the same method as in Step 2 of Example 1, (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (17.8 mg, 86.9%).

[0298] 11H 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] + <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 Step 1: (4-(1-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0299]

Chemical Structure

[0300] 5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) were used to obtain the title compound as an off-white solid (38.3 mg, 84.9%).

[0301] LCMS m / z 544 [M+H] + 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

[0302]

Chem.

[0303] (4-(1-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 used in the same method as in Step 2 of Example 1 to obtain the title compound as a white solid (15.6 mg, 51.7%).

[0304] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (broad, 2H), 8.23 (d, J = 6.8 Hz, 1H), 7.79 (s, 1H), 7.23 - 7.07 (m, 4H), 4.77 - 4.61 (m, 1H), 3.88 (d, J = 9.7 Hz, 1H), 3.76 - 3.62 (m, 1H), 3.62 - 3.48 (m, 2H), 3.27 (dd, J = 15.8, 7.6 Hz, 2H), 2.93 (dd, J = 15.8, 6.9 Hz, 2H), 2.44 - 2.31 (m, 1H), 2.21 - 2.06 (m, 1H); LCMS m / z 430 [M+H] + <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 Step 1: (4-(1-(5-(2-((3,5-Dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0305]

Chemical Structure

[0306] The title compound was obtained as a white solid (29.6 mg, 68.1%) using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0307] LCMS m / z 600 [M+H] + Step 2: Preparation of 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

[0308]

Chemical Structure

[0309] The title compound was obtained as a white solid (15.4 mg, 64.2%) using (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0310] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 6.6 Hz, 3H), 7.97 (t, J = 5.8 Hz, 2H), 7.85 (broad, 1H), 7.42 (s, 1H), 7.32 (s, 2H), 3.86 (d, J = 9.7 Hz, 2H), 3.72 - 3.62 (m, 2H), 3.62 - 3.48 (m, 4H), 2.88 (t, J = 6.9 Hz, 2H), 2.42 - 2.31 (m, 1H), 2.18 - 2.05 (m, 1H), 1.45 (s, 3H); LCMS m / z 486 [M+H] + <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 Step 1: 1-(5-(2-((3,5-Difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0311]

Chem.

[0312] The title compound was obtained as a white solid (25.7 mg, 68.4%) using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0313] LCMS m / z 554 [M+H] + 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

[0314]

Chem.

[0315] In the same manner as in Step 2 of Example 1, (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 used to obtain the title compound as an off-white solid (16.2 mg, 79.5%).

[0316] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.45 (t, J = 6.4 Hz, 1H), 7.79 (broad, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.02 (d, J = 6.5 Hz, 2H), 4.58 (d, J = 6.3 Hz, 2H), 3.87 (d, J = 9.5 Hz, 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] + <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 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

[0317]

Chemical formula

[0318] In the same manner as in Step 2 of Example 20, (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (21.1 mg, 0.075 mmol) and (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) were used to obtain the title compound as a white solid (29.7 mg, 75%).

[0319] LCMS m / z 530 [M+H] + Step 2: (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

[0320]

Chemical formula

[0321] In the same manner as in Step 2 of Example 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 (29.7 mg, 0.056 mmol), K2CO3 (15.5 mg, 0.11 mmol), and MeOH (2 mL) were used to obtain the title compound as an off-white solid (8.6 mg, 36.9%).

[0322] 11H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 2H), 7.98 (d, J = 7.0 Hz, 1H), 7.33 (dd, J = 15.6, 2.9 Hz, 1H), 7.27 - 7.08 (m, 4H), 6.90 (dd, J = 20.5, 15.9 Hz, 1H), 4.73 - 4.56 (m, 1H), 4.01 (d, J = 8.2 Hz, 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), 3.25 (dd, J = 15.7, 7.5 Hz, 6H), 2.91 (dd, J = 15.7, 6.6 Hz, 2H), 1.40 (d, J = 7.9 Hz, 3H); LCMS m / z 416 [M+H] + <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 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

[0323]

Chem.

[0324] The title compound was obtained as an orange solid (59.5 mg, 68.9%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0325] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.71 (m, 2H), 8.30 (d, J = 6.7 Hz, 1H), 7.32 (t, J = 9.2 Hz, 2H), 4.73 (dd, J = 13.6, 6.8 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.63 (s, 1H), 3.55 (t, J = 8.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.37 (s, 2H), 3.29 (dd, J = 16.1, 7.5 Hz, 2H), 2.92 (dd, J = 15.9, 6.5 Hz, 2H), 2.30 (d, J = 6.9 Hz, 1H), 2.04 (dd, J = 12.2, 7.5 Hz, 1H); LCMS m / z 409 [M+H] + 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

[0326]

Chemical Structure

[0327] 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 (20 mg, 0.049 mmol) was dissolved in MeOH (45 μL), and then a solution of azidomethane (66 μL), ascorbic acid (1.7 mg, 0.010 mmol) in DW (12 μL) and a solution of CuSO4·5H2O (1.0 mg, 0.004 mmol) in DW (12 μL) were added, followed by stirring at room temperature overnight. The residue obtained by concentrating the reaction mixture was purified by column chromatography (MeOH / DCM) to give the title compound as a yellow solid (5 mg, 21.9%).

[0328] 1 H NMR (400 MHz, CD3OD) δ 8.77 (s, 2H), 7.89 (s, 1H), 7.12 (t, J = 9.0 Hz, 2H), 4.38 (s, 2H), 4.25 (dd, J = 9.4, 6.2 Hz, 2H), 3.73 (dd, J = 21.0, 7.3 Hz, 4H), 3.36 (s, 5H), 2.97 - 2.89 (m, 2H); LCMS m / z 466 [M+H] + <Example 36>5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: 5-(2-((5-Fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0329]

Chem.

[0330] The title compound was produced in the same manner as in Production Example 3, except that 5-fluoro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0331] LCMS m / z 314 [M+H] + Step 2: (4-(1-(5-(2-((5-Fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0332]

Chemical Structure

[0333] The title compound was obtained as an off-white solid (19.5 mg, 55%) using 5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (20.4 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) in the same manner as in Step 1 of Example 1.

[0334] 11H NMR (400 MHz, CDCl3) δ 8.78 (s, 2H), 7.66 (s, 1H), 7.16 (dd, J = 7.9, 5.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 8.2 Hz, 1H), 6.21 (s, 2H), 5.68 (d, J = 7.5 Hz, 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 (td, J = 16.0, 4.9 Hz, 2H), 2.57 - 2.43 (m, 1H), 2.41 - 2.26 (m, 1H), 1.19 (s, 9H); LCMS m / z 548 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-Triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0335]

Chemical formula

[0336] The title compound was obtained as a yellow solid (13.5 mg, 99%) using (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0337] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.24 (d, J = 6.6 Hz, 1H), 7.80 (br s, 1H), 7.28 - 7.19 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.96 (t, J = 9.0 Hz, 1H), 4.70 (dd, J = 14.3, 6.9 Hz, 1H), 3.93 (t, J = 8.0 Hz, 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] + <Example 37>5-(5-(3-(1H-1,2,3-Triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine <Step 1: 5-(2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0338]

Chemical formula

[0339] The title compound was prepared in the same manner as in Production Example 3, except that 5-chloro-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0340] 11H NMR (400 MHz, DMSO-d6) δ12.44 (br s, 1H), 8.66 (d, J = 17.0 Hz, 2H), 8.34 (d, J = 6.9 Hz, 1H), 7.29 (s, 1H), 7.22 (dd, J = 18.6, 8.0 Hz, 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] + Step 2: (4-(1-(5-(2-((5-Chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0341]

Chemical formula

[0342] The title compound was obtained as a white solid (7.5 mg, 20%) using 5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0343] 11H NMR (400 MHz, CDCl3) δ 8.78 (s, 2H), 7.66 (s, 1H), 7.22 (s, 1H), 7.16 (s, 2H), 6.21 (s, 2H), 5.69 (d, J = 7.6 Hz, 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, 5.2 Hz, 2H), 2.56 - 2.45 (m, 1H), 2.39 - 2.27 (m, 1H), 1.19 (s, 9H); LCMS m / z 564 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0344]

Chemical formula

[0345] The title compound was obtained as an off-white solid (5 mg, 89%) using (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0346] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.24 (d, J = 6.6 Hz, 1H), 7.80 (br s, 1H), 7.29 (s, 1H), 7.22 (dd, J = 19.3, 7.8 Hz, 2H), 4.68 (q, J = 6.8 Hz, 1H), 3.92 (dd, J = 9.0, 7.7 Hz, 1H), 3.75 - 3.54 (m, 4H), 3.32 - 3.20 (m, 2H), 2.98 - 2.84 (m, 2H), 2.40 (dt, J = 11.8, 6.2 Hz, 1H), 2.23 - 2.09 (m, 1H); LCMS m / z 450 [M+H] + <Example 38>5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: Preparation of 4-(pyrrolidin-3-yl)-1H-imidazole, 2,2,2-trifluoroacetate

[0347] [Chemical formula]

[0348] The title compound was obtained quantitatively (50 mg, 0.21 mmol) using tert-butyl 3-(1H-imidazol-4-yl)pyrrolidine-1-carboxylate, TFA (2 mL), and DCM (4 mL) in the same manner as in Step 2 of Production Example 1, and used in the next reaction without purification (23 mg).

[0349] LCMS m / z 138 [M+H] + Step 2: 5-(5-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0350] [ka]

[0351] The same procedure as in Step 1 of Example 1 was repeated using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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 as a white solid (3 mg, 7%).

[0352] 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 2H), 7.70 (s, 1H), 7.14 (t, J = 8.0 Hz, 2H), 4.87 - 4.84 (m, 1H), 3.79 - 3.64 (m, 4H), 3.38 - 3.36 (m, LCMS m / z 451 [M+H] + Example 39: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0353] [ka]

[0354] In the same manner as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) were used to obtain the title compound as a yellow solid (21.3 mg, 53.8%).

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 10.0 Hz, 2H), 8.28 (d, J = 6.6 Hz, 1H), 7.91 (s, 1H), 7.27 (t, J = 9.4 Hz, 2H), 4.69 (dd, J = 13.7, 6.8 Hz, 1H), 4.50 (s, 2H), 4.21 (s, 3H), 3.24 (dd, J = 15.9, 7.6 Hz, 2H), 2.88 (dd, J = 16.1, 6.7 Hz, 2H); LCMS m / z 438[M+H] + <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 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

[0356]

Chemical formula

[0357] In the same manner as in Step 3 of Example 9, (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) were used to obtain the title compound as a white solid (86.1 mg, 84.7%).

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.24 (s, 1H), 8.00 (d, J = 6.5 Hz, 1H), 7.27 (dd, J = 23.0, 12.7 Hz, 3H), 6.66 (d, J = 15.8 Hz, 1H), 6.28 (s, 2H), 4.66 - 4.62 (m, 1H), 4.31 (t, J = 6.9 Hz, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.22 (dd, J = 16.1, 7.7 Hz, 2H), 3.14 - 3.11 (m, 1H), 2.86 (dd, J = 16.2, 6.8 Hz, 2H), 1.11 (s, 9H); LCMS m / z 538 [M+H] + 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

[0359]

Chem.

[0360] Using the same method as in Example 3, (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 (80 mg, 0.149 mmol), K2CO3 (41.1 mg, 0.298 mmol), and MeOH (0.7 mL), the title compound was obtained as a yellow solid (32 mg, 50.8%).

[0361] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.00 (d, J = 7.0 Hz, 1H), 7.87 (s, 1H), 7.27 (dd, J = 22.4, 12.6 Hz, 3H), 6.66 (d, J = 15.7 Hz, 1H), 4.65 (dd, J = 14.6, 7.0 Hz, 1H), 4.33 - 4.26 (m, 2H), 4.04 - 3.94 (m, 2H), 3.22 (dd, J = 16.0, 7.2 Hz, 2H), 3.15 (d, J = 5.1 Hz, 1H), 2.86 (dd, J = 16.3, 6.4 Hz, 2H); LCMS m / z 424 [M+H] + <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 Step 1: (4-(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-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0362]

Chemical formula

[0363] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (47.8 mg, 28.7%).

[0364] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 2H), 8.29 - 8.28 (m, 1H), 7.27 (t, J = 9.2 Hz, 2H), 6.28 (s, 2H), 4.69 (dd, J = 14.3, 7.1 Hz, 1H), 4.50 (s, 2H), 4.22 (d, J = 3.3 Hz, 3H), 3.24 (dd, J = 15.9, 7.8 Hz, 2H), 2.88 (dd, J = 16.1, 6.7 Hz, 2H), 1.14 - 1.08 (m, 9H); LCMS m / z 552 [M+H] + 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

[0365]

Chemical Structure

[0366] (4-(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-yl)-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 the addition of K2CO3 (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 resulting residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as a yellow solid (3.4 mg, 8.9%).

[0367] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 11.5 Hz, 2H), 8.31 - 8.24 (m, 1H), 7.88 (s, 1H), 7.31 - 7.22 (m, 2H), 4.69 (dd, J = 13.5, 6.7 Hz, 1H), 4.54 (dt, J = 7.5, 3.8 Hz, 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] + <Example 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 Step 1: (4-(1-(5-(2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0368]

Chemical formula

[0369] In the same manner as in Step 1 of Example 1, 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (29 mg, 0.1 mmol), (4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (42 mg, 0.1 mmol), DIPEA (84 μL, 0.49 mmol), BOP reagent (52.3 mg, 0.12 mmol), and DMF (2 mL) were used to obtain the title compound as a white solid (42.4 mg, yield 83.4%).

[0370] 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 2H), 7.76 (s, 1H), 7.26 - 7.16 (m, 4H), 6.23 (s, 2H), 5.78 (d, J = 7.8 Hz, 1H), 4.92 - 4.84 (m, 1H), 4.60 (t, J = 8.3 Hz, 2H), 4.41 (t, J = 7.6 Hz, 2H), 4.27 - 4.20 (m, 1H), 3.42 (dd, J = 15.9, 6.9 Hz, 2H), 2.91 (dd, J = 15.9, 5.1 Hz, 2H), 1.20 (s, 9H); LCMS m / z 516 [M+H] + Step 2: 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

[0371]

Chemical formula

[0372] The title compound was obtained as a white solid (19.5 mg, 63.6%) using (4-(1-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0373] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 16.6 Hz, 2H), 8.27 (d, J = 6.9 Hz, 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, 7.5 Hz, 2H), 2.93 (dd, J = 15.7, 6.8 Hz, 2H); LCMS m / z 402 [M+H] + <Example 43>5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisoxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0374]

Chemical formula

[0375] In the same manner as in Step 3 of Example 17, 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-(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, 0.949 mmol), and t-BuOH (3.4 mL) were used to obtain the title compound as a yellow solid (43.8 mg, 20.9%).

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 8.22 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.25 (s, 2H), 6.28 (s, 2H), 5.27 (d, J = 19.1 Hz, 2H), 4.65 - 4.59 (m, 2H), 4.20 (dd, J = 12.1, 4.7 Hz, 2H), 3.95 (d, J = 6.8 Hz, 1H), 3.19 (s, 4H), 2.83 (d, J = 9.6 Hz, 2H), 1.11 (s, 9H); LCMS m / z 553 [M+H] + Step 2: 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0377]

Chemical formula

[0378] Using the same method as in Example 3, (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisoxazol-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), the title compound was obtained as an off-white solid (10.8 mg, 90.7%).

[0379] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 7.77 (s, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.25 (t, J = 9.3 Hz, 2H), 5.27 (t, J = 9.1 Hz, 1H), 4.61 (dd, J = 14.1, 7.2 Hz, 1H), 4.20 (t, J = 7.7 Hz, 2H), 4.03 (dd, J = 12.0, 4.9 Hz, 2H), 3.93 (d, J = 5.8 Hz, 2H), 3.20 (d, J = 8.4 Hz, 2H), 3.02 (dd, J = 15.9, 9.6 Hz, 1H), 2.83 (dd, J = 15.8, 6.5 Hz, 2H); LCMS m / z 439 [M+H] + <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 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

[0380]

Chemical Structure

[0381] In the same manner as in Step 3 of Example 9, 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) were used to obtain the title compound as a yellow solid (60 mg, 68.3%).

[0382] LCMS m / z 540 [M+H] + 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

[0383]

Chemical formula

[0384] In the same manner as in Example 3, (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) were used to obtain the title compound as a yellow solid (18.4 mg, 58.3%).

[0385] 11H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 2H), 7.28 (d, J = 6.9 Hz, 1H), 7.24 (t, J = 9.4 Hz, 2H), 4.57 (dd, J = 14.0, 6.9 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H), 4.20 (t, J = 8.5 Hz, 1H), 4.10 (d, J = 6.3 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.19 (dd, J = 16.3, 7.6 Hz, 2H), 2.81 (dd, J = 15.6, 6.7 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.3 Hz, 2H); LCMS m / z 426 [M+H] + <Example 45>5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)isoxazol-3-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0386]

Chem.

[0387] The title compound was obtained as a white solid (6.5 mg, 26.1%) using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4,5-dihydroisoxazol-3-yl)azetidin-3-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) in the same manner as in Example 18.

[0388] 1 H NMR (400 MHz, CD3OD) δ 8.66 (s, 2H), 8.10 (s, 1H), 7.10 (t, J = 9.0 Hz, 2H), 6.30 (s, 2H), 6.29 (s, 1H), 4.83 - 4.77 (m, 3H), 4.39 (t, J = 7.5 Hz, 2H), 4.19 (dd, J = 13.6, 7.7 Hz, 1H), 4.14 - 4.10 (m, 2H), 2.91 (dd, J = 15.8, 6.1 Hz, 2H), 1.18 (s, 8H); LCMS m / z 551 [M+H] + Step 2: 5-(3-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0389]

Chem.

[0390] The title compound was obtained as a white solid (0.8 mg, 15.5%) using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)isoxazol-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) in the same manner as in Example 3.

[0391] 1 H NMR (400 MHz, CD3OD) δ 8.66 (s, 2H), 7.80 (s, 1H), 7.11 (t, J = 9.0 Hz, 2H), 6.29 (s, 1H), 4.81 (dd, J = 13.8, 7.3 Hz, 3H), 4.40 (t, J = 7.7 Hz, 2H), 4.22 (dt, J = 15.6, 7.8 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 2.91 (dd, J = 15.8, 6.1 Hz, 2H); LCMS m / z 437 [M+H] + <Example 46> 1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-sulfonamide

[0392]

Chemical Structure

[0393] Using the same method as in Step 1 of Example 1, the title compound was obtained as a white solid (31 mg, 38.3%) from a solution of 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (60 mg, 0.181 mmol) with 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).

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 13.8 Hz, 2H), 8.29 (d, J = 6.8 Hz, 1H), 7.30 - 7.24 (m, 4H), 4.68 (dd, J = 13.9, 6.9 Hz, 1H), 4.44 (d, J = 7.6 Hz, 2H), 4.30 - 4.24 (m, 3H), 3.24 (dd, J = 16.0, 7.5 Hz, 2H), 2.88 (dd, J = 16.0, 6.5 Hz, 2H); LCMS m / z 450 [M+H] + <Example 47> Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carboxylate

[0395]

Chemical formula

[0396] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (60 mg, 0.18 mmol), methyl pyrrolidine-3-carboxylate hydrochloride (33 mg, 0.22 mmol), DIPEA (92 μL, 0.54 mmol), BOP reagent (96 mg, 0.22 mmol), and DMF (0.9 mL), the title compound was obtained as a white solid (46 mg, 59%).

[0397] 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.67 (d, J = 7.4 Hz, 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, 7.0 Hz, 2H), 2.85 (dd, J = 16.0, 5.4 Hz, 2H); LCMS m / z 429 [M+H] + <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 Step 1: (4-(1-(5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0398]

Chemical formula

[0399] The title compound was obtained as a white solid (48.9 mg, 71.6%) using 5-(2-((3,5-difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0400] 1 H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 1.5 Hz, 2H), 8.13 (s, 1H), 6.94 (d, J = 6.7 Hz, 2H), 6.79 (t, J = 9.2 Hz, 1H), 6.30 (s, 2H), 4.65 (s, 2H), 4.61 (t, J = 8.2 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 4.32 - 4.24 (m, 1H), 1.17 (s, 9H); LCMS m / z 526 [M+H] + 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

[0401]

Chemical Structure

[0402] (4-(1-(5-(2-((3,5-Difluorobenzyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) were used in the same manner as in Step 2 of Example 1 to obtain the title compound as a white solid (31.7 mg, 81.3%).

[0403] 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] + <Example 49>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

[0404]

Chemical formula

[0405] 5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) were used in the same manner as in Step 1 of Example 1 to obtain the title compound as a white solid (25 mg, 35.7%).

[0406] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 2H), 8.26 (d, J = 6.9 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 5.84 (d, J = 6.6 Hz, 1H), 4.68 (dd, J = 13.6, 7.0 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.33 - 4.27 (m, 2H), 3.89 (dd, J = 8.6, 4.9 Hz, 2H), 3.24 (dd, J = 16.0, 7.6 Hz, 2H), 2.87 (dd, J = 16.0, 6.4 Hz, 2H); LCMS m / z 387 [M+H] + <Example 50>1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carboxylic acid

[0407]

Chemical formula

[0408] Methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain the title compound as a white solid (32 mg, 97%).

[0409] 11H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.71 (s, 2H), 8.29 (d, J = 6.8 Hz, 1H), 7.29 (t, J = 9.2 Hz, 2H), 4.75 - 4.64 (m, 1H), 4.32 (t, J = 8.5 Hz, 2H), 4.24 - 4.15 (m, 2H), 3.70 - 3.58 (m, 1H), 3.26 (dd, J = 16.2, 7.6 Hz, 2H), 2.89 (dd, J = 16.1, 6.7 Hz, 2H); LCMS m / z 415 [M+H] + 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 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

[0410]

Chemical Structure

[0411] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a yellow solid (60.0 mg, 68.8%).

[0412] LCMS m / z 409 [M+H] + 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

[0413]

Chem.

[0414] The title compound was obtained as an off-white solid (5.15 mg, yield 21.2%) using 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 (22 mg, 0.05 mmol), TMSN3 (7.5 mg, 0.06 mmol), CuI (0.51 mg, 0.003 mmol), and DMF / MeOH (1.8 mL / 0.2 mL) in the same manner as in Step 1 of Production Example 2.

[0415] 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] + <Example 52> Methyl 2-(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-yl)acetate

[0416]

Chem.

[0417] 5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (60 mg, 0.18 mmol) was dissolved in DMF (0.9 mL), then methyl 2-(azetidin-3-yl)acetate hydrochloride (36 mg, 0.22 mmol) was added and the mixture was cooled to 0 °C. Then, DIPEA (92 μL, 0.54 mmol) was added and the mixture was stirred for 30 minutes, followed by the addition of BOP reagent (96 mg, 0.22 mmol) and stirring 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 as a white solid without further purification (59 mg, 74%).

[0418] 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.63 (d, J = 7.6 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.39 (t, J = 8.3 Hz, 2H), 3.93 (dd, J = 8.0, 5.8 Hz, 2H), 3.71 (s, 3H), 3.36 (dd, J = 15.8, 7.0 Hz, 2H), 3.26 - 3.17 (m, 1H), 2.85 (dd, J = 16.1, 5.3 Hz, 2H), 2.75 (d, J = 7.7 Hz, 2H); LCMS m / z 443 [M+H] + <Example 53> 2-(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-yl)acetic acid

[0419]

Chemical Structure

[0420] In the same manner as in Example 50, methyl 2-(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-yl)acetate (39 mg, 0.09 mmol), 1N NaOH (0.22 mL, 0.22 mmol), and THF (0.44 mL) were used to obtain the title compound as a white solid (23 mg, 61%).

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.71 (s, 2H), 8.28 (d, J = 6.7 Hz, 1H), 7.29 (t, J = 9.3 Hz, 2H), 4.75 - 4.65 (m, 1H), 4.23 (t, J = 8.1 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.25 (dd, J = 16.2, 7.4 Hz, 2H), 3.11 - 3.02 (m, 1H), 2.89 (dd, J = 16.1, 6.4 Hz, 2H), 2.67 (d, J = 7.8 Hz, 2H); LCMS m / z 429 [M+H] + <Example 54>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine Step 1: 5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one

[0422]

Chemical Structure

[0423] The title compound was prepared in the same manner as in Production 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.

[0424] LCMS m / z 331 [M+H] + Step 2: (4-(1-(5-(6-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0425]

Chemical formula

[0426] The title compound was obtained as an off-white solid (41.3 mg, 81.2%) using 5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0427] 11H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.8 Hz, 1H), 7.96 (dd, J = 8.8, 2.2 Hz, 1H), 7.76 (s, 1H), 7.02 (t, J = 8.8 Hz, 2H), 6.45 (d, J = 8.7 Hz, 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 = 8.3 Hz, 2H), 4.44 - 4.37 (m, 2H), 4.26 - 4.18 (m, 1H), 3.37 (dd, J = 16.0, 6.9 Hz, 2H), 2.85 (dd, J = 16.0, 4.7 Hz, 2H), 1.20 (s, 9H); LCMS m / z 551 [M+H] + Step 3: 5-(5-(3-(1H-1,2,3-Triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine

[0428]

Chemical Structure

[0429] The title compound was obtained as a white solid (17.8 mg, 63.7%) using (4-(1-(5-(6-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0430] 11H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.0 Hz, 2H), 7.86 (s, 1H), 7.78 (dd, J = 8.8, 2.2 Hz, 2H), 7.57 (d, J = 6.5 Hz, 2H), 7.31 (t, J = 9.3 Hz, 4H), 6.60 (d, J = 8.8 Hz, 2H), 4.74 - 4.63 (m, 1H), 4.56 - 4.46 (m, 2H), 4.21 (s, 3H), 3.28 (dd, J = 16.2, 7.3 Hz, 2H), 2.82 (dd, J = 16.1, 5.4 Hz, 2H); LCMS m / z 437 [M+H] + Example 55. 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-ylmethanesulfonate

[0431] [Chemical Structure]

[0432] The title compound was obtained as a white solid (15 mg, 59.4%) 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) in the same manner as in Example 27.

[0433] 11H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 13.7 Hz, 2H), 8.30 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 5.45 (ddd, J = 10.7, 6.7, 3.9 Hz, 1H), 4.73 - 4.63 (m, 1H), 4.57 - 4.50 (m, 2H), 4.26 (dd, J = 9.7, 4.3 Hz, 2H), 3.28 (s, 3H), 3.24 (dd, J = 16.1, 7.7 Hz, 2H), 2.87 (dd, J = 16.1, 6.4 Hz, 2H); LCMS m / z 465 [M+H] + <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 Step 1: 3-Ethynyl-3-fluoroazetidine, 2,2,2-trifluoroacetate

[0434]

Chem.

[0435] The title compound was obtained (quantitatively) using tert-butyl 3-ethynyl-3-fluoroazetidine-1-carboxylate (199 mg, 1.0 mmol), TFA (3.3 mL), and DCM (10 mL) in the same manner as in Step 2 of Production Example 1, and was used in the next reaction without purification (196 mg).

[0436] 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

[0437]

Chem.

[0438] In the same manner as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 used to obtain the title compound as a white solid (200 mg, 69%).

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 7.27 (t, J = 8.0 Hz, 2H), 4.71 - 4.68 (m, 1H), 4.58 - 4.46 (m, 4H), 3.27 - 3.21 (m, 2H), 2.90 - 2.85 (m, 2H); LCMS m / z 413 [M+H] + 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

[0440]

Chemical Structure

[0441] Using the same method as in Step 1 of Production Example 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 (100 mg, 0.24 mmol), TMSN3 (38 μL, 0.29 mmol), CuI (5 mg, 0.0265 mmol), DMF (3 mL) / MeOH (0.3 mL) were used to obtain the title compound as a white solid (10 mg, 9%).

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.23 (s, 1H), 7.27 (t, J = 8.0 Hz, 2H), 4.71 - 4.63 (m, 5H), 3.27 -3.21 (m, 2H), 2.90 - 2.85 (m, 2H); LCMS m / z 456 [M+H] + <Example 57>1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carbonitrile

[0443]

Chemical formula

[0444] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), DMF (3 mL) were used to obtain the title compound as a white solid (53 mg, 44%).

[0445] 11H NMR (400 MHz, DMSO-d6) δ8.72 (d, J = 16.8 Hz, 2H), 8.32 (d, J = 6.7 Hz, 1H), 7.29 (t, J = 9.3 Hz, 2H), 4.76 - 4.64 (m, 1H), 4.45 - 4.37 (m, 2H), 4.36 - 4.29 (m, 2H), 4.05 - 3.96 (m, 1H), 3.25 (dd, J = 16.1, 7.5 Hz, 2H), 2.89 (dd, J = 16.1, 6.5 Hz, 2H); LCMS m / z 396 [M+H] + <Example 58>N-(5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine Step 1: tert-Butyl 3-(1H-tetrazol-5-yl)azetidine-1-carboxylate

[0446]

Chem.

[0447] tert-Butyl 3-cyanoazetidine-1-carboxylate (1.0 g, 5.5 mmol) was dissolved in DMF (30 mL), then NaN3 (1.1 g, 18 mmol) and NH4Cl (0.94 g, 18 mmol) were added and stirred at 110 °C overnight. After concentrating the reaction mixture, distilled water was added and the pH was adjusted to 1 - 2 with 1N HCl, and then extracted with EtOAc (3 times). The organic layers were collected, dried over MgSO4, filtered and concentrated, and the residue obtained was purified by column chromatography (0 - 3% MeOH in DCM) to obtain the title compound as a colorless solid (1.2 g, 97%).

[0448] LCMS m / z 224 [M-H] - Step 2: tert-Butyl 3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate

[0449]

Chem.

[0450] tert-Butyl 3-(1H-tetrazol-5-yl)azetidine-1-carboxylate (30 mg, 0.13 mmol) was dissolved in DCM (2 mL), and then trifluoroacetic anhydride (28 μL, 0.20 mmol) was added at 0 °C, followed by stirring at room temperature for 1.5 h. The reaction mixture was concentrated to obtain the title compound as a colorless oil (quantitative), which was used in the next reaction without purification (39 mg).

[0451] 1 H NMR (400 MHz, DMSO-d6) δ4.29 - 4.10 (m, 4H), 3.85 (s, 1H), 1.40 (s, 9H). Step 3: 2-(Azetidin-3-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole, 2,2,2-trifluoroacetate

[0452]

Chem.

[0453] The title compound was obtained as a colorless oil (quantitative) using tert-butyl 3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate (39 mg, 0.13 mmol), TFA (1 mL), and DCM (2 mL) in the same manner as in Step 2 of Production Example 1, and was used in the next reaction without purification (41 mg).

[0454] Step 4: N-(5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

[0455]

Chem.

[0456] The title compound was obtained as a white solid (35 mg, 62%) 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) in the same manner as in Step 1 of Example 1.

[0457] 1 H NMR (400 MHz, DMSO-d6) δ8.74 (d, J = 13.6 Hz, 2H), 8.31 (d, J = 6.8 Hz, 1H), 7.29 (t, J = 9.2 Hz, 2H), 4.76 - 4.66 (m, 1H), 4.62 - 4.41 (m, 5H), 3.26 (dd, J = 16.0, 7.5 Hz, 2H), 2.89 (dd, J = 16.0, 6.5 Hz, 2H); LCMS m / z 507 [M+H] + <Example 59> 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine Step 1: (4-(1-(5-(2-((3,5-Dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0458]

Chem.

[0459] The title compound was obtained as a white solid (43.4 mg, 72.8%) using 5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0460] 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 2H), 7.76 (s, 1H), 7.24 (s, 1H), 7.13 (d, J = 1.6 Hz, 2H), 6.23 (s, 2H), 5.62 (t, J = 6.0 Hz, 1H), 4.60 (t, J = 8.3 Hz, 2H), 4.42 (t, J = 7.2 Hz, 2H), 4.28 - 4.19 (m, 1H), 3.74 (q, J = 6.8 Hz, 2H), 2.94 - 2.87 (m, 2H), 1.20 (s, 9H); LCMS m / z 572 [M+H] + Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine

[0461] [Chem.]

[0462] Using the same method as in Step 2 of Example 1, (4-(1-(5-(2-((3,5-dichlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (17.8 mg, 63.7%).

[0463] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 9.2 Hz, 2H), 8.01 (t, J = 5.7 Hz, 1H), 7.92 (s, 1H), 7.42 (s, 1H), 7.32 (d, J = 1.4 Hz, 2H), 4.56 - 4.48 (m, 2H), 4.28 - 4.18 (m, 3H), 3.58 (q, J = 6.8 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H); LCMS m / z 458 [M+H] + <Example 60>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazine-2-amine Step 1: (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0464] [Chem.]

[0465] In the same manner as in Step 1 of Example 1, 5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-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) were used to obtain the title compound as a brown oil (49.5 mg, 93%).

[0466] LCMS m / z 552 [M+H] + Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrazine-2-amine

[0467]

Chemical formula

[0468] In the same manner as in Step 2 of Example 1, (4-(1-(5-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-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 used to obtain the title compound as a brown solid (11.7 mg, 33.9%).

[0469] 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] + <Example 61>N-(5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine <Step 1>tert-Butyl 3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate

[0470]

Chemical formula

[0471] In the same manner 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 then purified by column chromatography ((0 - 3% MeOH / DCM) to obtain the title compound as a colorless oil (53 mg, 43%).

[0472] 1 H NMR (400 MHz, DMSO-d6) δ7.47 (t, J = 51.3 Hz, 1H), 4.29 - 4.05 (m, 5H), 1.39 (s, 9H) Step 2: 2-(Azetidin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole, 2,2,2-trifluoroacetate

[0473] [Chemical formula]

[0474] The title compound was obtained as a colorless oil (quantitatively) using tert-butyl 3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate (50 mg, 0.18 mmol), TFA (1 mL), and DCM (2 mL) in the same manner as in Step 2 of Production Example 1, and was used in the next reaction without purification (58 mg).

[0475] LCMS m / z 176 [M+H] + Step 3: N-(5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(3-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

[0476] [Chemical formula]

[0477] The title compound was obtained as a white solid (39 mg, 75%) 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) in the same manner as in Step 1 of Example 1.

[0478] 1 1H NMR (400 MHz, DMSO-d6) δ8.74 (d, J = 14.9 Hz, 2H), 8.31 (d, J = 6.7 Hz, 1H), 7.50 (t, J = 51.3 Hz, 1H), 7.29 (t, J = 9.3 Hz, 2H), 4.75 - 4.65 (m, 1H), 4.64 - 4.55 (m, 2H), 4.54 - 4.45 (m, 1H), 4.45 - 4.37 (m, 2H), 3.25 (dd, J = 16.1, 7.5 Hz, 2H), 2.89 (dd, J = 16.1, 6.5 Hz, 2H); LCMS m / z 489 [M+H] + <Example 62> (4-(1-(5-(2-((5-Bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0479]

Chemical formula

[0480] The title compound was obtained as a white solid (83 mg, 77%) using 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0481] 11H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.65 (m, 2H), 8.32 - 8.24 (m, 2H), 7.43 (s, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.3 Hz, 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, 6.5 Hz, 2H), 1.13 (s, 9H); LCMS m / z 594 [M+H] + <Example 63> (4-(1-(5-(2-((5-Fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0482]

Chem.

[0483] The title compound was obtained as a white solid (66 mg, 71%) using 5-(2-((5-Fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0484] 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 8.30 (s, 1H), 8.29 (d, J = 6.9 Hz, 1H), 7.23 (dd, J = 8.3, 5.4 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 6.30 (s, 2H), 4.75 - 4.66 (m, 1H), 4.52 (s, 2H), 4.24 (d, J = 3.3 Hz, 3H), 3.24 (dd, J = 16.3, 7.3 Hz, 2H), 2.98 - 2.83 (m, 2H), 1.13 (s, 9H); LCMS m / z 534 [M+H] + <Example 64>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0485]

Chem.

[0486] The title compound was obtained as a white solid (33 mg, 82%) using (4-(1-(5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0487] 11H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.64 (m, 2H), 8.28 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.33 (d, J = 7.7 Hz, 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, 6.7 Hz, 2H), 2.91 (ddd, J = 22.1, 16.0, 6.3 Hz, 2H); LCMS m / z 480 [M+H] + <Example 65>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0488]

Chemical Structure

[0489] The title compound was obtained as a white solid (30 mg, 86%) using (4-(1-(5-(2-((5-fluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0490] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 13.3 Hz, 2H), 8.29 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 7.23 (dd, J = 8.1, 5.8 Hz, 1H), 7.06 (d, J = 9.1 Hz, 1H), 7.00 - 6.92 (m, 1H), 4.75 - 4.65 (m, 1H), 4.57 - 4.47 (m, 2H), 4.28 - 4.17 (m, 3H), 3.24 (dd, J = 16.0, 7.4 Hz, 2H), 2.99 - 2.83 (m, 2H); LCMS m / z 420 [M+H] + <Example 66>5-(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-yl)-1,3,4-oxadiazol-2(3H)-one <Step 1: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carbohydrazide

[0491]

Chemical formula

[0492] The title compound was obtained as a white solid (44.9 mg, 72.4%) using methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carboxylate (62 mg, 0.14 mmol), hydrazine monohydrate (0.3 mL, 2.9 mmol), and EtOH (3 mL) in the same manner as in Step 1 of Example 23.

[0493] LCMS m / z 429 [M+H] + Step 2: 5-(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-yl)-1,3,4-oxadiazol-2(3H)-one

[0494]

Chem.

[0495] The title compound was obtained as a white solid (11.4 mg, 27.5%) using 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 23.

[0496] 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (broad, 1H), 8.73 (d, J = 17.5 Hz, 2H), 8.31 (d, J = 6.7 Hz, 1H), 7.29 (t, J = 9.3 Hz, 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, 7.5 Hz, 2H), 2.89 (dd, J = 16.0, 6.6 Hz, 2H); LCMS m / z 455 [M+H] + <Example 67>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine Step 1: (4-(1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0497]

Chem.

[0498] The title compound was obtained as a brown oil (34.8 mg, 54.2%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0499] 1 H NMR (400 MHz, CDCl3) δ 8.61 (broad, 1H), 7.76 (s, 1H), 7.02 (t, J = 8.8 Hz, 2H), 6.23 (s, 2H), 5.61 (d, J = 7.8 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.59 (t, J = 8.3 Hz, 2H), 4.41 (t, J = 7.2 Hz, 2H), 4.28 - 4.19 (m, 1H), 3.36 (dd, J = 16.1, 7.0 Hz, 2H), 2.84 (dd, J = 15.9, 5.3 Hz, 2H), 2.69 (s, 3H), 1.20 (s, 9H) Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0500]

Chem.

[0501] The title compound was obtained as a fox-colored solid (11.7 mg, 33.9%) using (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-4-methylpyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0502] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 18.0 Hz, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.28 (t, J = 9.3 Hz, 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, 6.7 Hz, 2H), 2.65 - 2.53 (m, 3H); LCMS m / z 452 [M+H] + <Example 68>5-(5-(3-(1H-tetrazol-5-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0503]

Chem.

[0504] 1-(5-(2-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidine-3-carbonitrile (101 mg, 0.25 mmol) was dissolved in DMF (3 mL), then NaN3 (53 mg, 0.81 mmol) and NH4Cl (29 mg, 0.81 mmol) were added and stirred at 80 °C overnight. After concentrating the reaction mixture, the obtained residue was purified by column chromatography (0 - 20% MeOH in DCM) to obtain the title compound as a white solid (7 mg, 6.3%).

[0505] 1 H NMR (400 MHz, DMSO-d6) δ8.70 (s, 5H), 8.30 (d, J = 6.7 Hz, 2H), 7.28 (t, J = 9.2 Hz, 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, 6.6 Hz, 5H); LCMS m / z 439 [M+H] + <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 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

[0506]

Chemical Structure

[0507] In the same manner as in Step 1 of Example 1, 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (65 mg, 0.22 mmol), 3-ethynyl-3-methylazetidine, 2,2,2-trifluoroacetate (55 mg, crude), DIPEA (190 μL, 1. mmol), BOP reagent (116.7 mg, 0.26 mmol), and DMF (2 mL) were used to obtain the title compound as an off-white solid (78.0 mg, 95.3%).

[0508] LCMS m / z 373 [M+H] + 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

[0509]

Chemical formula

[0510] In the same manner as in Step 1 of Production Example 2, 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 (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) were used to obtain the title compound as a white solid (10.7 mg, 14.3%).

[0511] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 18.1 Hz, 2H), 8.27 (d, J = 6.9 Hz, 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 = 7.6 Hz, 2H), 3.27 (dd, J = 15.9, 7.6 Hz, 2H), 2.93 (dd, J = 15.8, 6.8 Hz, 2H), 1.72 (s, 3H); LCMS m / z 416 [M+H] + <Example 70> (4-(1-(5-(2-((5-Methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0512]

Chemical Structure

[0513] The title compound was obtained as an off-white solid (34 mg, 68%) using 5-(2-((5-Methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0514] 11H NMR (400 MHz, DMSO-d6) δ8.72 (d, J = 18.9 Hz, 2H), 8.30 (s, 1H), 8.26 (d, J = 6.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 6.71 (d, J = 8.3 Hz, 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] + <Example 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

[0515]

Chemical formula

[0516] The title compound was obtained as a white solid (15 mg, 68%) using (4-(1-(5-(2-((5-methoxy-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 2 of Example 1.

[0517] 11H NMR (400 MHz, DMSO-d6) δ8.72 (d, J = 17.1 Hz, 2H), 8.25 (d, J = 6.9 Hz, 1H), 7.93 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.55 - 4.47 (m, 2H), 4.23 (s, 3H), 3.71 (s, 3H), 3.23 - 3.16 (m, 2H), 2.93 - 2.79 (m, 2H); LCMS m / z 432[M+H] + <Example 72> (4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0518]

Chemical formula

[0519] The title compound was obtained as a white solid (23 mg, 26%) using 5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 0.17 mmol), (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) in the same method as in Step 1 of Example 1.

[0520] 11H NMR (400 MHz, DMSO-d6) δ 8.75 (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, 7.9 Hz, 2H), 3.05 (dd, J = 17.2, 5.5 Hz, 2H), 1.13 (s, 9H); LCMS m / z 518 [M+H] + <Example 73> (4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0521]

Chemical Structure

[0522] The title compound was obtained as a white solid (54 mg, 56%) using 5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (55 mg, 0.19 mmol), (4-(Azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-Trifluoroacetate (106 mg, 0.30 mmol), DIPEA (161 μL, 0.95 mmol), BOP reagent (99 mg, 0.22 mmol), and DMF (3.7 mL) in the same manner as in Step 1 of Example 1.

[0523] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.37 - 8.25 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.15 (dd, J = 7.4, 5.0 Hz, 1H), 6.30 (s, 2H), 4.78 - 4.67 (m, 1H), 4.57 - 4.47 (m, 2H), 4.29 - 4.19 (m, 3H), 3.38 - 3.27 (m, 2H), 2.98 (ddd, J = 22.5, 16.3, 6.1 Hz, 2H), 1.13 (s, 9H); LCMS m / z 517 [M+H] + <Example 74>N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine

[0524]

Chem.

[0525] The title compound was obtained as a white solid (9 mg, 64%) using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 3 of Example 7.

[0526] 11H NMR (400 MHz, DMSO-d6) δ 8.75 (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, 8.0 Hz, 2H), 3.05 (dd, J = 17.3, 5.5 Hz, 2H); LCMS m / z 404 [M+H] + <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 Step 1: tert-Butyl 3-(prop-1-yn-1-yl)azetidine-1-carboxylate

[0527]

Chemical formula

[0528] tert-Butyl 3-ethynylazetidine-1-carboxylate (500 mg, 2.76 mmol) was dissolved in THF (8 mL), cooled to -78 °C under a N2 stream, and then n-BuLi (2.5 M in hexane, 1.10 mL, 2.78 mmol) was gradually added dropwise over 10 minutes and stirred for 30 minutes. The temperature was raised to room temperature, CH3I (259 μL, 4.14 mmol) was gradually added dropwise over 5 minutes, and then stirred for 5 hours. DW was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography (0 - 3% MeOH / DCM) to obtain the title compound as a yellow oil (500 mg, 93%).

[0529] LCMS m / z 196 [M+H] + Step 2: tert-Butyl 3-(5-methyl-1H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0530]

Chem.

[0531] tert-Butyl 3-(prop-1-yn-1-yl)azetidine-1-carboxylate (195 mg, 1.0 mmol) and TMSN3 (200 μL, 1.55 mmol) were placed in a reaction vessel and reacted in a microwave reactor (200 °C, 2 h). The reaction mixture was purified by column chromatography (0 - 5% MeOH in DCM) to obtain the title compound as a brown oil (19 mg, 8%).

[0532] 1 H NMR (400 MHz, CDCl3) δ 4.33 - 4.28 (m, 2H), 4.18 - 4.14 (m, 2H), 3.85 - 3.79 (m, 1H), 2.28 (s, 3H), 1.45 (s, 9H) Step 3: 4-(Azetidin-3-yl)-5-methyl-1H-1,2,3-triazole, 2,2,2-trifluoroacetate

[0533]

Chem.

[0534] The title compound was obtained (quantitatively) 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) in the same manner as in Step 2 of Production Example 1 and used in the next reaction without purification (19 mg).

[0535] 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

[0536]

Chem.

[0537] The title compound was obtained as a brown solid (7 mg, 20%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) in the same manner as in Step 1 of Example 1.

[0538] 1 H NMR (400 MHz, CD3OD) δ 8.72 (s, 2H), 7.09 (t, J = 8.0 Hz, 2H), 4.85 - 4.78 (m, 1H), 4.60 (t, J = 8.0 Hz, 2H), 4.39 (t, J = 8.0 Hz, 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] + <Example 76>5-(5-(3-(1H-imidazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0539]

Chem.

[0540] The title compound was obtained as a white solid (3.5 mg, 9%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) in the same manner as in Step 1 of Example 1.

[0541] 1 H NMR (400 MHz, CD3OD) 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 = 8.0 Hz, 2H), 4.31 (t, J = 8.0 Hz, 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] + <Example 77>N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-6-amine

[0542]

Chemical formula

[0543] Using the same method as in Step 3 of Example 7, (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-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), the title compound was obtained as a white solid (21 mg, 64%).

[0544] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.37 - 8.25 (m, 2H), 7.92 (s, 1H), 7.61 (d, J = 7.3 Hz, 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] + <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 Step 1: (4-(3-methylazetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate, 2,2,2-trifluoroacetate

[0545]

Chemical formula

[0546] The title compound was prepared in the same manner as in Production Example 5, except that tert-butyl 3-ethynyl-3-methylazetidine-1-carboxylate was used instead of tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate.

[0547] LCMS m / z 253 [M+H] + 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

[0548]

Chem.

[0549] The title compound was obtained as a white solid (51.7 mg, 90.9%) 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) in the same manner as in Step 2 of Example 20.

[0550] LCMS m / z 552 [M+H] + 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

[0551]

Chem.

[0552] In the same manner as in Step 2 of Example 1, (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 (45.7 mg, 0.083 mmol), K2CO3 (23 mg, 0.17 mmol), and MeOH (1.6 mL) were used to obtain the title compound as a white solid (16.9 mg, 46.6%).

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 2H), 8.01 (d, J = 6.7 Hz, 1H), 7.90 (broad, 1H), 7.36 - 7.23 (m, 3H), 6.67 (d, J = 15.8 Hz, 1H), 4.71 - 4.61 (m, 1H), 4.46 (d, J = 7.6 Hz, 1H), 4.24 (d, J = 8.2 Hz, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.92 (d, J = 9.2 Hz, 1H), 3.24 (dd, J = 16.1, 7.6 Hz, 2H), 2.87 (dd, J = 16.0, 6.5 Hz, 2H), 1.63 (s, 3H); LCMS m / z 438 [M+H] + <Example 79>5-(5-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0554]

Chemical formula

[0555] Using the same method as in Example 28, 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-ylmethanesulfonate (30 mg, 0.065 mmol), 1,2,4-triazole (5.4 mg, 0.078 mmol), NaH (57 - 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%).

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 - 8.68 (m, 2H), 8.68 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.27 (t, J = 9.4 Hz, 2H), 5.63 - 5.55 (m, 1H), 4.73 - 4.66 (m, 1H), 4.63 (t, J = 8.3 Hz, 2H), 4.42 (dd, J = 8.6, 5.6 Hz, 2H), 3.24 (d, J = 8.6 Hz, 2H), 2.88 (dd, J = 15.9, 6.3 Hz, 2H); LCMS m / z 438 [M+H] + <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

[0557]

Chemical formula

[0558] Using the same method as in Example 28, 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-ylmethanesulfonate (30 mg, 0.065 mmol), 3-methyl-1H-1,2,4-triazole (6.4 mg, 0.078 mmol), NaH (57-63% 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%).

[0559] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 - 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 (m, 1H), 4.59 (t, J = 8.9 Hz, 2H), 4.43 - 4.37 (m, 2H), 3.22 (d, J = 7.8 Hz, 2H), 2.88 (dd, J = 15.9, 6.3 Hz, 2H), 2.27 (s, 3H); LCMS m / z 452 [M+H] + <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

[0560]

Chemical Structure

[0561] Using the same method as in Step 1 of Example 1, 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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), the title compound was obtained as a white solid (45.8 mg, 83.3%).

[0562] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.27 (d, J = 6.3 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (d, J = 6.5 Hz, 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, 6.4 Hz, 2H), 2.52 (s, 2H), 2.33 (s, 3H); LCMS m / z 456 [M+H] + <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 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

[0563]

Chemical formula

[0564] In the same manner as in Step 2 of Example 20, (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) were used to obtain the title compound as a pale peach solid (45.7 mg, 67.8%).

[0565] LCMS m / z 516 [M+H] + Step 2: (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

[0566]

Chemical formula

[0567] In the same manner as in Step 2 of Example 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 (40.4 mg, 0.078 mmol), K2CO3 (63 mg, 0.16 mmol), and MeOH (2 mL) were used to obtain the title compound as a white solid (13.1 mg, 41.7%).

[0568] 11H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 2H), 8.00 (d, J = 6.8 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 7.25 - 7.11 (m, 4H), 6.67 (d, J = 15.8 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.46 (d, J = 8.5 Hz, 1H), 4.25 (d, J = 8.3 Hz, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.92 (d, J = 9.5 Hz, 1H), 3.25 (dd, J = 15.9, 7.5 Hz, 2H), 2.91 (dd, J = 15.8, 6.9 Hz, 2H), 1.65 (s, 3H); LCMS m / z 402 [M+H] + <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 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

[0569]

Chemical Structure

[0570] The title compound was obtained as a white solid (100 mg, 78%) using 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) in the same manner as in Step 1 of Example 1.

[0571] 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (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] + 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

[0572]

Chem.

[0573] The title compound was obtained as a white solid (10 mg, 16%) using 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 (55 mg, 0.15 mmol), TMSN3 (25 μL, 0.19 mmol), CuI (3.3 mg, 0.018 mmol), DMF (2 mL) / MeOH (0.2 mL) in the same manner as in Step 1 of Production Example 2.

[0574] 1 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 2H), 8.01 (s, 1H), 7.22 - 7.20 (m, 2H), 7.14 - 7.12 (m, 2H), 4.81 - 4.68 (m, 5H), 3.37 - 3.30 (m, 2H), 2.97 - 2.90 (m, 2H); LCMS m / z 420 [M+H] + <Example 84>(4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate Step 1: 5-(2-((6,7-Dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0575]

Chemical formula

[0576] The title compound was produced in the same manner as Production 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.

[0577] 1 H NMR (400 MHz, DMSO-d6) δ12.14 (s, 1H), 8.67 (d, J = 13.9 Hz, 2H), 8.44 (s, 1H), 8.39 - 8.32 (m, 2H), 7.28 (d, J = 4.7 Hz, 1H), 4.76 - 4.68 (m, 1H), 3.31 - 3.27 (m, 2H), 2.96 (dd, J = 16.5, 6.0 Hz, 2H); LCMS m / z 297 [M+H] + Step 2: (4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0578]

Chemical formula

[0579] In the same manner as in Step 1 of Example 1, 5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-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) were used to obtain the title compound as an off-white solid (4.0 mg, 23%).

[0580] 1 H NMR (400 MHz, DMSO-d6) δ8.74 (d, J = 17.8 Hz, 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, 6.6 Hz, 2H), 1.13 (s, 9H); LCMS m / z 517 [M+H] + <Example 85>N-(5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-6-amine

[0581]

Chemical formula

[0582] Using the same method as in Step 2 of Example 1, the title compound was obtained as an off-white solid (2.9 mg, 99%) using (4-(1-(5-(2-((6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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).

[0583] 1 H NMR (400 MHz, DMSO-d6) δ8.76 (s, 2H), 8.44 (s, 1H), 8.33 (dd, J = 14.9, 5.9 Hz, 2H), 7.93 (s, 1H), 7.29 (d, J = 4.6 Hz, 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, 5.9 Hz, 2H); LCMS m / z 403 [M+H] + <Example 86>(4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0584]

Chemical Structure

[0585] The title compound was obtained as a yellow solid (24 mg, 56%) using 5-(2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0586] 1 H NMR (400 MHz, DMSO-d6) δ8.70 (s, 2H), 8.38 (t, J = 6.2 Hz, 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] + <Example 87>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine

[0587]

Chemical Structure

[0588] (4-(1-(5-(2-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 used to obtain the title compound as a white solid (8.7 mg, 59%) in the same manner as in Step 2 of Example 1.

[0589] 1 H NMR (400 MHz, DMSO-d6) δ8.70 (s, 2H), 8.39 (t, J = 6.2 Hz, 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 = 6.3 Hz, 2H), 4.22 (s, 3H); LCMS m / z 420 [M+H] + <Example 88>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine Step 1: Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate

[0590]

Chem.

[0591] The title compound was prepared in the same manner as in Step 1 of Production 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.

[0592] LCMS m / z 320 [M+H] + Step 2: Ethyl 2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidine-5-carboxylate

[0593]

Chem.

[0594] 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 then NaH (57 - 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, and the mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography (EtoAc / Hex) to obtain the title compound as a white solid (22 mg, 42.1%).

[0595] 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 7.30 (t, J = 9.3 Hz, 2H), 5.78 (dt, J = 15.3, 7.7 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.14 (dd, J = 16.4, 8.3 Hz, 2H), 3.02 (q, J = 7.0 Hz, 5H), 1.28 (t, J = 7.1 Hz, 3H); LCMS m / z 334 [M+H] + Step 3: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0596]

Chem.

[0597] The title compound was prepared in the same manner as in Steps 2 and 3 of Production Example 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.

[0598] LCMS m / z 346 [M+H] + Step 4: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

[0599]

Chemical formula

[0600] The title compound was obtained as a yellow solid (3.1 mg, 36.5%) using 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4-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) in the same manner as in Step 1 of Example 1.

[0601] 11H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 2H), 7.31 (t, J = 9.3 Hz, 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, 9.1 Hz, 2H), 3.05 (d, J = 7.0 Hz, 2H), 3.00 (s, 3H); LCMS m / z 452 [M+H] + <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 <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

[0602]

Chem.

[0603] The title compound was obtained as a white solid (50 mg, 73%) using 5-(2-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-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) in the same method as in Step 1 of Example 1.

[0604] 11H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2H), 7.41 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 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] + 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

[0605]

Chemical Structure

[0606] Using the same method as in Step 1 of Production Example 2, the title compound was obtained as a white solid (1.3 mg, 1.3%) using 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 (90 mg, 0.2 mmol), TMSN3 (36 μL, 0.28 mmol), CuI (4.8 mg, 0.018 mmol), DMF (3 mL) / MeOH (0.3 mL).

[0607] 1 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 2H), 8.04 (s, 1H), 7.38 (s, 1H), 7.22 - 7.20 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 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] + <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 Step 1: Methyl 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoate

[0608]

Chemical formula

[0609] 5,6-Difluoro-2,3-dihydro-1H-inden-2-amine (32.8 mg, 0.120 mmol), methyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)butanoate (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 then stirred at room temperature for 4 hours. After adding DW to the reaction mixture, it was extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to obtain the title compound as a brown solid (8.5 mg, 25.2%).

[0610] 1 1H NMR (400 MHz, CD3OD) δ 7.11 (t, J = 9.0 Hz, 2H), 4.45 - 4.35 (m, 1H), 3.65 (d, J = 2.2 Hz, 3H), 2.91 (dd, J = 16.1, 5.2 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.06 - 1.85 (m, 4H). LCMS m / z 338[M+H] + Step 2: 4-(5-((5,6-Difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoic acid

[0611]

Chem.

[0612] Methyl 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoate (3.0 mg, 0.025 mmol) was dissolved in MeOH / THF (0.45 mL / 0.05 mL), and then 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 concentrating the reaction mixture, distilled water was added and the mixture was acidified to pH 1 - 2 with 3N HCl. After extraction with EtOAc, it was washed with distilled water, dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography (MeOH / DCM) to give the title compound as a white solid (8.0 mg, 98.2%).

[0613] 1 H NMR (400 MHz, CD3OD) δ 7.11 (t, J = 9.0 Hz, 2H), 4.40 (dd, J = 11.8, 6.0 Hz, 1H), 2.91 (dd, J = 16.1, 5.0 Hz, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.37 (t, J = 7.1 Hz, 2H), 2.10 - 1.80 (m, 4H); LCMS m / z 324[M+H] + 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

[0614]

Chem.

[0615] In the same manner as in Step 3 of Example 9, 4-(5-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-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) were used to obtain the title compound as a colorless oil (1.0 mg, 9.4%).

[0616] 1 H NMR (400 MHz, CD3OD) δ 7.28 (s, 1H), 7.11 (t, J = 9.2 Hz, 2H), 4.43 - 4.29 (m, 3H), 4.04 (d, J = 6.1 Hz, 2H), 3.76 - 3.68 (m, 1H), 3.22 (d, J = 7.6 Hz, 2H), 2.92 (dd, J = 16.0, 4.8 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.28 (t, J = 7.1 Hz, 2H), 2.05 - 1.99 (m, 2H); LCMS m / z 430[M+H] + <Example 91>5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine Step 1: (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate

[0617]

Chemical formula

[0618] The title compound was obtained as an off-white solid (54 mg, 93%) using 5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0619] 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 15.6 Hz, 2H), 8.35 - 8.23 (m, 2H), 7.29 (s, 1H), 7.22 (dd, J = 18.9, 8.0 Hz, 2H), 6.30 (s, 2H), 4.69 (dd, J = 14.1, 6.9 Hz, 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] + Step 2: 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0620]

Chemical formula

[0621] Using the same method as in Step 2 of Example 1, (4-(1-(5-(2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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), the title compound was obtained as a white solid (25 mg, 63%).

[0622] 1 H NMR (400 MHz, DMSO-d6) δ8.73 (d, J = 15.2 Hz, 2H), 8.29 (d, J = 6.3 Hz, 1H), 7.92 (s, 1H), 7.29 (s, 1H), 7.22 (dd, J = 19.7, 7.9 Hz, 2H), 4.69 (dd, J = 13.9, 7.0 Hz, 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] + <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 Step 1: 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

[0623]

Chemical Structure

[0624] The title compound was prepared in the same manner as in Production Example 3, except that 2-(4-chlorophenyl)ethylamine was used instead of 2,3-dihydro-1H-inden-2-amine.

[0625] 11H NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H), 8.60 (d, J = 15.6 Hz, 2H), 8.04 (t, J = 5.7 Hz, 1H), 7.28 (dd, J = 32.0, 8.3 Hz, 4H), 3.53 (dd, J = 13.4, 6.7 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H); LCMS m / z 318 [M+H] + 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

[0626]

Chemical Structure

[0627] The title compound was obtained as a white solid (49.5 mg, 60%) using 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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 μL, 0.567 mmol), BOP reagent (100 mg, 0.227 mmol), and DMF (3.8 mL) in the same manner as in Step 1 of Example 1.

[0628] 1 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 13.4 Hz, 2H), 7.94 (t, J = 5.7 Hz, 1H), 7.39 (s, 1H), 7.33 - 7.23 (m, 4H), 3.94 - 3.87 (m, 1H), 3.66 (d, J = 8.3 Hz, 2H), 3.55 (dd, J = 16.4, 8.8 Hz, 6H), 2.83 (t, J = 7.4 Hz, 2H); LCMS m / z 438 [M+H]+ <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

[0629]

Chemical formula

[0630] The title compound was obtained as a yellow solid (43 mg, 53.7%) using 5-(2-((4-chlorophenethyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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) in the same manner as in Step 1 of Example 1.

[0631] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 16.6 Hz, 2H), 7.98 (t, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.28 (dd, J = 30.5, 8.5 Hz, 4H), 4.50 (s, 2H), 4.20 (s, 3H), 3.53 (dd, J = 13.0, 6.5 Hz, 2H), 2.84 (dd, J = 14.4, 6.9 Hz, 2H); LCMS m / z 424 [M+H] + <Test Example 1>Evaluation of the inhibitory activity against human autotaxin protein (1) Experimental method Solutions of each synthesized compound (80 μM, 100% dimethyl sulfoxide) were serially diluted 5-fold each using dimethyl sulfoxide to prepare six concentrations. Each concentration of the compound was diluted 2-fold with 1× test buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 140 mM NaCl, triple-distilled water, 1 mg / mL BSA), and 1 μL (1.25% dimethyl sulfoxide) was dispensed into a 96-well clear round-bottom plate. 9 μL of 1× test buffer was added, and 20 μL of 240 nM human autotaxin protein (buffer: 50 mM Tris-HCl (pH 8.0), 150 mM sodium chloride, 20% glycerol) was added. 10 μL of 360 μM 18:1LysoPC diluted with 1× test buffer and sonicated 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) (65 μL of 1× test buffer: 1 μL of choline oxidase: 1 μL of dye probe) was prepared. 60 μL of the secondary reaction mixture was added to the plate where the reaction was carried out, and the reaction was carried out with a stirrer for 30 minutes. The absorbance value was measured at a wavelength of 570 nm using a SpectraMax® iD3 microplate reader. (1 - absorbance value 試験群 / absorbance value 対照群 ) × 100 was used to calculate the inhibition activity percentage value (inhibition %).

[0632] (2) Results The activity inhibition rates measured as described above are shown in Table 1 below.

[0633]

Table 1

[0634] All of the compounds of Examples 1 to 93 synthesized showed excellent inhibitory activity against human autotaxin protein.

[0635] The above description of the present invention is for illustrative purposes, and those with ordinary knowledge in the technical field to which the present invention pertains will be able to understand that it can be easily transformed into other specific forms without changing the technical idea and essential features of the present invention. Therefore, it should be understood that the above-described embodiments are illustrative in every aspect and not limiting. For example, it is also possible to implement each component described as a single type separately, and similarly, it is also possible to implement the separated components in a combined form.

[0636] The scope of the present invention is indicated by the claims described below, and it should be interpreted that any changes or modified forms derived from the meaning and scope of the claims and their equivalent concepts are included in the scope of the present invention.

Claims

1. A heterocyclic compound represented by the following Chemical Formula 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. 【Chemical 1】 In Chemical Formula 1, X is aryl; a bicyclic fused ring in which an aryl ring and a non-aromatic cycloalkyl ring are fused; a bicyclic fused ring in which an aryl ring and a non-aromatic heterocyclic ring having 1 to 3 O atoms are fused; a bicyclic fused ring in which a heteroaryl ring having 1 to 3 N atoms and a non-aromatic cycloalkyl ring are fused, and the X is substituted or unsubstituted with a single or a plurality of independent R ｘ and is either unsubstituted or substituted with Said R ｘ is C １－４ alkoxy or halogen, and p is an integer from 0 to 2, R Ｎ is hydrogen or C １－４ alkyl, and A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N and O, and said A is substituted or unsubstituted with R ａ and is either substituted or unsubstituted with The aforementioned R ａ is C １－４ alkyl, and L is —(CH ２ ) １－５ CO—; —(CHCH) １－２ CO—; or a 5-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of N and O, The Y ring is substituted with R ｙ or not substituted, The aforementioned R ｙ is C １－４ alkyl or halogen, and m is 0 or 1, B is cyano; OH; COOH; CH ２ COOH; sulfonyl; sulfonate (—O—SO ２ —); or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of N and O, and said B is R ｂ optionally substituted with oxo (O) or unsubstituted, Said R ｂ is C １－４ alkyl, C １－４ haloalkyl, amino, or C １－４ alkyl pivalate.

2. The heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to Claim 1, wherein X is one selected from the group consisting of phenyl, dihydroindenyl, benzodioxolyl, dihydro-cyclopentapyradinyl, and dihydro-cyclopentapyridinyl.

3. Said R ｘ The heterocyclic compound according to claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt, wherein R is one selected from the group consisting of methoxy, F, Cl, and Br.

4. Said R Ｎ The heterocyclic compound according to claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl.

5. The heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to Claim 1, wherein A is one selected from the group consisting of pyridine, pyrimidine, pyrazine, and oxadiazole.

6. The aforementioned R ａ The heterocyclic compound according to claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt, wherein R is methyl.

7. wherein L is selected from the group consisting of —(CH ２ ) ２ CO—, —(CH ２ ) ３ CO—, —(CH) ２ CO—, dihydroisoxazolyl, isoxazolyl, and oxadiazolyl, and the heterocyclic compound according to claim 1, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

8. Said R ｙ is methyl or F, the heterocyclic compound according to claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt.

9. The heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to Claim 1, wherein B is one selected from the group consisting of OH, cyano, carboxyl, carboxymethyl, sulfonyl, sulfonate, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxadiazolone, and morpholino.

10. Said R ｂ is one selected from the group consisting of methyl, difluoromethyl, trifluoromethyl, amino, and methyl pivalate, the heterocyclic compound according to claim 1, its hydrate, its solvate, or its pharmaceutically acceptable salt.

11. The heterocyclic compound is [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-oxadiazol-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-oxadiazol-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-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)pyrrolidine-3-carboxylate, [16] 5-(5-(3-(1H-1,2,3-triazol-4-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-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-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)isoxazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)pyrrolidin-3-yl)methanesulfonate, [28] 5-(5-(3-(1H-1,2,4-triazol-1-yl)pyrrolidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-dihydroisoxazol-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)isoxazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)azetidin-3-yl)acetic acid, [54] 5-(5-(3-(1H-1,2,3-triazol-4-yl)azetidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine [[68]]5-(5-(3-(1H-tetrazol-5-yl)azetidin-1-yl)-1,3,4-oxadiazol-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-oxadiazol-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-cyclopenta[b]pyrazin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate [[73]](4-(1-(5-(2-((6,7-Dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-azol-1-yl)azetidin-1-yl)-1,3,4-oxadiazol-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-cyclopenta[c]pyridin-6-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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-oxadiazol-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 The heterocyclic compound according to claim 1, which is a compound selected from the group consisting of, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition for preventing or treating an autotaxin activity-related disease, comprising, as an active ingredient, the heterocyclic compound according to any one of claims 1 to 11, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, wherein the autotaxin activity-related disease is selected from the group consisting of fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic forms and other forms of chronic pruritus, and acute or chronic organ transplant rejection reactions.

14. A pharmaceutical composition selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, renal fibrosis, dermal fibrosis, glomerulosclerosis, myocardial 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 asbestosis-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS); cardiovascular diseases selected from atherosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia, stroke and other vascular injuries; metabolic diseases selected from obesity and diabetes; cancers and cancer metastases selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion; ocular diseases selected from 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; cholestatic and other forms of chronic pruritus; and acute or chronic organ transplant rejection, comprising a heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11.

15. A pharmaceutical composition comprising a heterocyclic compound, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable additive.

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