NOVEL PIPERIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING SAME FOR INHIBITING AUTOTAXIN

Abstract

The present invention provides a novel piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt, and a pharmaceutical composition for preventing or treating autotaxin activity-related diseases containing the same as an active ingredient. The piperidine derivative compound according to the present invention exhibits excellent inhibitory activity against autotaxin, and can be usefully used for the treatment and prevention of autotaxin inhibition-related diseases, such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

Description

[Technical field]

[0001] The present invention relates to a novel piperidine derivative, more specifically, to a novel piperidine derivative and a pharmaceutical composition for inhibiting autotaxin containing the same. [Background technology]

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

[0003] Plasma LPA is a bioactive lipid that influences the migration, proliferation, and survival of a variety of cell types, and ATX-LPA signaling processes are involved in the physiological and pathophysiological effects of a variety of diseases, including nervous system effects, vascular 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., diabetes mellitus).

[0004] Therefore, increased ATX activity and increased 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 associated with 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 lower the levels of LPA and / or autotaxin (ATX) that induces it. Summary of the Invention [Problem to be solved by the invention]

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

[0006] Another problem to be solved by the present invention is to provide a pharmaceutical composition for inhibiting autotaxin, which contains the autotaxin-inhibiting compound having the novel structure.

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

[0008] Another problem to be solved by the present invention is to provide an autotaxin inhibitor having the novel structure, and a disease treatment use thereof.

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

[0010] In order to solve the above-mentioned problems, in one aspect of the present invention, there is provided a piperidine derivative compound represented by the following chemical formula 1, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0011] [ka] In Chemical Formula 1, X is an aryl C 1-4 alkyl; a bicyclic fused ring formed by fusing an aryl ring or a heteroaryl ring having 1 to 3 N with a non-aromatic cycloalkyl ring; or a bicyclic fused ring formed by fusing an aryl ring with a non-aromatic heterocycle having 1 to 3 O, where X is one or more R 1 or not replaced by, A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O, and S; L is for C 1-6 Alkylene;-(CH2) a CO-;-(CH) a CO-;-(CH2) b O(CH2) c or a 5-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of N and O, wherein a, b, and c are independently an integer of 1 to 5; B is a 4- or 5-membered non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of COOH; CH2COOH; CONHOH; SO2NH2; N and O; or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from the group consisting of N and O; R 1 is halogen or C 1-4 is alkylsulfonyl, R 2 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, oxo(O) or arylC 1-4 is alkyl, R 3 is hydrogen, C1-4 Alkyl, C 1-4 alkoxy or halogen; R 4 is hydrogen, halogen or C 1-4 is alkyl, R 5 is hydrogen or C 1-4 It is an alkyl.

[0012] In another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a disease associated with autotaxin activity, comprising the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0013] In yet another aspect of the present invention, there is provided a method for inhibiting autotaxin and treating or preventing a disease caused by the inhibition, using the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof.

[0014] In yet another aspect of the present invention, there is provided a use of the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof for inhibiting autotaxin and treating or preventing a disease thereby.

[0015] In yet another aspect of the present invention, there is provided a pharmaceutical composition comprising the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. Effect of the Invention

[0016] It has been revealed that the piperidine derivative having a novel structure according to the present invention exhibits excellent inhibitory activity against autotaxin.

[0017] Therefore, the piperidine derivatives having a novel structure 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, ocular diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection, which are diseases associated with autotaxin inhibition.

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

[0019] Herein, autotaxin (ATX) is a secreted 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, which converts lysophosphatidylcholine (LPC) to LPA. Thus, LPA levels in plasma and ascites are related to ATX activity.

[0020] The present invention provides a piperidine derivative compound represented by the following chemical formula 1, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof.

[0021] [ka] In Chemical Formula 1, X is an aryl C 1-4 alkyl; a bicyclic fused ring formed by fusing an aryl ring or a heteroaryl ring having 1 to 3 N with a non-aromatic cycloalkyl ring; or a bicyclic fused ring formed by fusing an aryl ring with a non-aromatic heterocycle having 1 to 3 O, where X is one or more R 1 or not replaced by, A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O, and S; L is for C 1-6 Alkylene;-(CH2) a CO-;-(CH) a CO-;-(CH2) b O(CH2) c or a 5-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of N and O, wherein a, b, and c are independently an integer of 1 to 5; B is a 4- or 5-membered non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of COOH; CH2COOH; CONHOH; SO2NH2; N and O; or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from the group consisting of N and O; R 1 is halogen or C 1-4 is alkylsulfonyl, R 2 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, oxo(O) or arylC 1-4 is alkyl, R 3 is hydrogen, C 1-4 Alkyl, C 1-4 alkoxy or halogen; R 4 is hydrogen, halogen or C 1-4 is alkyl, R 5 is hydrogen or C 1-4 It is an alkyl.

[0022] In some embodiments, X may be one selected from the group consisting of benzyl, phenethyl, dihydroindenyl, dihydrocyclopentapyrazinyl, and benzodioxolyl.

[0023] In one embodiment, A may be one selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine, oxadiazole, and thiadiazole.

[0024] In one embodiment, L may be one selected from the group consisting of -(CH2)3-, -(CH2)2CO-, -(CH2)3CO-, -(CH)2CO-, -CH2OCH2CO-, oxazole, isoxazole, dihydroisoxazole, and oxadiazole.

[0025] In one embodiment, B may be one selected from the group consisting of carboxyl, carboxymethyl, carboxamide, sulfonamide, azetidine, morpholine, oxadiazole, imidazole, triazole, and tetrazole.

[0026] In one embodiment, the R 1 can be a member selected from the group consisting of F, Cl, Br and methylsulfonyl.

[0027] In one embodiment, the R 2 can be a member selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxy, oxo(O) and benzyl.

[0028] In one embodiment, the R 3 can be a member selected from the group consisting of hydrogen, methyl, methoxy and F.

[0029] In one embodiment, the R 4 can be a member selected from the group consisting of hydrogen, Cl, and methyl.

[0030] In one embodiment, the R 5 can be hydrogen or alkyl.

[0031] Specific examples of the piperidine derivative compounds according to the present invention are as follows:

[0032] [1] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [2] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [3] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [4] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [5] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [6] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [7] N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine, [8] 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazin-3-amine, [9] 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

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

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

[12] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine,

[13] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine,

[14] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine,

[15] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine,

[16] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[17] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[18] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one,

[19] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one,

[20] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one,

[21] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one,

[22] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one,

[23] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethan-1-one,

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

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

[26] 5-(5-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[27] 5-(5-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[28] 5-(5-(4-(1H-tetrazol-1-yl)piperidin-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-(4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine,

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

[31] 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[32] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine,

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

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

[35] N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

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

[37] N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[38] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[39] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[40] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[41] N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[42] N-benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[43] N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine,

[44] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine,

[45] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine,

[46] N-(1,3-benzodioxol-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]isoxazol-5-yl]pyrimidin-2-amine,

[47] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine,

[48] ​​5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidin-2-amine,

[49] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidin-2-amine,

[50] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[51] 5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[52] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[53] N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine,

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

[55] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine,

[56] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine,

[57] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine,

[58] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine,

[59] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine,

[60] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[61] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[62] 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

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

[64] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol,

[65] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-sulfonamide,

[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)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one,

[67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid,

[68] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid,

[69] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-N-hydroxypiperidine-4-carboxamide,

[70] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-methoxy-4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, and

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

[0033] In defining the compounds of Formula 1 herein, the following definitions apply unless otherwise stated.

[0034] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon having a C1-C 10Alkyl is preferred, for example, including, but 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.

[0035] The term "alkylene" refers to a divalent functional group derived from an alkyl group, preferably containing, but not limited to, 1 to 10 carbon atoms. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0036] The term "cycloalkyl" refers to a partially or fully saturated single or fused ring hydrocarbon having a C3-C 10 -Cycloalkyl is preferred, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like.

[0037] The term "hydroxy" is defined as -OH and the term "alkoxy", unless otherwise defined, means an alkyloxy radical in which the hydrogen atom of a hydroxy group is replaced with one to ten alkyl groups.

[0038] The term "halogen" or "halo" means fluorine / fluoro (F), chlorine (Cl), bromine (Br) or iodine (I).

[0039] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy substituted with one or more halogen atoms.

[0040] The term "heteroatom" means N, O or S.

[0041] The term "aryl" means an aromatic hydrocarbon, including polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings. 12 Aryl, more preferably C5-C 10 For example, the aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0042] Also included are radicals in which a heteroaryl ring is fused to a cycloalkyl or non-aromatic heterocycle, such as, for example, dihydrocyclopentapyrazinyl.

[0043] The term "heteroaryl" or "aromatic heterocycle" refers to an aromatic hydrocarbon having 3 to 12 members, more preferably 5 to 10 members, containing one or more heteroatoms selected from N, O, and S as ring atoms, forming a single or fused ring that can be fused to a benzo or C3-C8 cycloalkyl. For example, the heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, and the like.

[0044] Arylalkyl, alkylaryl, and heteroarylalkyl refer to groups formed by combining an aryl with an alkyl, or a heteroaryl with an alkyl, as defined above, and include, but are not limited to, benzyl, phenethyl, and the like.

[0045] The compound represented by the formula 1 according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt in order to enhance in vivo absorption or increase solubility, and the prodrug, hydrate, solvate, and pharmaceutically acceptable salt are also within the scope of the present invention. In addition, the compound represented by the formula 1 has a chiral carbon, and its chiral carbon exists, and such chiral carbon is also included in the scope of the present invention.

[0046] The term "prodrug" refers to a substance that is transformed into the parent drug in vivo. Prodrugs are used because in some cases they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration whereas the parent drug may not be. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of the compounds according to the invention and pharma- ceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group that is converted by metabolism to reveal the active site of the peptide.

[0047] The term "hydrate" means a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0048] The term "solvate" refers to 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, where preferred solvents are volatile, non-toxic, and / or suitable for administration to humans.

[0049] The term "isomer" refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or stereochemically different. Such isomers include all structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers, and geometric isomers (trans, cis). All of these isomers and mixtures thereof are also included within the scope of the present invention.

[0050] The term "pharmaceutical acceptable salt" refers to a salt form of a compound that does not induce significant irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical acceptable salt includes acid addition salts formed with pharmaceutical acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, organic carbonic acids, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid, and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, which form non-toxic acid addition salts. For example, pharma- ceutically acceptable carboxylate salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compound of formula 1 according to the present invention can also be converted into its salt by a conventional method.

[0051] The present invention also provides a method for preparing the compound of Formula 1.

[0052] Reaction schemes 1 to 26 are illustrated as examples of methods for preparing the compound of formula 1 of the present invention, but the following preparation methods are not intended to limit the methods for preparing the compound of formula 1 of the present invention. It is obvious that the preparation methods of reaction schemes 1 to 26 are merely examples and can be easily modified by those skilled in the art depending on specific substituents.

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[0053] The present invention also provides a pharmaceutical composition for preventing or treating a disease associated with autotaxin activity, comprising the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0054] The present invention also provides a method for inhibiting autotaxin and treating or preventing a disease caused by the inhibition by administering the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof to a patient in need thereof.

[0055] The present invention also provides the use of the piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutical acceptable salt for inhibiting autotaxin and for treating or preventing a disease thereby.

[0056] As a result of measuring the autotaxin protein inhibitory activity of the piperidine derivative compound of the present invention, it was confirmed that the compound exhibited excellent autotaxin inhibitory activity even at a very low compound concentration (nM level), and thus can be used for the treatment and prevention of diseases associated with autotaxin activity.

[0057] In one embodiment, the disease associated with autotaxin activity 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 and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0058] The fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, liver sclerosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, myocardial and vascular fibrosis, renal fibrosis, skin fibrosis, glomerulosclerosis, and myocardial and vascular fibrosis.

[0059] Such inflammatory diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma.

[0060] Such autoimmune diseases include, but are not limited to, multiple sclerosis and scleroderma.

[0061] Such respiratory diseases include, but are not limited to, asbestos-induced pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS).

[0062] Said cardiovascular diseases include, but are not limited to, arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias, stroke and other vascular injuries.

[0063] Such metabolic diseases include, but are not limited to, obesity and diabetes.

[0064] The cancers and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatocarcinoma, gastrointestinal cancer, pancreatic cancer, and the progression and metastatic invasion thereof.

[0065] Such ocular diseases include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet Age-related Macular Degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury, and glaucoma.

[0066] The present invention also provides a pharmaceutical composition comprising the piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0067] The additives may contain pharma- ceutically acceptable carriers or diluents, and may be formulated by conventional methods into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions.

[0068] The pharma- ceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc. Also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and such solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., and may include lubricants such as magnesium stearate, talc, etc. Oral liquid preparations include suspensions, oral liquids, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, flavorings, preservatives, etc. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, freeze-dried preparations, and suppositories, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. As the base for suppositories, witepsol, macrogol, tween 61, cacao gum, lauring gum, glycerol gelatin, etc. may be used.

[0069] 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 severity of the disease, the form of the active ingredient, the route of administration and the period of administration, 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 can be administered once or several times a day. In addition, the pharmaceutical composition of the present invention can contain the active ingredient in an amount of 0.001 to 90% by weight based on the total weight of the composition.

[0070] The pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, by oral, intradermal, peritoneal, rectal, or intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebroventricular injection.

[0071] The present invention will be described in more detail below with reference to Production Examples, Examples and Test Examples. However, the following Production Examples, Examples and Test Examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0072] <Production Example 1> Production of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3)

[0073] [ka] Step 1: Preparation of tert-butyl 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (2): tert-Butyl 4-ethynylpiperidine-1-carboxylate (1, 1.05 g, 5.00 mmol), trimethylsilyl azide (5.5 mmol) and copper(I) iodide (0.25 mmol) were added to a mixture of N,N-dimethylformamide / methanol (9:1, 2 mL) under argon gas. The reaction mixture was heated at 100° C. for 12 h under argon gas. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane / methanol) to obtain the title compound as a white solid (1.03 g, 81.3% yield).

[0074] 1 H NMR (400 MHz, CDCl3) δ 12.73 (br s, 1H), 7.52 (s, 1H), 4.32 - 4.01 (m, 2H), 3.00 - 2.86 (m, 3H), 2.04 - 1.97 (m, 2H), 1.73 - 1.60 (m, 2H), 1.48 (s, 9H). Step 2: Preparation of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3): To a solution of tert-butyl 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (3.60 mmol) obtained in the previous step in dioxane (10 mL) was added 4.0 M hydrogen chloride solution in dioxane (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the title compound as a white solid (quantitative).

[0075] 1 H NMR (400 MHz, MeOD) δ 8.37 (s, 1H), 3.56 - 3.47 (m, 2H), 3.44 - 3.35 (m, 1H), 3.27 - 3.18 (m, 2H), 2.37 - 2.30 (m, 2H), 2.12 - 1.98 (m, 2H). <Preparation Example 2> Preparation of 4-(1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2a) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b)

[0076] [ka] Step 1: Preparation of tert-butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) and tert-butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b) 1,2,4-Triazole or 3-methyl-1,2,4-triazole (1 mmol) and sodium hydride (1.3 mmol) were dissolved in 5 mL of DMF and stirred at 0° C. for 1 h. 4-[(methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol) was added to the reaction mixture under argon gas. The reaction mixture was heated at 90° C. for 5 h. The solvent was evaporated to dryness, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (EA / Hex) to give the title compound as a white solid.

[0077] tert-Butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) Yield: 43.5%; 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.95 (s, 1H), 4.34 (tt, J = 11.5, 4.1 Hz, 2H), 4.26 (s, 1H), 2.91 (s, 1H), 2.21 - 2.11 (m, MS (ESI, m / z) calculated for C 12 H 21 N4O2[M+H] + 253.15, found 253.15. tert-Butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b) Yield: 38.5%; 1H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.79 (s, 1H), 4.25 (dd, J = 11.5, 4.0 Hz, 2H), 4.13 - 4.07 (m, 1H), 2.44 (d, J = 34.8 Hz, 3H), 2.17 - 2.06 (m, 3H), 2.00 - 1.82 (m, 3H), 1.48 (d, J = 2.5 Hz, 9H); MS (ESI, m / z) calculated for C 13 H 23 N4O2[M+H] + 267.15, found 267.15. Step 2: Preparation of 4-(1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2a) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b) Tert-butyl 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1a) or tert-butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (Im15-1b) (3.60 mmol) obtained in the previous step was dissolved in 4 M HCl in dioxane (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the title compound as a white solid (quantitative).

[0078] 4-(1H-1,2,4-Triazol-1-yl)piperidine·HCl (Im15-2a) Yield: 97.8%; MS (ESI, m / z) calculated for C7H13N4 [M+H]+ 153.11, found 153.10. 4-(3-Methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b) Yield: 95.7%; MS (ESI, m / z) calculated for C8H15N4 [M+H]+ 167.12, found 167.15. <Production Example 3> Production of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e)

[0079] [ka] Step 1: Preparation of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b) 3,4-Difluorophenylpropionic acid (925.8 mg, 4.97 mmol) was dissolved in DCM (20 mL). Oxalyl chloride (9.94 mmol) and one drop of DMF were added to the reaction mixture. The resulting solution was stirred for 3-5 h. After completion of the reaction, the solvent was removed under vacuum. Then, 3-(3,4-difluorophenyl)propanoyl chloride was dissolved in DCM and slowly added to AlCl3 (17.4 mmol) in DCM at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and refluxed for 4 h. After cooling to room temperature, the reaction mixture was poured onto ice and extracted with DCM (2 x 30 mL). The organic layer was dried over MgSO4 and filtered. The solvent was concentrated under vacuum and the residue was purified by silica gel column chromatography (EA / Hex) to obtain the title compound (yield: 78.0%).

[0080] 1 H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J = 8.7, 7.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 3.16 - 3.08 (m, 2H), 2.79 - 2.70 (m, 2H). Step 2: Preparation of (Z)-5,6-difluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (E3c) To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b, 3 mmol) in MeOH at 40° C., isoamyl nitrite (3.6 mmol) was added followed by concentrated HCl (1 mL). The reaction mixture was stirred at 40° C. for 2-5 h, cooled to room temperature, and water (50 mL) was added. The precipitate was collected by filtration and dried to obtain the title compound (yield: 54.0%).

[0081] 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.82 (dd, J = 9.3, 7.7 Hz, 1H), 7.75 (dd, J = 10.3, 7.0 Hz, 1H), 3.76 (s, 2H). Step 3: Preparation of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) 5,6-Difluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (E3c, 1 mmol) obtained in the previous step was dissolved in acetic acid (37.5 mL) and sulfuric acid (1.5 mL). Palladium, 10 wt % was added. The reaction mixture was hydrogenated overnight. After filtration through a celite pad, 4N NaOH was added to pH 12 and extracted with EA (3×100 mL). The organic layer was dried over Na2SO4 and filtered. The solvent was concentrated under vacuum, and the residue was purified by amino silica gel column chromatography (DCM / MeOH) to obtain the title compound (yield: 12.1%).

[0082] 1 H NMR (400 MHz, CDCl3) δ 6.98 (t, J = 8.9 Hz, 2H), 3.87 (tt, J = 6.7, 4.9 Hz, 1H), 3.12 (dd, J = 15.8, 6.7 Hz, 2H), 2.62 (dd, J = 15.7, 4.9 Hz, 2H), 1.40 (s, 2H); MS (ESI, m / z) calculated for C9H 10 F2N[M+H] + 170.07, found 170.01. <Production Example 4> Production of 5,6-dichloro-2,3-dihydro-1H-inden-2-amine (4f)

[0083] [ka] Step 1: Preparation of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (F4b) A catalytic amount of DMF was added to a solution of 3-(3,4-dichlorophenyl)propanoic acid (4.56 mmol) in DCM, and excess oxalyl chloride was added dropwise under ice bath. The reaction mixture was stirred at room temperature for 30 min, and then the solvent was removed. DCM was added to the crude acyl chloride mixture, and aluminum chloride (16 mmol) was added to the solution under ice bath. The reaction mixture was refluxed for 1.5 h and cooled at room temperature. The crude mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layer was evaporated and purified by silica gel flash chromatography (hexane / ethyl acetate) to obtain the title compound (yield: 75.4%).

[0084] 1 H NMR (400 MHz, Chloroform-d) δ 7.87-7.75 (m, 1H), 7.61 (s, 1H), 3.18-3.06 (m, 2H), 2.76-2.64 (m, 2H). Step 2: Preparation of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c) Sodium borohydride (4.5 mmol) was added to a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (F4b, 2.16 mmol) in anhydrous EtOH and stirred at room temperature overnight. The crude mixture was poured into DCM, washed with H2O (40 ml) and dried over MgSO4. The crude mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to give the title compound (yield: 88.8%).

[0085] 1H NMR (400 MHz, Chloroform-d) δ 7.49-7.41 (m, 1H), 7.31 (s, 1H), 5.18 (q, J = 6.3 Hz, 1H), 2.99 (ddd, J = 16.3, 8.6, 4.5 Hz, 1H), 2.83-2.69 (m, 1H), 2.50 (dddd, J = 12.8, 8.2, 6.9, 4.5 Hz, 1H), 2.06 (d, J = 6.4 Hz, 1H), 1.95 (dddd, J = 13.2, 8.6, 7.0, 5.7 Hz, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 145.26, 143.36, 132.22, 130.68, 126.81, 126.22, 75.72, 36.39, 29.41. Step 3: Preparation of 5,6-dichloro-1H-indene (F4d) A solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c, 1.92 mmol) in toluene was added with p-toluenesulfonic acid (0.1 equiv.) and refluxed for 2 h using a Dean-Stark trap. The resulting mixture was cooled to room temperature and the solvent was removed under vacuum. The crude mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to obtain the title compound (yield: 65.5%).

[0086] 1 H NMR (400 MHz, Chloroform-d) δ 7.55-7.48 (m, 1H), 7.45 (s, 1H), 6.79 (dtd, J = 5.5, 1.9, 0.7 Hz, 1H), 6.61 (dt, J = 5.5, 2.0 Hz, 1H), 3.38 (td, J = 2.0, 0.8 Hz, 2H); 13 C NMR (100 MHz, Chloroform-d) δ 144.96, 143.44, 136.36, 130.95, 130.43, 128.56, 125.64, 122.50, 38.90. Step 4: Preparation of 3,4-dichloro-1a,6a-dihydro-6H-indeno-[1,2-b]oxirane (F4e) To a solution of 5,6-dichloro-1H-indene (F4d, 1.2 mmol) in DCM, m-CPBA (1.8 mmol) and NaHCO3 (1.8 mmol) were added and stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were evaporated and purified by silica gel flash chromatography (hexane / ethyl acetate) to give the title compound (yield: 84.9%).

[0087] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (s, 1H), 7.31 (s, 1H), 4.25-4.18 (m, 1H), 4.14 (t, J = 2.8 Hz, 1H), 3.18 (d, J = 18.2 Hz, 1H), 2.99-2.89 (m, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 143.62, 141.21, 132.60, 130.30, 128.14, 127.15, 58.20, 58.03, 34.26. Step 5: Preparation of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f) To a solution of 3,4-dichloro-1a,6a-dihydro-6H-indeno-[1,2-b]oxirane (F4e, 0.98 mmol) in THF, 2.5 M lithium aluminum hydride in THF (1.1 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 30 min and quenched with ice water. The solution was extracted with ethyl acetate and purified by silica gel flash chromatography (hexane / ethyl acetate) to obtain the title compound (yield: 86.3%).

[0088] 1H NMR (400 MHz, Chloroform-d) δ 7.31 (s, 2H), 4.72 (ddq, J = 8.7, 5.8, 3.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.87 (dd, J = 16.7, 2.9 Hz, 2H), 1.70 (d, J = 5.0 Hz, 1H); 13 C NMR (100 MHz, Chloroform-d) δ 141.29, 130.54, 126.87, 73.32, 42.30. Step 6: Preparation of 5,6-dichloro-2,3-dihydro-1H-inden-2-amine (4f) To a solution of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f, 0.84 mmol) in THF was added phthalimide (1.7 mmol), triphenylphosphine (1.7 mmol), and diisopropyl azodicarboxylate (1.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h and the solvent was removed under vacuum. Water and EtOH were poured into the crude mixture and hydrazine monohydrate (1.7 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight. The resulting mixture was poured into DCM (40 ml), washed with H2O (40 ml), and dried over MgSO4. The crude mixture was purified by silica gel flash chromatography (dichloromethane / methanol) to give the title compound (yield: 20.2%).

[0089] 1 H NMR (400 MHz, Methanol-d4) δ 7.36 (s, 2H), 3.87 (s, 1H), 3.21 (dd, J = 15.8, 7.1 Hz, 2H), 2.77 (dd, J = 16.7, 5.2 Hz, 2H); 13 C NMR (100 MHz, Methanol-d4) δ 143.28, 131.29, 127.62, 41.35, 20.36; MS (ESI, m / z) calculated for C9H 10 Cl2N [M+H] + 202.02 found 202.05. <Production Example 5> Production of 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole trifluoroacetate (im19)

[0090] [ka] tert-Butyl 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (23.5 mg, 0.103 mmol) was dissolved in 2 ml of DCM, and then 600 μL of trifluoroacetic acid was added and stirred at room temperature for 1 hour (DCM:TFA=3:1). After confirming the completion of the reaction by LCMS and TLC, the mixture was concentrated to remove TFA and dried in vacuum to obtain the title compound (im19) in salt form without purification (17.8 mg, yield: 54%).

[0091] LCMS m / z 222 [M+H] + <Production Example 6> Production of 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20)

[0092] [ka] Step 1: Preparation of tert-butyl 4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (im20-1) tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (100 mg, 0.395 mmol) and difluoroacetic anhydride (64 μL, 0.592 mmol) were dissolved in DCM (3.9 mL) and stirred at room temperature for 1 hour. The reaction was terminated with water, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated. The title compound (im20-1) was obtained as a colorless oil (77 mg, yield: 64.7%) after purification by column chromatography (DCM:MeOH).

[0093] 1 H NMR (400 MHz, CDCl3) δ 6.83 (t, J = 51.8 Hz, 2H), 4.12 (d, J = 7.7 Hz, 2H), 3.19 - 3.11 (m, 1H), 2.96 (t, J = 13.2 Hz, 2H), 2.09 (d, J = 12.9 Hz, 3H), 1.84 (ddd, J = 24.6, 11.3, 4.1 Hz, 3H), 1.47 (s, 9H). Step 2: Preparation of 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20) To a solution of im20-1 (76 mg, 0.251 mmol) in DCM (2.5 mL), TFA (833 μL) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 8-10 with 1N NaOH, and the mixture was extracted with DCM, dried over Na2SO4, filtered, and concentrated to obtain the title compound (im20) as a yellow oil. The product was used in the next reaction without purification (32 mg, yield: 63%).

[0094] <Production Example 7> Production of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21)

[0095] [ka] Step 1: Preparation of tert-butyl 3-(prop-1-yn-1-yl)piperidine-1-carboxylate (im21-1) tert-Butyl 4-ethynylpiperidine-1-carboxylate (1.0g, 4.8mmol) was dissolved in tetrahydrofuran (14mL) and kept at -78℃ under nitrogen atmosphere. 2.5M n-butyllithium (1.92mL, 4.8mmol) was added and stirred for 30 minutes. After warming to room temperature, iodomethane (450μL, 7.2mmol) was added and reacted for 12 hours. After the reaction, ethyl acetate and H2O were added for extraction, and the organic layer was dried over Na2SO4 and concentrated. The obtained residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain the title compound (im21-1) as a brown liquid (1.09g, yield: 100%).

[0096] 1 H NMR (400 MHz, CDCl3) δ 3.69 (d, J = 11.7 Hz, 2H), 3.18 - 3.06 (m, 2H), 2.49 (d, J = 2.1 Hz, 1H), 1.79 (d, J = 2.3 Hz, 3H), 1.77 - 1.67 (m, 2H), 1.57 - 1.48 (m, 2H), 1.45 (s, 9H). Step 2: Preparation of tert-butyl 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (im21-2) Im21-1 (170 mg, 0.75 mmol) and trimethylsilyl azide (150 μL, 1.16 mmol) were reacted for 2 hours at 200 ° C. using a microwave reactor. The reaction solution was purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain the title compound (im21-2) as a yellow liquid (30 mg, yield: 15%).

[0097] 1 H NMR (400 MHz, CDCl3) δ 4.18 (m, 2H), 2.91 - 2.75 (m, 3H), 2.30 (s, 3H), 1.89 - 1.66 (m, 4H), 1.46 (s, 9H). Step 3: Preparation of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21) tert-Butyl 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (30 mg, 0.11 mmol) was dissolved in DCM (1.5 mL) and trifluoroacetic acid (350 uL) was added at 0° C. After warming to room temperature and reacting for 12 hours, the reaction solution was concentrated to obtain the title compound (im21). It was used in the next reaction without further purification (yield: 100%).

[0098] LCMS m / z 167 [M+H] + <Production Example 8> Production of 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25)

[0099] [ka] tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (0.3 g, 1.1844 mmol) and 3.9 mL of TFA were dissolved in 30 mL of DCM, and the mixture was stirred at room temperature. After confirming the completion of the reaction by TLC, the mixture was concentrated and used in the next reaction without purification (yield: 100%).

[0100] [Example 1] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a)

[0101] [ka] Step 1: Preparation of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (5a) A mixture of 2,3-dihydro-1H-inden-2-amine (4a, 1.68 mmol), ethyl 2-chloropyrimidine-5-carboxylate (1.4 mmol) and triethylamine (3 mmol) in dioxane (5 mL) was stirred at 100° C. for 3 h. After cooling, the solvent was evaporated and the crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane / ethyl acetate) to give the title compound as a white solid (yield: 89.2%).

[0102] 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.75 (s, 1H), 7.25 - 7.15 (m, 4H), 6.00 (d, J = 7.8 Hz, 1H), 4.97 - 4.79 (m, 1H), 4.35 (q, J = 7.1 MS (ESI, m / z) calculated for C 16 H 18 N3O2[M+H] + 284.14, found 284.05. Step 2: Preparation of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbohydrazide (6a) Compound 5a (5 mmol) and hydrazine monohydrate (50 mmol) were dissolved in EtOH and refluxed for 6 h. After the reaction was completed, the reaction mixture was evaporated under vacuum to obtain the title compound (yield: 93.4%).

[0103] 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.27 - 7.08 (m, 4H), 4.66 (h, J = 7.2 Hz, MS (ESI, m / z) calculated for C 14 H 16 N5O [M+H] + 270.13, found 270.05. Step 3: Preparation of 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (7a) A mixture of compound 6a (0.1 mmol), TEA (0.5 mmol) in THF (5 mL) was slowly added to a solution of triphosgene (0.04 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated to dryness. The product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (EA / Hex) to obtain the title compound (yield: 27.4%).

[0104] 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.67 (s, 1H), 7.26 - 7.17 (m, 4H), 5.79 (d, J = 7.9 Hz, 1H), 4.92 - 4.83 (m, 1H), 3.42 (dd, J = MS (ESI, m / z) calculated for C 15 H 14 N5O2[M+H] + 296.11, found 296.05. Step 4: Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a) 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (7a, 1 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3, 1.2 mmol) prepared in Preparation 1, DIEA (3 mmol) and BOP reagent (1.2 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness. The crude product was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was separated by column chromatography (DCM / MeOH) to obtain the title compound as a white solid (yield: 46.1%).

[0105] 1 H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.26 - 7.22 (m, 2H), 7.21 - 7.16 (m, 2H), 5.88 (d, J = 7.7 Hz, 1H), 4.93 - 4.83 (m, 1H), 4.21 - 4.09 (m, 2H), 3.42 (dd, J = 16.0, 7.0 Hz, 2H), 3.33 - 3.22 (m, 2H), 3.11 - 3.02 (m, 1H), 2.92 (dd, J = 16.0, 5.0 Hz, 2H), 2.21 - 2.11 (m, 2H), 1.97 - 1.83 (m, 2H); HRMS (ESI, m / z) calculated for C 22 H 24 NO [M+H] + 430.2098, found 430.2103. [Example 2] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8b) The title compound was prepared in the same manner as in Example 1, except that 5-fluoro-2,3-dihydro-1H-inden-2-amine (4b) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 83.0%). 1 H NMR (400 MHz, Chloroform-d) δ 12.69 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.16 (dd, J = 8.3, 5.2 Hz, 1H), 7.01 - 6.79 (m, 2H), 5.97 (d, J = 7.6 Hz, 1H), 4.96 - 4.82 (m, 1H), 4.21 - 4.09 (m, 2H), 3.38 (td, J = 15.1, 14.7, 7.0 Hz, 2H), 3.28 (ddd, J = 13.1, 11.7, 2.9 Hz, 2H), 3.07 (tt, J = 11.5, 3.7 HRMS (ESI, m / z) calculated for C 22 H 23 FN9O [M+H] + 448.2004, found 448.2003. [Example 3] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8c) The title compound was prepared in the same manner as in Example 1, except that 5-chloro-2,3-dihydro-1H-inden-2-amine (4c) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 62.5%).

[0106] 1 H NMR (400 MHz, Chloroform-d) δ 12.37 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.22 (q, J = 1.2 Hz, 1H), 7.16 (d, J = 1.3 Hz, 2H), 5.84 (d, J = 7.6 Hz, 1H), 4.88 (qt, J = 7.2, 5.1 Hz, 1H), 4.15 (dt, J = 13.3, 4.0 Hz, 2H), 3.45-3.33 (m, 2H), 3.27 (ddd, J = 13.2, 11.9, 2.9 Hz, 2H), 3.07 (tt, J = 11.4, 3.7 MS (ESI, m / z) calculated for C 22 H 23 ClNO [M+H] + 464.1709, found 464.1709. [Example 4] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8d) The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2,3-dihydro-1H-inden-2-amine (4d) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 38.0%).

[0107] 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J = 8.0, 1.9 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 5.70 (d, J = 7.6 Hz, 1H), 4.95-4.79 (m, 1H), 4.20-4.10 (m, 2H), 3.45-3.21 (m, 4H), 3.06 (tt, J = 11.5, 3.8 Hz, 1H), 2.88 (ddd, J = 20.9, 16.2, 5.1 Hz, 2H), 2.21-2.10 (m, 2H), 1.98-1.81 (m, 2H); MS (ESI, m / z) calculated for C 22 H 23 BrNO [M+H] + 508.1203, found 508.1202. [Example 5] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8e) The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 63.8%).

[0108] 1H NMR (400 MHz, Chloroform-d) δ 13.08 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.02 (t, J = 8.8 Hz, 2H), 6.03 (d, J = 7.6 Hz, 1H), 4.89 (qt, J = 7.2, 5.2 Hz, 1H), 4.14 (dt, J = 13.4, 3.8 Hz, 2H), 3.42 - 3.19 (m, 4H), 3.07 (tt, J = 11.4, 3.7 Hz, 1H), 2.97 - 2.82 (m, 2H), 2.16 (dd, J = 13.7, 3.7 Hz, 2H), 1.99 - 1.82 (m, 2H); HRMS (ESI, m / z) calculated for C 22 H 22 F2N9O [M+H] + 466.1910, found 466.1913. [Example 6] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8f) The title compound was prepared in the same manner as in Example 1, except that 5,6-dichloro-2,3-dihydro-1H-inden-2-amine (4f) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 54.3%).

[0109] 1H NMR (400 MHz, Chloroform-d) δ 12.17 (s, 1H), 8.80 (s, 2H), 7.54 (s, 1H), 7.32 (s, 2H), 5.79 (d, J = 7.5 Hz, 1H), 4.88 (qt, J = 7.2, 5.2 Hz, 1H), 4.15 (dt, J = 12.6, 3.8 Hz, 2H), 3.38 (dd, J = 16.0, 7.3 Hz, 2H), 3.28 (td, J = 13.2, 2.9 Hz, 2H), 3.06 (ddt, J = 11.4, 7.4, 3.7 Hz, 1H), 2.88 (dd, J = MS (ESI, m / z) calculated for C 22 H 22 Cl2NO [M+H] + 498.13, found 498.15. [Example 7] Preparation of N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine (13)

[0110] [ka] The title compound was prepared in the same manner as in Example 1, except that 6,7-dihydro-5H-cyclopenta[b]pyrazine-6-amine (9) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) (yield: 53.0%).

[0111] 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 2H), 8.34 (s, 2H), 7.75 - 7.62 (m, 1H), 4.94 (tt, J = 7.8, 5.7 Hz, 1H), 4.11 (dt, J = 13.3, 3.7 Hz, MS (ESI, m / z) calculated for C 20 H 22 N 11 O [M+H] + 432.20, found 432.20. [Example 8] Preparation of 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazin-3-amine (14)

[0112] [ka] The title compound was prepared in the same manner as in Example 1, except that ethyl 6-chloropyridazine-3-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate (yield: 42.0%).

[0113] 1H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.72 (s, 1H), 7.30 - 7.24 (m, 2H), 7.19 - 7.15 (m, 2H), 6.94 (d, J = 9.4 Hz, 1H), 4.77 (h, J = 6.7, 6.1 Hz, 1H), 4.04 - 3.96 (m, 2H), 3.30 (d, J = 2.5 Hz, 4H), 3.08 - 2.99 (m, 1H), 2.90 (dd, J = 16.0, 5.4 HRMS (ESI) m / z (M+H) + calcd for C 22 H 24 NO = 430.21; found 430.2107. [Example 9] Preparation of 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (15a)

[0114] [ka] The title compound was prepared in the same manner as in Example 1, except that 4-(1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2a) obtained in Preparation Example 2 was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (yield: 65.2%).

[0115] 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.14 (s, 1H), 7.97 (s, 1H), 7.28 - 7.20 (m, 2H), 7.21 - 7.14 (m, 2H), 6.02 (d, J = 7.7 Hz, 1H), 4.87 (qt, J = 7.2, 5.0 Hz, 1H), 4.47 (tt, J= 11.1, 4.1 Hz, 1H), 4.29 - 4.17 (m, 2H), 3.52 - 3.35 (m, 3H), 3.30 (ddd, J=13.4, 11.7, 3.0 Hz, 2H), 2.91 (dd, J = HRMS (ESI, m / z) calculated for C 22 H 24 NO [M+H] + 430.2098, found 430.2098. [Example 10] Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (15b) The title compound was prepared in the same manner as in Example 1, except that 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b) obtained in Preparation Example 2 was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (yield: 57.4%).

[0116] 1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 2H), 7.90 (d, J = 77.3 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.23 - 7.15 (m, 2H), 5.82 (d, J = 7.7 Hz, 1H), 4.88 (dtd, J = 12.3, 7.3, 5.0 Hz, 1H), 4.42 - 4.16 (m, 3H), 3.42 (dd, J = 16.0, 7.0 Hz, 2H), 3.34 - 3.22 (m, 2H), 2.91 (dd, J = 16.0, 5.0 Hz, 2H), 2.46 (d, J = HRMS (ESI, m / z) calculated for C 23 H 26 NO [M+H] + 444.2255, found 444.2255. [Example 11] Preparation of N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (16)

[0117] [ka] Step 1-1: Preparation of tert-butyl 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylate (M2) The title compound was prepared in the same manner as in Step 1 of Preparation 1, except that tert-butyl 4-ethynyl-2-methylpiperidine-1-carboxylate was used instead of tert-butyl 4-ethynylpiperidine-1-carboxylate (yield: 47.0%).

[0118] 1H NMR (400 MHz, Methanol-d4) δ 7.64 (s, 1H), 4.51 (t, J = 6.4 Hz, 1H), 4.04 (ddd, J = 13.8, 4.6, 2.3 Hz, 1H), 3.28 - 3.16 (m, 1H), 3.06 (s, MS (ESI, m / z) calculated for C 13 H 23 N4O2[M+H] + 267.18, found 267.20. Step 1-2: Preparation of 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (M3) The title compound was prepared from M2 obtained in the above step in the same manner as in Step 2 of Preparation Example 1 (quantitative).

[0119] MS (ESI, m / z) calculated for C8H14N4 [M+H]+ 166.12, found 166.10. Step 2: Preparation of N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (16) The title compound was prepared in the same manner as in Example 4, except that 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (M3) prepared in the above step was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (yield: 11.2%).

[0120] 1H NMR (400 MHz, Methanol-d4) δ 8.77 (s, 2H), 7.67 (s, 1H), 7.39 (s, 1H), 7.33 - 7.26 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.36 - 5.32 (m, 1H), 4.58 (s, 1H), 4.50 (dd, J = 7.1, 3.3 Hz, 1H), 4.05 - 3.95 (m, 1H), 2.93 (ddd, J = 21.7, 16.1, 6.3 Hz, 2H), 2.14 (d, J = 12.4 Hz, 1H), 2.04 - 2.02 (m, 2H), 1.80 (qd, J = 13.0, 4.7 Hz, 1H), 1.62 - 1.56 (m, 2H), 1.42 (d, J = 6.9 Hz, 3H); MS (ESI, m / z) calculated for C 23 H 25 BrNO [M+H] + 522.13, found 522.15. [Example 12] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine (17a)

[0121] [ka] Step 1: Preparation of ethyl 6-chloronicotinate (A4a) 6-Chloronicotinic acid (3.2 mmol) and 1,1'-carbonyldiimidazole (3.5 mmol) were added to THF under Ar gas at room temperature. The reaction mixture was stirred at the same temperature for 3 h. Excess EtOH was slowly added to the mixture and stirred overnight. The THF solvent was removed under vacuum, and the resulting mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to produce the title compound (yield: 62.8%).

[0122] 1H NMR (400 MHz, Chloroform-d) δ 9.00 (dd, J = 2.4, 0.6 Hz, 1H), 8.25 (dd, J = 8.3, 2.4 Hz, 1H), 7.42 (dd, J = 8.3, 0.7 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); MS (ESI, m / z) calculated for C8H9ClNO2[M+H] + 186.03 found 186.05. Step 2: Preparation of ethyl 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)nicotinate (A5a) The title compound was prepared in the same manner as in Step 1 of Example 1, except that 5-bromo-2,3-dihydro-1H-inden-2-amine was used instead of 2,3-dihydro-1H-inden-2-amine and ethyl 6-chloronicotinate (A4a) was used instead of ethyl 2-chloropyrimidine-5-carboxylate (yield: 12.4%).

[0123] 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.8, 2.2 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.30 (d, J = 8.1 Hz, 1H), 4.78-4.59 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.42-3.25 (m, 2H), 2.93-2.74 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); MS (ESI, m / z) calculated for C 17 H 18 BrN2O2[M+H] + 361.05 found 361.00. Step 3: Preparation of 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)nicotinohydrazide (A6a) The title compound was prepared in the same manner as in Step 2 of Example 1, except that Compound A5a was used instead of Compound 5a (yield: 84.1%).

[0124] 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.84-7.74 (m, 3H), 7.44 (s, 1H), 7.39-7.30 (m, 2H), 7.25-7.17 (m, MS (ESI, m / z) calculated for C 15 H 16 BrNO [M+H] + 347.05 found 347.05. Step 4: Preparation of 5-(6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (A7a) To a solution of compound A6a (0.2 mmol) in DMF, 1,1'-carbonyldiimidazole (0.22 mmol) and TEA (0.2 mmol) were added at room temperature and stirred for 3 hours. The DMF solvent was removed under vacuum and the crude mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to prepare the title compound (yield: 84.0%).

[0125] 1H NMR (400 MHz, DMSO-d6) δ 10.94-10.85 (m, 1H), 10.21 (dd, J = 8.9, 2.4 Hz, 1H), 10.13-10.07 (m, 1H), 9.95 (s, 1H), 9.87-9.82 (m, MS (ESI, m / z) calculated for C 16 H 14 BrNO2[M+H] + 373.03 found 373.00. Step 5: Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine (17a) The title compound was prepared by the same method as in Step 4 of Example 1, except that Compound A7a was used instead of Compound 7a (yield: 57.2%).

[0126] 1H NMR (400 MHz, Chloroform-d) δ 8.60 (dd, J = 2.4, 0.7 Hz, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J = 7.8, 1.9 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.46 (dd, J = 8.9, 0.8 Hz, 1H), 5.24 (d, J = 7.5 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.19 - 4.09 (m, 2H), 3.45 - 3.20 (m, 4H), 3.06 (tt, J = 11.4, 3.7 Hz, 1H), 2.95 - 2.80 (m, 2H), 2.15 (dd, J = 13.8, 3.8 Hz, 2H), 1.97 - 1.83 (m, 2H); MS (ESI, m / z) calculated for C 23 H 24 BrNO [M+H] + 507.13, found 507.15. [Example 13] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine (17b) The title compound was prepared in the same manner as in Example 12, except that 5-chloropyrazine-2-carboxylic acid was used instead of 6-chloronicotinic acid (yield: 48.5%).

[0127] 1H NMR (400 MHz, Methanol-d4) δ 8.60 (d, J = 1.3 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.68 (s, 1H), 7.40 (s, 1H), 7.30 (dd, J = 8.1, 1.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.77 (tt, J = 7.2, 3.6 Hz, 2H), 4.13 (dt, J = 13.3, 3.5 Hz, 2H), 3.44 - 3.32 (m, 4H), 3.10 (ddt, J = 11.6, 7.4, 3.7 Hz, 1H), 2.90 (ddd, J = 19.0, 16.1, 5.4 Hz, 2H), 2.18 - 2.08 (m, 2H), 1.93 - 1.76 (m, 2H); MS (ESI, m / z) calculated for C 22 H 23 BrNO [M+H] + 508.12, found 508.15. [Example 14] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine (18)

[0128] [ka] Step 1: Preparation of ethyl 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinate (A5c) The title compound was prepared in the same manner as compound A5a using ethyl 4,6-dichloronicotinate (yield: 64.2%).

[0129] 1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.40 (d, J = 6.3 Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J = 8.0, 1.8 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 4.40-4.26 (m, 3H), 3.40 (td. (ESI, m / z) calculated for C 17 H 17 BrClN2O2[M+H] + 395.02 found 395.05. Step 2: Preparation of 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinic acid (A6c) To a solution of compound A5c (0.50 mmol) in EtOH and water, lithium hydroxide (1.5 mmol) was added at room temperature and stirred overnight. The resulting mixture was poured into DCM, washed with H2O (40 ml) and dried over MgSO4. The crude mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to produce the title compound (yield: 64.2%).

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 6.1 Hz, 1H), 8.51 (s, 1H), 7.47 (s, 1H), 7.35 (dd, J = 8.0, 1.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), MS (ESI, m / z) calculated for C 15 H 13BrClN2O2[M+H] + 366.98 found 366.95. Step 3: Preparation of 5-(6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloropyridin-3-yl)-1,3,4-oxadiazol-2(3H)-yl (A7c) To a solution of compound A6c (0.25 mmol) in THF, 1,1'-carbonyldiimidazole (0.27 mmol) was added at room temperature under argon gas and stirred for 3 hours. Hydrazine monohydrate (2.5 mmol) was added to the solution and stirred overnight. The resulting mixture was evaporated under vacuum. 1,1'-carbonyldiimidazole (0.27 mmol) and triethylamine (0.25 mmol) were added to a solution of the crude mixture in DMF. The reaction mixture was stirred for 3 hours, and the crude mixture was purified by silica gel flash chromatography (hexane / ethyl acetate) to obtain the title compound (yield: 59.6%).

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.30 (s, 1H), 7.48 (s, 1H), 7.43-7.33 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 4.65-4.53 (m, 1H), 3.49-3.36 (m, 2H), 2.91-2.76 (m, 2H); MS (ESI, m / z) calculated for C 16 H 13 BrClNO2[M+H] + 406.99 found 407.00. Step 4: Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine (18) The title compound was prepared by the same method as in Step 4 of Example 1 using compound A7c (yield: 67.8%).

[0132] 1 H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 8.49 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.0, 2.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 4.60 (tt, J = 6.9, 2.8 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.42 (ddd, J = 19.8, 16.3, 6.8 Hz, 2H), 3.25 (td, J = 12.5, 2.7 Hz, 2H), 3.01 (tt, J = 11.5, 3.7 Hz, 1H), 2.87 (ddd, J = 20.8, 16.4, 4.1 Hz, 2H), 2.06 - 1.96 (m, 2H), 1.70 (qd, J = 12.6, 4.2 Hz, 2H); MS (ESI, m / z) calculated for C 23 H 23 BrClNO [M+H] + 541.09, found 541.10. [Example 15] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine (19a)

[0133] [ka] The title compound was prepared in the same manner as in Example 1, except that (3,5-dichlorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 48.7%).

[0134] 1H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.67 (m, 2H), 8.46 (t, J = 6.4 Hz, 1H), 7.69 (s, 1H), 7.48 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 2H), 4.57 (d, J = 6.3 Hz, 2H), 3.99 (dt, J = 13.1, 3.5 Hz, 2H), 3.27 - 3.16 (m, 2H), 3.05 - 2.95 (m, 1H), 2.07 - 1.98 (m, 2H), 1.77 - 1.62 (m, 2H); MS (ESI, m / z) calculated for C 20 H 20 Cl2NO [M+H] + 472.12, found 472.10. [Example 16] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine (19b) The title compound was prepared in the same manner as in Example 1, except that diisopropylethylamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 54.6%).

[0135] 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 8.1 Hz, 2H), 7.97 (t, J = 5.8 Hz, 1H), 7.70 (s, 1H), 7.42 (t, J = 1.9 Hz, 1H), 7.32 (d, J = 1.9 Hz, 2H), 3.99 (dt, J = 13.1, 3.6 Hz, 2H), 3.59 (q, J = 6.7 Hz, 2H), 3.23 (td, J = 12.7, 2.8 Hz, 2H), 3.01 (tt, J = 11.6, 3.7 Hz, 1H), 2.89 (t, J = 6.9 Hz, 2H), 2.03 (dd, J = 13.5, 3.4 Hz, 2H), 1.79 - 1.61 (m, 2H); MS (ESI, m / z) calculated for C 21 H 22 Cl2NO [M+H] + 486.13, found 486.15. [Example 17] Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (20a)

[0136] [ka] Step 1: Preparation of (E)-ethyl 3-(2-chloropyrimidin-5-yl)acrylate (imL14-1): A mixture of 5-bromo-2-chloropyrimidine (0.19 g, 1.00 mmol), ethyl acrylate (0.42 mL, 4.00 mmol), palladium(II) diacetate (8.98 mg, 0.04 mmol), tri(o-tolyl)phosphine (30.43 mg, 0.10 mmol) in dimethylformamide (2 mL) and diisopropylethylamine (1 mL) was heated under reflux for 4 h and then cooled to room temperature. The solvent was evaporated to dryness and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was separated by column chromatography (ethyl acetate / hexane) to give the title compound as a bright yellow solid (0.15 g, 71.2%).

[0137] 1 H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 0.6 Hz, 2H), 7.59 (d, J = 16.2 Hz, 1H), 6.58 (d, J = 16.2 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.1Hz, 3H). Step 2: Preparation of (E)-ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (imL14-2) The title compound was obtained as a white solid (0.11 g, 71.5%) in the same manner as in Example 1, Step 1, except that imL14-1 (0.11 g, 0.50 mmol) was used instead of ethyl 2-chloropyrimidine-5-carboxylate, 2-aminoindan (0.80 g, 6.00 mmol) and triethylamine (1.01 g, 10 mmol).

[0138] 1H NMR (400 MHz, CDCl3) δ 8.38 (br s, 2H), 7.48 (d, J = 16.1 Hz, 1H), 7.26 - 7.14 (m, 4H), 6.29 (d, J = 16.1 Hz, 1H), 6.01 (s, 1H), 4.96 - 4.78 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.41 (dd, J = 16.0, 7.0 Hz, 2H), 2.90 (dd, J = 16.0, 4.8 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). Step 3: Preparation of ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoate (imL14-3) In a round-bottom flask containing imL14-2 (92.81 mg, 0.30 mmol) in ethyl acetate / methanol / tetrahydrofuran (1:2:1) (20 mL), palladium hydroxide on carbon (50 mg) was slowly added to the mixture at room temperature. The reaction mixture was stirred at room temperature under hydrogen gas for 6 hours. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / hexane) to give the title compound as a white solid (78.56 mg, 84.1%).

[0139] 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 2H), 7.25 - 7.13 (m, 4H), 5.65 (d, J = 7.8 Hz, 1H), 4.84 - 4.68 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.38 (dd, J = 16.0, 7.0 Hz, 2H), 2.86 (dd, J = 15.9, 5.0 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). Step 4: Preparation of 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propanoic acid (L14) A solution of lithium hydroxide (5.00 mmol) in water (2 mL) was added to a solution of imL14-3 (1.00 mmol) in a mixture of tetrahydrofuran / methanol (18 ml:2 ml). The reaction mixture was stirred at room temperature for 6 hours. After evaporating the solvent, the mixture was dissolved in water again and acidified with 1M hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate / hexane) to obtain the title compound as a white solid (60.33 mg, 84.4%).

[0140] Step 5: Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (20a) To a 10 mL vial containing 2 mL of N,N'-dimethylformamide was added L14 (0.10 mmol), 4-(1H-1,2,3)-triazol-5-yl)piperidine·HCl (22.64 mg, 0.12 mmol) and N,N-diisopropylethylamine (38.77 mg, 0.30 mmol). N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (45.51 mg, 0.12 mmol) was then added to the stirred mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and the crude product was separated by column chromatography (dichloromethane / methanol) to give the title compound as a white solid (36.95 mg, 88.5%).

[0141] 1H NMR (400 MHz, CDCl3) δ 13.71 (s, 1H), 8.19 (s, 2H), 7.47 (s, 1H), 7.23 - 7.18 (m, 2H), 7.18 - 7.13 (m, 2H), 5.77 (d, J = 7.6 Hz, 1H), 4.83 - 4.70 (m, 1H), 4.71 - 4.57 (m, 1H), 3.94 - 3.81 (m, 1H), 3.37 (dd, J = 16.0, 7.1 Hz, 2H), 3.21 - 3.09 (m, 1H), 3.07 - 2.94 (m, 1H), 2.91 - 2.73 (m, 5H), 2.60 (t, J = 7.2 Hz, 2H), 2.08 - 1.98 (m, 2H), 1.71 - 1.49 (m, 2H); HRMS (ESI) m / z (M+H) + calcd for C 23 H 28 NO = 418.24; found 418.2354. [Example 18] Preparation of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (20b) The title compound was prepared in the same manner as in Example 17, except that in Step 5, (1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) was used instead of 4-(1H-1,2,3)-triazol-5-yl)piperidine·HCl (27.49 mg, 68.0%).

[0142] 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.17 (s, 2H), 7.55 (d, J = 1.2 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.19 - 7.13 (m, 2H), 6.74 (s, 1H), 5.40 (d, J = 7.8 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.69 - 4.61 (m, 1H), 3.90 - 3.80 (m, 1H), 3.37 (dd, J = 15.9, 7.0 Hz, 2H), 3.16 - 3.07 (m, 1H), 2.89 - 2.77 (m, HRMS (ESI) m / z (M+H)+ calcd for C 24 H 29 NO = 417.24; found 417.2400. [Example 19] Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21a)

[0143] [ka] Step 1: Preparation of 2-isothiocyanato-2,3-dihydro-1H-indene (imL15-1) Thiophosgene (115.00 μL, 0.15 mmol) was added dropwise to a cooled mixture of 2-aminoindan (0.13 g, 1.00 mmol) and N,N-diisopropylethylamine (38.77 mg, 0.30 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h, and then the solvent was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (hexane) to give the title compound as a light brown solid (0.173 g, 98.8%).

[0144] 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.19 (m, 4H), 4.53 (tt, J = 6.9, 5.2 Hz, 1H), 3.32 (dd, J = 15.9, 7.0 Hz, 2H), 3.16 (dd, J = 15.8, 5.2 Hz, 2H). Step 2: Preparation of N-(2,3-dihydro-1H-inden-2-yl)hydrazinecarbothioamide (imL15-2) Hydrazine hydrate (200 μL) was added to a solution of imL15-1 (0.14 g, 0.08 mmol) in ethanol (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate / hexane) to give the title compound as a light yellow solid (0.156 g, 94.3%).

[0145] 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.28 - 7.14 (m, 4H), 5.24 - 5.13 (m, 1H), 3.68 (s, 1H), 3.43 (dd, J = 16.2, 7.2 Hz, 2H), 2.93 (dd, J = 16.2, 4.7 Hz, 2H), 1.37 - 1.16 (m, 2H). Step 3: Preparation of ethyl 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butanoate (imL15-3) A mixture of ethyl 4-cyanobutanoate (70.59 mg, 0.50 mmol) and imL15-2 (0.10 g, 0.50 mmol) was stirred in trifluoroacetic acid (3 mL) at 80° C. overnight. The mixture was cooled to 0° C., quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane / methanol) to obtain the title compound as a white solid (0.10 g, 62.5%).

[0146] 1 H NMR (400 MHz, CDCl3) δ 7.26 - 7.13 (m, 4H), 6.01 (s, 1H), 4.42 (p, J = 5.7 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.38 (dd, J = 16.1, 6.9 Hz, 2H), 3.11 - 2.86 (m, 4H), 2.41 (t, J = 7.4 Hz, 2H), 2.05 (p, J = 7.4 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). Step 4: Preparation of 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butanoic acid (L15) Using imL15-3 (0.10 g, 0.30 mmol), the title compound was obtained as a white solid (68.90 mg, 75.7%) in the same manner as in Step 4 of Example 17.

[0147] Step 5: Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21a) To a 10 mL vial containing 2 mL of N,N'-dimethylformamide was added L15 (0.10 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (0.12 mmol) and N,N-diisopropylethylamine (0.30 mmol). N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (0.12 mmol) was then added to the stirred mixture. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and the crude product was separated by column chromatography (dichloromethane / methanol) to give the title compound as a white solid (19.34 mg, 44.2%).

[0148] 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.24 - 7.16 (m, 4H), 6.33 - 5.57 (m, 1H), 4.66 - 4.56 (m, 1H), 4.50 - 4.40 (m, 1H), 3.94 - 3.85 (m, 1H), 3.43 - 3.33 (m, 2H), 3.19 - 3.09 (m, 1H), 3.06 - 2.92 (m, 5H), 2.77 - 2.68 (m, 1H), 2.53 - 2.39 (m, 2H), 2.19 - 2.04 (m, 2H), 2.04 - 1.92 (m, 2H), 1.80 - 1.61 (m, 2H); HRMS (ESI) m / z (M+H)+ calcd for C 22 H 28 N7OS = 438.21; found 438.2076 [Example 20] Preparation of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one (21b): In step 5 of Example 19, 4-(1H-imidazol-5-yl)piperidine·HCl (0.12 mmol) was used instead of 4-(1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) to obtain the title compound as a white solid (38.24 mg, 68.0%).

[0149] 1 H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.22 - 7.12 (m, 4H), 6.73 (s, 1H), 6.62 - 6.51 (m, 1H), 4.60 - 4.53 (m, 1H), 4.49 - 4.39 (m, 1H), 3.87 - 3.78 (m, 1H), 3.40 - 3.28 (m, 2H), 3.12 - 3.03 (m, 1H), 3.01 - 2.90 (m, 4H), 2.88 - 2.78 (m, 1H), 2.70 - 2.59 (m, 1H), 2.48 - 2.34 (m, 2H), 2.11 - 1.89 (m, 4H), 1.68 - 1.49 (m, 2H); HRMS (ESI) m / z (M+H)+ calcd for C 23 H 29 N6OS = 437.21; found 437.2126. [Example 21] Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22a)

[0150] [ka] Step 1: Preparation of tert-butyl 2-(5-methoxy-5-oxopentanoyl)hydrazinecarboxylate (imL17-1) To a mixture of monomethyl glutarate (5.00 mmol), tert-butyl carbazate (6.00 mmol) and 4-dimethylaminopyridine (0.025 mmol) in dichloromethane (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.00 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (ethyl acetate / hexane) to obtain the title compound as a white solid (1.14 g, 87.6%).

[0151] Step 2: Preparation of methyl 5-hydrazinyl-5-oxopentanoic acid hydrochloride (imL17-2) The title compound was obtained as a white solid (quantitative) using imL17-1 (0.52 g, 2.00 mmol) in the same manner as in Step 2 of Preparation Example 1.

[0152] 1 H NMR (400 MHz, MeOD) δ 3.66 (s, 3H), 2.41 (t, J = 7.3 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.4 Hz, 2H). Step 3: Preparation of methyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)butanoate (imL17-3) To a solution of im17-2 (0.52 g, 2.00 mmol) in dioxane (10 mL) was added 4.0 M hydrogen chloride in dioxane (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness to give the title compound as a white solid (quantitative).

[0153] 1H NMR (400 MHz, MeOD) δ 3.66 (s, 3H), 2.41 (t, J = 7.3 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.94 (p, J = 7.4 Hz, 2H). Step 4: Preparation of methyl 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoate (imL17-4) The title compound was obtained as a white solid (0.12 g, 50.2%) using imL17-3 (0.149 mg, 0.80 mmol) and 2-aminoindan (0.13 g, 0.96 mmol) in the same manner as in Step 4 of Example 1.

[0154] 1 H NMR (400 MHz, CDCl3) δ 7.27 - 7.15 (m, 4H), 5.34 (s, 1H), 4.51 (qt, J = 6.9, 4.6 Hz, 1H), 3.67 (s, 3H), 3.36 (dd, J = 16.1, 6.9 Hz, 2H), 2.97 (dd, J = 16.1, 4.6 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.3 Hz, 2H). Step 5: Preparation of 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butanoic acid (L17) The title compound was obtained as a white solid (0.11 g, 96.8%) in the same manner as in Step 4 of Example 17, except that imL17-4 (0.12 g, 0.40 mmol) was used instead of imL14-3.

[0155] 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.25 - 7.14 (m, 4H), 6.09 (br s, 1H), 4.47 (tt, J = 7.0, 5.2 Hz, 1H), 3.35 (dd, J = 16.0, 7.0 Hz, 2H), 2.95 (dd, J = 16.0, 5.2 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 2.02 (p, J = 7.2 Hz, 2H). Step 6: Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22a) Using L17 (28.73 mg, 0.10 mmol) and 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (22.64 mg, 0.12 mmol), the title compound was obtained as a white solid (28.37 mg, 67.3%) in the same manner as in Step 5 of Example 19.

[0156] 1 H NMR (400 MHz, CDCl3) δ 13.51 (s, 1H), 7.46 (s, 1H), 7.25 - 7.14 (m, 4H), 5.54 - 5.41 (m, 1H), 4.63 - 4.55 (m, 1H), 4.55 - 4.48 (m, 1H), 3.95 - 3.87 (m, 1H), 3.41 - 3.32 (m, 2H), 3.19 - 3.10 (m, 1H), 3.06 - 2.92 (m, 3H), 2.83 - 2.70 (m, 3H), 2.54 - 2.41 (m, 2H), 2.17 - 1.93 (m, 4H), 1.78 - 1.58 (m, 2H); HRMS (ESI) m / z (M+H)+ calcd for C 22 H 28 N7O2= 422.2299; found 422.2300 [Example 22] Preparation of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one (22b) The title compound was prepared in the same manner as in Example 21, except that in Step 6, 4-(1H-imidazol-5-yl)piperidine (18.14 mg, 0.12 mmol) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (yield: 69.4%).

[0157] 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 1.2 Hz, 1H), 7.23 - 7.14 (m, 4H), 6.73 (s, 1H), 6.00 - 5.92 (m, 1H), 4.62 - 4.55 (m, 1H), 4.53 - 4.44 (m, 1H), 3.93 - 3.81 (m, 1H), 3.38 - 3.30 (m, 2H), 3.13 - 3.05 (m, 1H), 3.02 - 2.92 (m, 2H), 2.89 - 2.80 (m, 1H), 2.79 - 2.70 (m, 2H), 2.70 - 2.61 (m, HRMS (ESI) m / z (M+H)+ calcd for C 23 H 29 N6O2= 421.2347; found 421.2348. [Example 23] Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethanone (23)

[0158] [ka] Step 1: Preparation of methyl 2-(cyanomethoxy)acetate (imL18-1) To a solution of methyl glycolate (0.45 g, 5.00 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride 60% (0.24 g, 6.00 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 1 h until bubbling ceased. Bromoacetonitrile (0.72 g, 6.00 mmol) was added to the mixture and the reaction mixture was stirred at room temperature overnight. The mixture was extracted with diethyl ether and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (ethyl acetate / hexane) to obtain the title compound as a colorless oil (0.395 g, 61.2%).

[0159] 1 H NMR (400 MHz, CDCl3) δ 4.46 (s, 2H), 4.25 (s, 2H), 3.80 (s, 3H). Step 2: Preparation of methyl 2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetate (imL18-2) A mixture of imL15-2 (0.41 g, 2.00 mmol) and imL18-1 (0.26 g, 2.00 mmol) was heated in trifluoroacetic acid (3 mL) at 80° C. overnight. The mixture was cooled to 0° C., quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane / methanol) to obtain the title compound as a white solid (0.29 g, 62.5%).

[0160] 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.16 (m, 4H), 6.04 (s, 1H), 4.84 (s, 2H), 4.52 - 4.38 (m, 1H), 4.17 (s, 2H), 3.77 (s, 3H), 3.40 (dd, J = 16.1, 6.8 Hz, 2H), 2.99 (dd, J = 16.1, 4.7 Hz, 2H). Step 3: Preparation of 2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetic acid (L18) The title compound was prepared in the same manner as in Step 4 of Example 17 using imL18-2 (0.32 g, 1.00 mmol) (yield: 91.3%).

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.2 Hz, 1H), 7.30 - 7.11 (m, 4H), 4.70 (s, 2H), 4.52 - 4.39 (m, 1H), 3.91 (s, 2H), 3.29 (dd, J = 16.1, 7.1 Hz, 2H), 2.89 (dd, J = 16.1, 5.1 Hz, 2H). Step 4: Preparation of 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethanone (23) Using L18 (30.53 mg, 0.10 mmol) and 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (22.64 mg, 0.12 mmol), the title compound was obtained as a white solid (yield: 60.2%) in the same manner as in Step 5 of Example 17.

[0162] 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.24 - 7.12 (m, 4H), 6.49 (br s, 1H), 4.86 - 4.73 (m, 2H), 4.60 - 4.49 (m, 1H), 4.48 - 4.41 (m, 1H), 4.33 - 4.18 (m, 2H), 3.80 - 3.70 (m, 1H), 3.42 - 3.33 (m, 2H), 3.17 - 3.07 (m, 1H), 3.06 - 2.93 (m, 3H), 2.83 - 2.73 (m, 1H), 2.06 - 1.95 (m, 2H), 1.79 - 1.58 (m, 2H); HRMS (ESI) m / z (M+H) + calcd for C 21 H 25 N7O2S = 462.1863; found 462.1686. [Example 24] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole trifluoroacetate (im19) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (14.7 mg, yield: 30%).

[0163] 1H NMR (400 MHz, CDCl3): δ 8.79 (s, 2H), 7.03 (t, J = 8.7 Hz, 2H), 5.71 (d, J = 7.6 Hz, 1H), 4.94 - 4.84 (m, 1H), 4.14 (d, J = 13.6 Hz, 2H), 3.49 (d, J = 4.7 Hz, 1H), 3.43 - 3.25 (m, 5H), 2.86 (dd, J = 16.0, 5.2 Hz, 2H), 2.30 (dd, J = 13.7, 3.0 Hz, 2H), 2.17 - 2.02 (m, 2H); LCMS m / z 535 [M+H] + [Example 25] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (32.5 mg, yield: 62.4%).

[0164] 1H NMR (400 MHz, CDCl3): δ 8.78 (s, 2H), 7.03 (t, J = 8.8 Hz, 2H), 6.72 - 6.98 (t, J = 52 Hz, 1H), 5.77 (d, J = 7.4 Hz, 7H), 4.89 (m, 1H), 4.13 (d, J = 13.5 Hz, 2H), 3.43 - 3.23 (m, 4H), 2.86 (dd, J = 16.0, 5.2 Hz, 2H), 2.29 (dd, J = 10.6, 3.2 Hz, 2H), 2.18 - 2.01 (m, 2H), 1.51 (dd, J = 12.0, 6.8 Hz, 1H); LCMS m / z 517[M+H] + [Example 26] Preparation of 5-(5-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 3-(piperidin-4-yl)-1,2,4-oxadiazole was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (12.6 mg, yield: 29.8%).

[0165] 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.75 (s, 2H), 8.25 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.69 (dd, J = 13.8, 7.2 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.24 (dd, J = 16.1, 7.6 Hz, 4H), 3.17 (dd, J = 9.0, 6.4 Hz, 1H), 2.88 (dd, J = 16.1, 6.5 Hz, 2H), 2.06 (d, J = 11.1 Hz, 2H), 1.83 - 1.70 (m, 2H); LCMS m / z 467[M+H] + [Example 27] Preparation of 5-(5-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 2-(piperidin-4-yl)-1,3,4-oxadiazole was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (7.6 mg, yield: 6.7%).

[0166] 1H NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.76 (d, J = 11.8 Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 9.1 Hz, 2H), 4.69 (dd, J = 15.0, 7.9 Hz, 1H), 3.95 (d, J = 12.5 Hz, 2H), 3.24 (dd, J = 18.0, 9.2 Hz, 5H), 2.88 (dd, J = 16.3, 6.2 Hz, 2H), 2.12 (d, J = 13.3 Hz, 2H), 1.81 (dd, J = 22.6, 9.9 Hz, 2H); LCMS m / z 467 [M+H] + [Example 28] Preparation of 5-(5-(4-(1H-tetrazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 4-(1H-tetrazol-1-yl)piperidine was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (20.9 mg, yield: 54.4%).

[0167] 1H NMR (400 MHz, DMSO-d6) : (DMSO-d6) δ 9.00 (s, 1H), 8.77 (d, J = 10.6 Hz, 2H), 8.27 (d, J = 6.7 Hz, 1H), 7.28 (t, J = 9.4 Hz, 2H), 5.21 (dd, J = 14.3, 8.5 Hz, 1H), 4.68 (dd, J = 14.1, 6.9 Hz, 1H), 4.02 (d, J = 13.5 Hz, 2H), 3.39 (t, J = 11.3 Hz, 2H), 3.24 (dd, J = 16.2, 7.6 Hz, 2H), 2.88 (dd, J = 16.0, LCMS m / z 467 [M+H] + [Example 29] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2,3-dihydro-1H-inden-2-amine (4a) and 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine (im21) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (3.7 mg, yield: 20%).

[0168] 1H NMR (400 MHz, CDCl3): δ 8.79 (s, 2H), 7.02 (t, J = 8.8 Hz, 2H), 5.90 (d, J = 7.7 Hz, 1H), 4.88 (dd, J = 12.6, 5.4 Hz, 1H), 4.16 (d, J = 12.9 Hz, 2H), 3.36 (dd, J = 16.0, 7.0 Hz, 2H), 3.30 - 3.20 (m, 2H), 2.88 (d, J = 5.1 Hz, 1H), 2.84 (d, J = 5.0 Hz, 1H), 2.33 (s, 3H), 2.06 - 1.90 (m, 2H), 1.52 - 1.39 (m, 2H); LCMS m / z 480 [M+H] + [Example 30] Preparation of (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-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: Preparation of ethyl (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylate (imL22-1) A mixture of imL14-1 (0.249 g, 1.17 mmol), 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (0.160 g, 0.585 mmol), diisopropylethylamine (1.5 g, 11.7 mmol) and n-BuOH (1.2 mL) was stirred for 2 hours at 150° C. using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the product was purified by column chromatography (hexane / ethyl acetate) to obtain the title compound as a brown solid (0.132 g, 65.3%).

[0169] 1H NMR (400 MHz, DMSO-d6) δ8.67 (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: Preparation of (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (L22) The same procedure as in Step 4 of Example 17 was repeated except that imL22-1 was used instead of imL14-3 to obtain the title compound as a pale yellow solid (0.90 g, 97.0%).

[0170] 1 H NMR (400 MHz, DMSO-d6) δ12.17 (bs, 1H), 8.64 (s, 2H), 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 LCMS m / z 318[M+H] + Step 3: Preparation of (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one (30) The same procedure as in step 5 of example 17 was repeated except that L22 was used instead of L14 to give the title compound as a yellow solid (0.019 g, 29.3%).

[0171] 1 H NMR (400 MHz, DMSO-d6): δ8.71 (s, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.35 (d, J = 15.3 Hz, 1H), 7.26 (t, J = 9.2 Hz, 2H), 7.21 (d, J = 15.5 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.39 (dd, J = 62.1, 11.5 Hz, 4H), 3.23 (dd, J = 16.0, 7.5 Hz, 2H), 3.00 (dd, J = 18.4, 7.4 Hz, 1H), 2.86 (dd, J = 16.2, 6.6 Hz, 2H), 1.95 (s, 2H), 1.51 (s, 2H); LCMS m / z 452[M+H] + [Example 31] Preparation of 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (31)

[0172] [ka] Step 1-1: Preparation of 4-ethynylpiperidine hydrochloride (imL23-1) tert-Butyl 4-ethynylpiperidine-1-carboxylate (12.0 g, 57.4 mmol) was dissolved in Et2O (100 mL) and cooled to 0 °C. HCl in Et2O (4 M, 100 mL) was added and the mixture was stirred for 20 h. After evaporation of Et2O and addition of PE, the solid was filtered and washed with PE and Et2O to obtain the title compound (imL23-1) as a white solid (8.3 g, yield: 99.4%).

[0173] LCMS m / z 110 [M+H] + Step 1-2: Preparation of tert-butyl (2-(4-ethynylpiperidin-1-yl)-2-oxoethyl)carbamate (imL23-2) EDCI (13.1g, 68.5mmol) and HOBt (9.2g, 68.5mmol) were added to a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (10.0g, 57.1mmol) in DMF (50mL) at 0℃, and the mixture was stirred at room temperature for 0.5 hours. imL23-1 (8.3g, 57.1mmol, HClsalt) and TEA (17.3g, 171.3mmol) were added and the mixture was stirred at room temperature overnight. The mixture was extracted with EA, washed with water and NaCl, dried over Na2SO4, filtered and concentrated to obtain the title compound (imL23-2) as a yellow oil (15.1g, yield: 99.7%).

[0174] LCMS m / z 267[M+H] + Step 1-3: Preparation of 2-amino-1-(4-ethynylpiperidin-1-yl)ethanone hydrochloride (imL23-3) imL23-2 (15.1 g, 57.1 mmol) was dissolved in Et2O (100 mL) and cooled to 0 °C. HCl in Et2O (4 M, 70 mL) was added and the mixture was stirred for 20 h. Et2O was evaporated, PE was added, and the solid was filtered and washed with PE and Et2O to obtain the title compound (imL23-3) as a white solid (17.7 g, yield: 100%).

[0175] LCMS m / z 167 [M+H] + Step 2-1: Preparation of 2-chloropyrimidine-5-carbonyl chloride (imL23-4) To a solution of 2-chloropyrimidine-5-carboxylic acid (30.0 g, 189 mmol) in DCM (200 mL), oxalyl dichloride (48.0 g, 378 mmol) and 6 drops of DMF were slowly added at 0° C., and the mixture was stirred at room temperature for 20 hours. The mixture was evaporated to obtain the title compound (imL23-4) as a white solid, which was used in the next reaction without purification (33 g, yield: 99.8%).

[0176] Step 2-2: Preparation of 2-chloro-N-(2-(4-ethynylpiperidin-1-yl)-2-oxoethyl)pyrimidine-5-carboxamide (imL23-5) To a solution of imL23-3 (17.7 g, 87.0 mmol) in DCM (400 mL), TEA (52.7 g, 522 mmol) and DMAP (600 mg) were added and stirred at room temperature for 1 hour, cooled to 0 ° C., imL23-4 (16.9 g, 95.7 mmol) was added, and stirred at room temperature overnight. Extracted with DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated. Purified by column chromatography (DCM:MeOH = 100:1 to 20:1) to obtain the title compound (imL23-5) as a yellow solid (15.8 g, yield: 59.4%).

[0177] LCMS m / z 307 [M+H] + Step 2-3: Preparation of 2-(2-chloropyrimidin-5-yl)-5-(4-ethynylpiperidin-1-yl)oxazole (imL23-6) Under argon gas, perchloroethane (46.5 g, 193.9 mmol) cooled to 0°C was added to a solution of PPh3 (51.0 g, 193.9 mmol) in DCM (400 mL), and the mixture was stirred at 0-20°C for 0.5 h. The mixture was cooled to 0°C again, imL23-5 (15.0 g, 48.9 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Na2CO3 (aq) was added to adjust the pH to 9-10, and the reaction mixture was stirred at room temperature overnight. The mixture was extracted with DCM, washed with water, NaCl, and saturated Na2CO3, dried over Na2SO4, filtered, and concentrated. The mixture was diluted with Et2O to remove the P(O)Ph3 solid, and the filtrate was concentrated and purified on an Al2O3 column (PE:EA=20:1-10:1-DCM:EA=100:0-20:1) to obtain 7.3 g of a yellow solid. (Crude, 88% purity) Again, purified with Al2O3 column (0.1% TEA) (PE:EA = 50:1 to 1:1) to obtain 5.3 g of a yellow solid, which was purified with PE to obtain the title compound (imL23-6) as a yellow solid (5.2 g, yield: 36.9%).

[0178] 1 H NMR (400 MHz, CDCl3): δ 9.04 (s, 2H), 6.21 (s, 1H), 3.44-3.50 (m, 2H), 3.10-3.16 (m, 2H), 2.68-2.70 (m, 1H), 2.15 (brs, 1H), 1.95-2.01 (m, 2H), 2.12-2.06 (m, 2H), 1.80-1.87 (m, 2H); LCMS m / z 289 [M+H] + Step 2-4: Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl)oxazol-2-yl)pyrimidin-2-amine (L23) A mixture of 2-aminoindan (0.703 g, 4.16 mmol), imL23-6 (1 g, 3.46 mmol), triethylamine (1.2 mL, 8.30 mmol) and dioxane (35 mL) was stirred for 1 h at 100° C. After cooling, the solvent was evaporated and the product was purified by column chromatography (hexane / ethyl acetate) to obtain the title compound as a brown solid (0.190 g, 14.2%).

[0179] Step 2-5: Preparation of 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)oxazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (31) To a solution of L23 (0.145 g, 0.376 mmol) in DMF / MeOH (3.4 mL / 0.38 mL), benzyl azide, 0.5 M solution in DCM (502 μL, 0.564 mmol), CuI (0.115 g, 0.602 mmol) and DIPEA (128 μL, 0.564 mmol) were added and stirred at 40° C. for 1 h. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography (DCM / MeOH) to give the title compound as a brown solid (1.3 mg, 6.7%).

[0180] 1H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 2H), 8.01 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.37 - 7.26 (m, 5H), 7.16 (d, J = 21.5 Hz, 4H), 6.23 (s, 1H), 5.53 (s, 2H), 3.57 (d, J = 12.6 Hz, 1H), 3.24 (dd, J = 15.1, 7.8 Hz, 4H), 2.91 (d, J = 7.8 Hz, 2H), 2.87 (t, J = 7.0 Hz, 3H), 2.00 (d, J = 12.8 Hz, 2H), 1.69 (dd, J = 13.4, 4.6 Hz, 2H); LCMS m / z 519[M+H] + [Example 32] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

[0181] [ka] Step 1: Preparation of 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one (L26) To a solution of 7e (20 mg, 0.060 mmol) in DMF (0.6 mL), NaH (60%) (7.2 mg, 0.181 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30 min., and CH3I (11 μL, 0.181 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (L26) as a white solid (9.9 mg, yield: 47.5%).

[0182] LCMS m / z 346[M+H]+ Step 2: Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine (32) L26 (8.1 mg, 0.024 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (3-1) (7.0 mg, 0.028 mmol), BOP reagent (12.4 mg, 0.028 mmol) and DIPEA (12 μL, 0.070 mmol) were dissolved in DMF (0.1 mL) and stirred at room temperature for 6 hours. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The title compound (32) was obtained as a white solid (1.5 mg, yield: 13.3%) by column chromatography (DCM / MeOH).

[0183] 1 H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 2H), 7.69 (s, 1H), 7.31 (t, J = 9.2 Hz, 2H), 5.75 (dt, J = 15.4, 7.9 Hz, 1H), 3.97 (d, J = 13.2 Hz, LCMS m / z 480 [M+H] + [Example 33] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

[0184] [ka] Step 1-1: Preparation of azidomethyl pivalate (im27-1) To a solution of chloromethyl pivalate (1 g, 6.64 mmol) in H2O (1.7 mL) was added NaN3 (0.648 g, 9.96 mmol), and the mixture was stirred at 90 °C overnight. The reaction mixture was diluted with water, extracted with EA, dried over Na2SO4, filtered, and concentrated. The title compound (im27-1) was obtained as a colorless liquid (1 g, yield: 96%) and used in the next reaction without purification.

[0185] Step 1-2: Preparation of tert-butyl 4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (im27-2) To a solution of im27-1 (1 g, 6.36 mmol) and tert-butyl 4-ethynyl-1-piperidinecarboxylate (1.3 g, 6.36 mmol) in THF / H2O (12.7 mL), CuOAc (78.0 mg, 0.636 mmol) and NaOAc (1.7 g, 19.1 mmol) were added and stirred at room temperature for 4 hours. The reaction mixture was extracted with EA, and the organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (im27-2) as a pale green oil (1.18 g, yield: 51%).

[0186] 1 H NMR (400 MHz, CDCl3):δ 7.53 (s, 1H), 6.20 (s, 2H), 4.15 (s, 2H), 2.88 (dd, J = 26.4, 13.4 Hz, 2H), 2.02 (d, J = 13.1 Hz, 2H), 1.65 - 1.56 (m, 3H), 1.46 (s, 9H), 1.18 (s, 9H). Step 1-3: Preparation of (4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate trifluoroacetate (im27) To a solution of im27-2 (0.658 g, 1.80 mmol) in DCM (17.9 mL) was added TFA (6.0 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (im27) as a white solid (0.493 g, yield: 74.9%), which was used in the next reaction without purification.

[0187] Step 2-1: Preparation of (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (L27) To a solution of 7e (0.374 mg, 1.13 mmol) in DMF (5.6 mL), im27 (0.494 g, 1.35 mmol) was added, cooled to 0° C., and DIPEA (576 μL, 3.39 mmol) was added. The mixture was stirred at 0° C. for 30 min, and then BOP reagent (0.599 g, 1.35 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (L27) as a yellow solid (0.344 g, yield: 52.61%).

[0188] LC / MS m / z 580[M+H] + Step 2-2: Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (33) L27 (0.25 g, 0.431 mmol) and MeOTf (57 μL, 0.518 mmol) were dissolved in DCM (500 μL) and stirred at room temperature overnight. The reaction mixture was dissolved in MeOH (2.2 mL), and K2CO3 (0.119 g, 1.24 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was filtered and washed with DCM, and the filtrate was concentrated to obtain a residue, which was purified by column chromatography (DCM / MeOH) to obtain the title compound (33) as a yellow solid (17.7 mg, yield: 6.9%).

[0189] 1 H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 2H), 8.25 (d, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.27 (t, J = 9.4 Hz, 2H), 4.69 (dd, J = 12.8, 5.5 Hz, 1H), 4.03 (d, J = 12.5 Hz, 1H), 3.99 (s, 3H), 3.24 (dd, J = 16.1, 8.0 Hz, 4H), 3.06 (t, J = 11.8 Hz, 2H), 2.91 - 2.85 (m, 2H), 1.95 (d, J = 13.7 Hz, 2H), 1.64 (dd, J = 23.9, 11.1 Hz, 2H); LCMS m / z 480 [M+H] + [Example 34] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine

[0190] [ka] Step 1: Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (L28) 4-Ethynylpiperidine trifluoroacetate (0.150 g, 0.724 mmol) was added to a solution of 7e (0.2 g, 0.603 mmol) in DMF (3.1 mL), cooled to 0° C., and DIPEA (308 μL, 1.81 mmol) was added. The mixture was stirred at 0° C. for 30 min, and then BOP reagent (0.320 g, 0.724 mmol) was added and stirred at room temperature for 3 h. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (L28) as a white solid (0.101 g, yield: 39.6%).

[0191] LCMS m / z 423[M+H] + Step 2: Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (34) MeI (33 mg, 0.232 mmol) and NaN3 (15.1 mg, 0.697 mmol) were dissolved in THF / H2O (v / v=1:1, 2.3 mL) and stirred at room temperature overnight. L28 (98 mg, 0.232 mmol), CuOAc (2.9 mg, 0.023 mmol) and NaOAc (57.2 mg, 0.697 mmol) were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was extracted with EA, and the organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (34) as a yellow solid (1.6 mg, yield: 1.4%).

[0192] 1H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 2H), 8.24 (d, J = 6.8 Hz, 1H), 7.87 (s, 1H), 7.27 (t, J = 9.4 Hz, 2H), 4.68 (dd, J = 13.8, 6.9 Hz, 1H), 3.97 (s, 5H), 3.24 (dd, J = 15.9, 7.3 Hz, 4H), 2.96 (d, J = 11.0 Hz, 1H), 2.88 (dd, J = 16.2, 6.5 Hz, 2H), 2.00 (d, J = 11.5 Hz, 2H), 1.66 (dd, J = 20.0, 11.1 Hz, 2H); LCMS m / z 480 [M+H] + [Example 35] Preparation of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35)

[0193] [ka] Step 1: Preparation of N-(2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidin-2-amine (imL24-1) 2-Aminoindan (1 g, 7.508 mmol), 2-chloro-5-vinylpyrimidine (0.704 g, 5.005 mmol), and DIPEA (17 mL, 100.1 mmol) were dissolved in 10 mL of n-BuOH and reacted in a microwave reactor for 2 hours. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated. The resulting residue was adsorbed onto silica gel and purified by silica gel column chromatography (15% EA in hexane) to obtain the title compound (imL24-1) as a white solid (0.837 g, yield: 47%).

[0194] LCMS m / z 238 [M+H] + Step 2: Preparation of 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (L24) 1,1-Dibromoformaldoxime (0.960g, 6.742mmol) was dissolved in DMF (7mL) and cooled to -10℃. A solution of imL24-1 (0.8g, 3.371mmol) and KHCO3 (0.843g, 8.428mmol) dissolved in H2O (7mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the reaction mixture was extracted with EtOAc (3 times), and the organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the obtained residue was adsorbed on silica gel and purified by silica gel column chromatography (25% EA in hexane) to obtain the title compound (L24) as a yellow solid (0.905g, yield: 74.8%).

[0195] 1 H NMR (400 MHz, CDCl3): δ 8.28 (s, 2H), 7.25 - 7.16 (m, 4H), 5.56 - 5.51 (m, 1H), 4.84 - 4.77 (m, 1H), 3.60 - 3.52 (m, 1H), 3.44 - 3.34 (m, 2H), 3.21 (dd, J = 17.3, 9.4 Hz, 1H), 2.92 - 2.83 (m, 2H); LCMS m / z 360 [M+H] + Step 3: Preparation of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (L24) (20 mg, 0.0557 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) (12.6 mg, 0.0668 mmol), and Na2CO3 (14.8 mg, 0.139 mmol) were dissolved in 1 mL of t-BuOH and reacted in a microwave reactor for 1 h. After confirming the completion of the reaction by TLC, the reaction was filtered and washed with a 10% MeOH solution in DCM. The filtrate was concentrated, and the residue was adsorbed on silica gel and purified by silica gel column chromatography (5% MeOH in DCM) to obtain the title compound (35) as a yellow solid (10.8 mg, yield: 45.1%).

[0196] 1 H NMR (400 MHz, CDCl3):δ 8.31 (s, 2H), 7.65 (s, 1H), 7.58 (d, J = 7.0 Hz, 1H), 7.15 (td, J = 8.3, 3.2 Hz, 4H), 5.25 (t, J = 9.4 Hz, 1H), 4.62 - 4.55 (m, 1H), 3.59 (d, J = 14.2 Hz, 2H), 3.25 - 3.10 (m, 4H), 2.99 - 2.81 (m, 5H), 1.91 (d, J = 14.6 Hz, 2H), 1.62 (d, J = 9.0 Hz, 2H); LCMS m / z 431 [M+H] + [Example 36] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (29.8 mg, 0.0692 mmol), I2 (26.3 mg, 0.104 mmol), and imidazole (14.1 mg, 0.208 mmol) were dissolved in toluene (3 mL) and stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was diluted with EA, and 10% Na2S2O4 was added and stirred for 10 min. The reaction mixture was adjusted to pH 8-10 by adding 1N NaOH, and then extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was adsorbed onto silica gel and then purified by silica gel column chromatography (2% MeOH in DCM) to obtain the title compound (36) as a white solid (12.8 mg, yield: 44.3%).

[0197] 1 H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 2H), 8.12 (d, J = 6.3 Hz, 1H), 7.22 - 7.10 (m, 4H), 6.73 (s, 1H), 4.66 (d, J = 6.8 Hz, 1H), 3.71 (d, J = 13.0 Hz, 2H), 3.25 (dd, J = 15.9, 7.6 Hz, 3H), 3.00 (d, J = 12.1 Hz, 2H), 2.90 (dd, J = 15.8, 7.0 Hz, 2H), 1.95 (s, 2H), 1.67 (d, J = 9.8 Hz, 2H); LCMS m / z 429 [M+H] + [Example 37] Preparation of N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine The title compound was obtained (7.3 mg, yield: 30.9%) in the same manner as in Example 35, except that 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2-aminoindan.

[0198] 1 H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.66 - 7.60 (m, 2H), 7.25 (t, J = 9.2 Hz, 2H), 5.26 (t, J = 9.2 Hz, 1H), 4.61 (dd, J = 14.0, 7.3 Hz, 1H), 3.59 (d, J = 13.2 Hz, 2H), 3.20 (dd, J = 15.9, 7.3 Hz, 2H), 3.17 - 3.09 (m, 2H), 2.98 - 2.88 (m, 3H), 2.83 (dd, J = 15.9, 6.8 Hz, 2H), 1.91 (d, J = 11.7 Hz, 2H), 1.62 (d, J = 13.4 Hz, 2H); LCMS m / z 467 [M+H] + [Example 38] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained in the same manner as in Example 36, except that N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (Example 37) was used instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) (9.2 mg, yield: 71.6%).

[0199] 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.13 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 23.5 Hz, 1H), 7.27 (t, J = 9.2 Hz, 2H), 6.73 (s, 1H), 4.68 (dd, J = 13.8, 6.9 Hz, 1H), 3.71 (d, J = 12.9 Hz, 2H), 3.24 (dd, J = 16.2, 7.5 Hz, 2H), 3.02 - 2.94 (m, 2H), 2.87 (dd, J = 16.2, 6.5 Hz, 2H), 1.97 (d, J = 12.5 Hz, 3H), 1.72 - 1.60 (m, 2H); LCMS m / z 465 [M+H] + [Example 39] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained (3.1 mg, yield: 17.5%) in the same manner as in Example 35, except that 5-fluoro-2,3-dihydro-1H-inden-2-amine (4b) was used instead of 2-aminoindan.

[0200] 1 H NMR (400 MHz, CDCl3): δ 8.35 (s, 2H), 7.53 (s, 1H), 7.11 - 7.19 (m, 1H), 6.82 - 6.97 (m, 2H), 5.49 (d, J = 6.8 Hz, 1H), 5.40 (t, J = 8.9 Hz, 1H), 4.87 - 4.77 (m, 1H), 3.73 (dd, J = 13.2, 3.1 Hz, 2H), 3.36 (m, 3H), 3.11 - 2.93 (m, 4H), 2.84 (td, J = 15.6, 5.1 Hz, 2H), 2.02 - 2.08 (m, 2H), 1.75 - 1.85 (m, 2H); LCMS m / z 449 [M+H] + [Example 40] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained by preparing in the same manner as in Example 36, except that 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Example 39) was used instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) was used to obtain the title compound (20.3 mg, yield: 58%).

[0201] 1 H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 8.02 (d, J = 6.7 Hz, 1H), 7.57 (s, 1H), 7.16 - 7.23 (m, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.89 (t, J = 8.7 Hz, 1H), 6.60 (s, 1H), 4.81 - 4.66 (m, 1H), 3.78 (d, J = 12.8 Hz, 2H), 3.42 - 3.21 (m, 3H), 2.96 (m, 2H), 2.02 (d, J = 10.9 Hz, 2H), 1.75 (m, 2H); LCMS m / z 447 [M+H] + [Example 41] Preparation of N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine The title compound was obtained (8.3 mg, yield: 18.2%) in the same manner as in Example 35, except that (3,5-difluorophenyl)methanamine was used instead of 2-aminoindan.

[0202] 1 H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.89 (t, J = 6.5 Hz, 1H), 7.65 (bs, 1H), 7.04 (t, J = 9.6 Hz, 1H), 6.97 (d, J = 6.7 Hz, 2H), 5.24 (t, J = 9.1 Hz, 1H), 4.49 (d, J = 6.2 Hz, 2H), 3.57 (d, J = 12.8 Hz, 2H), 3.13 (dd, J = 15.9, 9.3 Hz, 2H), 2.96 - 2.87 (m, 3H), 1.90 (d, J = 12.6 Hz, 2H), 1.61 (dd, J = 23.3, 14.4 Hz, 2H); LCMS m / z 441 [M+H] + [Example 42] Preparation of N-benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine The title compound was obtained (6.2 mg, yield: 12.8%) in the same manner as in Example 35, except that phenylmethanamine was used instead of 2-aminoindan.

[0203] 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.82 (t, J = 6.4 Hz, 1H), 7.64 (bs, 1H), 7.27 (d, J = 4.3 Hz, 4H), 7.19 (dd, J = 8.5, 4.2 Hz, 1H), 5.23 (t, J = 9.4 Hz, 1H), 4.48 (d, J = 6.4 Hz, 2H), 3.57 (d, J = 12.9 Hz, 2H), 3.12 (dd, J = 15.9, 9.2 Hz, 2H), 2.97 - 2.86 (m, 3H), 1.90 (d, J = 11.6 Hz, 2H), 1.61 (dd, J = 21.2, 11.8 Hz, 2H); LCMS m / z 405 [M+H] + [Example 43] Preparation of N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine The title compound was obtained (9.7 mg, yield: 20.3%) in the same manner as in Example 35, except that (3,4-difluorophenyl)methanamine was used instead of 2-aminoindan.

[0204] 1 H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.85 (t, J = 6.3 Hz, 1H), 7.64 (s, 1H), 7.32 (dt, J = 17.3, 7.3 Hz, 2H), 7.12 (s, 1H), 5.24 (t, J = 9.2 Hz, 1H), 4.45 (d, J = 6.1 Hz, 2H), 3.57 (d, J = 12.7 Hz, 2H), 3.12 (dd, J = 15.6, 9.4 Hz, 2H), 2.91 (dd, J = 24.4, 11.8 Hz, 3H), 1.90 (d, J = 12.0 Hz, 2H), 1.61 (dd, J = 20.6, 10.6 Hz, 2H); LCMS m / z 441 [M+H] + [Example 44] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine The title compound was obtained (4.8 mg, yield: 10.2%) in the same manner as in Example 35, except that (3,5-dichlorophenyl)methanamine was used instead of 2-aminoindan.

[0205] 1H NMR (400 MHz, DMSO-d6):δ 8.30 (s, 2H), 7.90 (t, J = 6.4 Hz, 1H), 7.62 (bs, 1H), 7.43 (s, 1H), 7.32 (s, 2H), 5.24 (t, J = 9.2 Hz, 1H), 4.48 (d, J = 6.4 Hz, 2H), 4.09 (dd, J = 10.5, 5.2 Hz, 1H), 3.57 (d, J = 12.8 Hz, 2H), 3.15 (d, J = 5.3 Hz, 2H), 2.96 - 2.88 (m, 2H), 1.90 (d, J = 10.3 Hz, 2H), 1.66 - 1.56 (m, 2H); LCMS m / z 474 [M+H] + [Example 45] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine The title compound was obtained (5.1 mg, yield: 10.7%) in the same manner as in Example 35, except that benzo[d][1,3]dioxol-5-ylmethanamine was used instead of 2-aminoindan.

[0206] 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.76 (t, J = 6.2 Hz, 1H), 7.62 (bs, 1H), 6.85 - 6.78 (m, 2H), 6.75 (d, J = 7.7 Hz, 1H), 5.94 (s, 2H), 5.23 (t, J = 9.0 Hz, 1H), 4.37 (d, J = 6.1 Hz, 2H), 3.57 (d, J = 12.8 Hz, 2H), 3.12 (dd, J = 15.9, 9.3 Hz, 2H), 2.96 - 2.88 (m, 3H), 1.90 (d, J = 12.8 Hz, 2H), 1.61 (dd, J = 19.9, 10.1 Hz, 2H); LCMS m / z 449 [M+H]+ [Example 46] Preparation of N-(1,3-benzodioxol-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]isoxazol-5-yl]pyrimidin-2-amine The title compound was obtained in the same manner as in Example 36, except that 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine (Example 45) was used instead of N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine (35) was used to obtain the title compound (3.4 mg, yield: 21%).

[0207] 1 H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 2H), 8.25 (t, J = 5.9 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 5.95 (s, 2H), 4.43 (d, J = 6.5 Hz, 2H), 3.70 (d, J = 12.5 Hz, 2H), 3.48 (s, 1H), 3.02 - 2.93 (m, 3H), 1.96 (d, J = 9.8 Hz, 2H), 1.66 (dd, J = 20.8, 12.7 Hz, 2H); LCMS m / z 447 [M+H] + [Example 47] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine The title compound was prepared and obtained in the same manner as in Example 35, except that 2-(3,5-dichlorophenyl)ethan-1-amine was used instead of 2-aminoindan (5.8 mg, yield: 12.4%).

[0208] 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 2H), 7.99 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.29 (s, 2H), 5.24 (t, J = 9.4 Hz, 1H), 3.49 (dd, J = 12.0, 6.3 Hz, 4H), 3.17 - 3.11 (m, 2H), 2.95 (d, J = 12.9 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 1.91 (d, J = 17.4 Hz, 3H), 1.62 (d, J = 10.8 Hz, 2H); LCMS m / z 487 [M+H] + [Example 48] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidin-2-amine The title compound was obtained (15.3 mg, yield: 32.6%) in the same manner as in Example 35, except that (3-(methylsulfonyl)phenyl)methanamine was used instead of 2-aminoindan.

[0209] 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 2H), 7.96 (t, J = 6.5 Hz, 1H), 7.85 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 5.24 (t, J = 9.2 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 3.57 (d, J = 12.8 Hz, 2H), 3.31 (dd, J = 15.6, 9.1 Hz, 1H), 3.17 (s, 3H), 2.91 (dd, J = 22.5, LCMS m / z 483 [M+H] + [Example 49] Preparation of 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidin-2-amine The title compound was obtained (13.2 mg, yield: 28.1%) in the same manner as in Example 35, except that (4-(methylsulfonyl)phenyl)methanamine was used instead of 2-aminoindan.

[0210] 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 2H), 7.97 (dd, J = 9.6, 3.2 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.63 (bs, 1H), 7.52 (d, J = 8.2 Hz, 2H), 5.23 (t, J = 9.2 Hz, 1H), 4.61 - 4.54 (m, 2H), 3.57 (d, J = 12.8 Hz, 2H), 3.31 (dd, J = 15.9, 9.3 Hz, 2H), 3.15 (d, J = 2.1 Hz, 3H), 3.13 - 3.08 (m, 1H), 2.96 - 2.88 (m, 2H), 1.90 (d, J = 12.3 Hz, 2H), 1.61 (dd, J = 21.0, 12.2 Hz, 2H); LCMS m / z 483 [M+H] + [Example 50] Preparation of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained (15.7 mg, yield: 65.4%) in the same manner as in Example 35, except that 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0211] 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 2H), 7.59 (d, J = 6.5 Hz, 1H), 7.15 (d, J = 20.3 Hz, 4H), 5.26 (t, J = 9.6 Hz, 1H), 4.62 - 4.57 (m, 1H), 4.08 (s, 1H), 3.59 (d, J = 12.9 Hz, 1H), 3.20 (dd, J = 14.3, 6.8 Hz, 3H), 3.15 (s, 2H), 3.02 - 2.93 (m, 2H), 2.89 - 2.82 (m, 2H), 1.95 (t, J = 11.6 Hz, 2H), 1.74 (d, J = 13.6 Hz, 2H); LCMS m / z 432 [M+H] + [Example 51] Preparation of 5-(3-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained in the same manner as in Example 35, except that 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (im20) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine.HCl (3) (3.7 mg, yield: 13.8%).

[0212] 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 1H), 7.59 (t J = 134.0 Hz, 1H), 7.59 ( J = 6.6 Hz, 1H), 7.20 - 7.10 (m, 4H), 5.26 (t, J = 9.4 Hz, 1H), 4.59 (d, J = 7.1 Hz, 1H), 3.58 (d, J = 13.1 Hz, 2H), 3.26 - 3.11 (m, 5H), 3.05 - 2.95 (m, 2H), 2.86 (dd, J = 15.7, 6.6 Hz, 2H), 2.01 (dd, J = 25.3, 16.9 Hz, 3H), 1.77 (d, J = 9.4 Hz, 1H); LCMS m / z 482 [M+H] + [Example 52] Preparation of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained in the same manner as in Example 35, except that in step 1, 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e) was used instead of 2-aminoindan, and in step 3, 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) was used, to obtain the title compound (18.7 mg, yield: 79%).

[0213] 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 2H), 7.62 (d, J = 6.5 Hz, 1H), 7.25 (t, J = 9.5 Hz, 2H), 5.26 (t, J = 9.4 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 3.59 (d, J = 12.8 Hz, 2H), 3.20 (dd, J = 16.2, 7.8 Hz, 5H), 3.01 - 2.93 (m, 2H), 2.83 (dd, J = 15.8, 7.0 Hz, 2H), 1.98 - 1.91 (m, 2H), 1.73 (dd, J = 22.3, 13.3 Hz, 2H); LCMS m / z 468 [M+H] + [Example 53] Preparation of N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine Step 1: Preparation of 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine The title compound was obtained in the same manner as in Example 35, except that in step 1, 5-fluoro-2,3-dihydro-1H-inden-2-amine (4b) was used instead of 2-aminoindan, and in step 3, 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) was used, to obtain the title compound (15.4 mg, yield: 46%).

[0214] LCMS m / z 450 [M+H] + Step 2: Preparation of N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)pyrimidin-2-amine 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (9.3 mg, 0.021 mmol) was dissolved in DCM, and trifluoroacetic anhydride (6.5 mg, 0.031 mmol) was added dropwise at 0° C., and the mixture was warmed to room temperature and stirred overnight. Trifluoroacetic anhydride (0.1 ml) was added and stirred for 2 hours, and the reaction mixture was extracted with DCM, and the organic layer was washed with saturated NaHCO3 aqueous solution, water, and brine. After drying over MgSO4, the residue obtained by filtration and concentration was purified by Prep-TLC (5% MeOH in DCM) to obtain the title compound (0.5 mg, yield: 4.7%).

[0215] 1 H NMR (400 MHz, CDCl3): δ 8.33 (s, 2H), 7.15 (m, 1H), 6.97 - 6.81 (m, 2H), 5.42 (m, 2H), 4.81 (m, 1H), 3.73 (d, J = 13.6 Hz, 2H), 3.35 LCMS m / z 518 [M+H] + [Example 54] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 11, except that 7e was used instead of 7d (yield: 8%).

[0216] 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 2H), 7.54 (s, 1H), 7.51 (s, 1H), 7.03 (t, J = 8.8 Hz, 2H), 5.68 (d, J = 7.6 Hz, 1H), 4.94 - 4.84 (m, 1H), 4.60 - 4.47 (m, 1H), 4.04 (dd, J = 13.4, 3.1 Hz, 1H), 3.41 - 3.34 (m, 3H), 3.31 - 3.24 (m, 1H), 2.86 (dd, J = 16.0, 5.3 Hz, 2H), 2.03 (d, J = 4.4 Hz, 2H), 1.81 (dd, J = 12.9, 4.8 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H); MS (ESI, m / z) calculated for C 23 H 24 F2N9O [M+H] + 480.21, found 480.15. [Example 55] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that benzo[d][1,3]dioxol-5-ylmethanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 46%).

[0217] 1H NMR (400 MHz, CDCl3) δ 12.36 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 6.86 - 6.75 (m, 3H), 5.95 (s, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.14 (dt, J = 13.6, 3.7 Hz, 2H), 3.27 (ddd, J = 13.2, 11.8, 2.9 Hz, 2H), 3.06 (tt, J = 11.4, 3.7 Hz, 1H), 2.19 - 2.13 (m, 2H), 1.95 - 1.84 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 163.93, 162.18, 156.08, 155.79, 150.40, 147.95, 147.03, 132.12, 130.02, 120.89, 109.48, 108.36, 108.25, 101.10, 46.34, 45.42, 32.56, 30.65; HRMS (ESI, m / z) calculated for C 21 H 22 N9O3[M+H] + 448.1840, found 448.1841. [Example 56] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that (3,4-dichlorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 36%).

[0218] 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 2H), 7.54 (s, 1H), 7.47 - 7.38 (m, 2H), 7.21 - 7.17 (m, 1H), 5.88 (t, J = 6.2 Hz, 1H), 4.67 (d, J = 6.3 HRMS (ESI, m / z) calculated for C 20 H 20 Cl2NO [M+H] + 472.1162, found 472.1162. [Example 57] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that (3,4-difluorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 40%).

[0219] 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 2H), 7.52 (s, 1H), 6.92 - 6.87 (m, 2H), 6.71 (tt, J = 8.9, 2.3 Hz, 1H), 4.67 (s, 2H), 4.14 - 4.09 (m, 2H), 3.29 (ddd, J = 13.2, 11.9, 2.9 Hz, 2H), 3.07 (tt, J = 11.5, 3.6 Hz, 1H), 2.20 - 2.14 (m, 2H), 1.92 - 1.82 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 163.99, 163.39 (q, J = 12.8 Hz), 162.41, 156.13, 156.05, 149.06, 143.21, 128.77 - 127.05 (m), 110.17 (dd, J = HRMS (ESI, m / z) calculated for C 20 H 20 F2N9O [M+H] + 440.1753, found 440.1755. [Example 58] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that (3,4-difluorophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 43.4%).

[0220] 1 H NMR (400 MHz, CD3OD) δ 8.77 (s, 2H), 7.51 (s, 1H), 7.22 - 7.07 (m, 3H), 4.64 (s, 2H), 4.12 (dt, J = 13.3, 3.5 Hz, 2H), 3.32 - 3.25 (m, 2H), 3.07 (ddt, J = 11.5, 7.8, 3.7 Hz, 1H), 2.20 - 2.14 (m, 2H), 1.87 (td, J = 12.0, 7.8 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 163.96, 162.32, 156.11, 156.00, 151.38 (dd, J = 74.0, 12.7 Hz), 149.02, 148.91 (dd, J = 60.1, 12.7 Hz), 135.93 (dd, J = 5.2, 3.7 Hz), 127.67, 123.55 (dd, J = 6.3, 3.6 Hz), 117.00 (dd, J = 90.3, 17.4 Hz), 109.33, 46.43, 44.37 (d, J = 1.5 Hz), 32.47, 30.83; HRMS (ESI, m / z) calculated for C 20 H 20 F2N9O + [M+H] + 440.1753, found 440.1754. [Example 59] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that (3,5-dibromophenyl)methanamine was used instead of 2,3-dihydro-1H-inden-2-amine (yield: 31.7%).

[0221] 1 H NMR (400 MHz, CD3OD) δ 8.78 (s, 2H), 7.57 (t, J = 1.8 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 1.7 Hz, 2H), 4.64 (s, 2H), 4.15 - 4.07 (m, 2H), 3.32 - 3.22 (m, 2H), 3.12 - 3.01 (m, 1H), 2.20 - 2.13 (m, 2H), 1.92 - 1.82 (m, 2H).; 13C NMR (100 MHz, CD3OD) δ 163.99, 162.31, 156.12, 156.05, 149.16, 143.10, 133.05, 129.37, 127.61, 123.22, 109.49, 46.45, 44.25, 32.48, 30.85; HRMS (ESI, m / z) calculated for C 20 H 20 Br2N9O + [M+H] + 560.0152, found 560.0132. [Example 60] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5-bromo-2,3-dihydro-1H-inden-2-amine (4d) was used instead of 2,3-dihydro-1H-inden-2-amine, and ethyl 2-chloro-4-methylpyrimidine-5-carboxylate was used instead of 2-chloropyrimidine-5-carboxylate (yield: 52%).

[0222] 1 H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 7.53 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.0, 1.9 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.15 - 4.08 (m, 4H), 3.43 - 3.38 (m, 1H), 3.34 - 3.32 (m, 1H), 3.30 - 3.26 (m, 1H), 3.08 (tt, J = 11.5, 3.7 Hz, 1H), 2.95 - 2.84 (m, 2H), 2.68 (s, 3H), 2.20 - 2.13 (m, 2H), 1.94 - 1.83 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 167.27, 163.85, 161.29, 157.08, 143.75, 140.30, 129.94, 128.07, 126.46, 120.51, 108.11, 52.82, 46.46, 39.90, 39.52, 32.52, 30.89, 24.59; HRMS (ESI, m / z) calculated for C 23 H 25 BrNO [M+H] + 522.1360, found 522.1359. [Example 61] Preparation of 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine The title compound was prepared in the same manner as in Example 1, except that 5,6-dibromo-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 2-chloropyrimidine-5-carboxylate (yield: 50%).

[0223] 1 H NMR (400 MHz, CDCl3) δ 11.96 (s, 1H), 8.63 (s, 1H), 7.54 (s, 1H), 7.49 (s, 2H), 5.65 (d, J = 7.5 Hz, 1H), 4.89 (d, J = 6.6 Hz, 1H), 4.16 - 4.11 (m, 2H), 3.38 - 3.24 (m, 4H), 3.07 (ddt, J = 11.5, 7.8, 3.7 Hz, 1H), 2.85 (dd, J = 16.3, 5.4 Hz, 2H), 2.71 (s, 3H), 2.19 - 2.13 (m, 2H), 1.95 - 1.85 (m, 2H); MS (ESI, m / z) calculated for C 23 H 24 BrNO [M+H]+ 600.04, found 600.05. [Example 62] Preparation of 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine 1-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one (Example 17, 0.47mmol) was dissolved in DMF, cooled to 0°C, and lithium aluminum hydride (LiAl4, 0.10mmol) in ACN was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then quenched with 1N HCl, adjusted to pH 7-8 with aqueous Na2CO3, and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (yield: 45%).

[0224] 1 H NMR (400 MHz, CD3OD): δ 8.17 (s, 2H), 7.55 (s, 1H), 7.25 - 7.20 (m, 2H), 7.18 - 7.13 (m, 2H), 4.75 - 4.72 (m, 1H), 3.41 - 3.35 (m, 2H), 3.14 - 3.08 (m, 2H), 2.94 - 2.84 (m, 3H), 2.58 - 2.50 (m, 4H), 2.33 (t, J = 11.7 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.90 - 1.78 (m, 4H); 13 C NMR (100 MHz, CD3OD) δ 161.24, 158.39, 148.90, 141.74, 127.35, 127.10, 125.17, 123.42, 58.21, 53.74, 53.12, 40.38, 32.70, 31.52, 28.14, 27.70; MS (ESI, m / z) calculated for C 23 H30 N7 + [M+H] + 404.26, found 404.30. [Example 63] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine The title compound was obtained as a white solid (14.8 mg, yield: 33.8%) by the same procedure as in Example 1, except that 4-(piperidin-4-yl)morpholine was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0225] 1 H NMR (400 MHz, DMSO-d6): δ8.73 (s, 2H), 8.24 (d, J = 6.5 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dd, J = 13.7, 7.0 Hz, 1H), 3.93 (d, J = 13.0 Hz, 2H), 3.59 - 3.48 (m, 4H), 3.24 (dd, J = 16.1, 7.6 Hz, 2H), 3.06 (t, J = 11.4 Hz, 2H), 2.87 (dd, J = 16.1, 6.5 Hz, 2H), 2.46 - 2.35 (m, 4H), 1.84 (d, J = LCMS m / z 484[M+H] + [Example 64] Preparation of 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol The title compound was obtained as a beautiful solid (25.1 mg, yield: 59%) by the same procedure as in Example 1, except that 1-(piperidin-4-yl)azetidin-3-ol was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0226] 1 H NMR (400 MHz, DMSO-d6): δ8.73 (s, 2H), 8.23 ​​(d, J = 6.8 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 5.31 (d, J = 3.2 Hz, 1H), 4.68 (dd, J = 14.0, 7.2 Hz, 1H), 4.23 - 3.99 (m, 2H), 3.74 (dd, J = 7.7, 5.4 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.30 (s, 2H), 3.23 (dd, J = 16.1, 7.5 Hz, 2H), 3.19 - 3.12 (m, 2H), 2.87 (dd, J = 15.9, 6.5 Hz, 2H), 2.74 (s, 1H), 2.25 (s, 1H), 1.71 (d, J = 10.5 Hz, 2H), 1.23 (d, J = 12.6 Hz, 2H); LCMS m / z 470[M+H] + [Example 65] Preparation of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-sulfonamide The title compound was obtained as a white solid (20.7 mg, yield: 47.9%) by the same procedure as in Example 1, except that piperidine-4-sulfonamide was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0227] 1H NMR (400 MHz, DMSO-d6): δ8.76 (d, J = 12.8 Hz, 2H), 8.26 (d, J = 6.9 Hz, 1H), 7.27 (t, J = 9.4 Hz, 2H), 6.82 (s, 2H), 4.68 (dd, J = 14.1, 7.0 Hz, 1H), 4.04 (d, J = 12.9 Hz, 2H), 3.24 (dd, J = 16.1, 7.5 Hz, 2H), 3.13 (t, J = 11.4 Hz, 3H), 2.87 (dd, J = 16.0, 6.5 Hz, 2H), 2.08 (d, J = 12.4 Hz, 2H), 1.64 (qd, J = 12.6, 4.5 Hz, 2H); LCMS m / z 478[M+H] + [Example 66] Preparation of 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one The title compound was obtained as a white solid (10.9 mg, yield: 24.9%) by the same procedure as in Example 1, except that 5-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine.HCl (3).

[0228] 1H NMR (400 MHz, DMSO-d6): δ12.14 (s, 1H), 8.75 (d, J = 9.9 Hz, 2H), 8.26 (d, J = 4.1 Hz, 1H), 7.28 (t, J = 8.8 Hz, 2H), 4.68 (d, J = 4.9 Hz, 1H), 3.92 (d, J = 13.0 Hz, 2H), 3.21 (t, J = 12.3 Hz, 4H), 2.83 (dd, J = 34.8, 13.5 Hz, 3H), 1.99 (d, J = 11.4 Hz, 2H), 1.68 (dd, J = 23.7, 12.3 Hz, 2H); LCMS m / z 483[M+H] + [Example 67] Preparation of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid Step 1: Preparation of methylpiperidine-4-carboxylate trifluoroacetate (im29) To a solution of methyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylate (0.2 g, 0.822 mmol) in DCM (8.2 mL), TFA (2.7 mL) was added at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (im29) as a white solid (0.181 g, yield: 91.5%), which was used in the next reaction without purification.

[0229] 1 H NMR (400 MHz, DMSO-d6): δ8.43 (bs, 1H), 3.61 (s, 3H), 3.23 (d, J = 12.9 Hz, 2H), 2.91 (td, J = 12.6, 3.0 Hz, 2H), 2.66 (dd, J = 12.9, 9.0 Hz, 1H), 1.96 (d, J = 14.5 Hz, 2H), 1.67 (td, J = 15.0, 4.0 Hz, 2H) Step 2: Preparation of methyl 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylate (L29) To a solution of 7e (60 mg, 0.181 mmol) in DMF (0.9 mL), im29 (52.2 mg, 0.217 mmol) was added, and the mixture was cooled to 0°C. DIPEA (52 μL, 0.543 mmol) was added to the reaction mixture, which was further stirred at the same temperature for 30 min, and then BOP reagent (96.1 mg, 0.217 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (L29) as a pale yellow solid (60.6 mg, 73.3%).

[0230] 1 H NMR (400 MHz, DMSO-d6): δ8.74 (s, 2H), 8.24 (d, J = 6.5 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dd, J = 14.0, 6.8 Hz, 1H), 3.87 (d, J = 13.0 Hz, 2H), 3.61 (s, 3H), 3.24 (dd, J = 16.1, 7.4 Hz, 2H), 3.15 (t, J = 11.0 Hz,2H), 2.87 (dd, J = 15.9, 6.5 Hz, 2H), 2.79 (d, J = 10.7 Hz, 1H), 1.92 (d, J = 10.6 Hz, 2H), 1.62 (dd, J = 20.8, 11.1 Hz, 2H); LCMS m / z 457[M+H] + Step 3: Preparation of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (67) 1N NaOH (55μL, 0.055mmol) was added to a solution of L29 (10mg, 0.022mmol) in THF (0.1mL) and stirred at room temperature overnight. The pH of the reaction mixture was adjusted to 2-4 using 3N HCl, extracted with EA, and the organic layer was collected and washed with brine. The mixture was dried over Na2SO4, filtered, and concentrated to obtain the title compound as a white solid (8.6mg, 88.7%).

[0231] 1 H NMR (400 MHz, DMSO-d6) δ12.30 (bs, 1H), 8.74 (s, 2H), 8.24 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dd, J = 13.7, 6.9 Hz, 1H), 3.86 (d, J = 12.9 Hz, 2H), 3.24 (dd, J = 16.1, 7.6 Hz, 2H), 3.14 (t, J = 11.0 Hz, 2H), 2.87 (dd, J = 15.9, 6.4 Hz, 2H), 1.91 (d, J = 13.5 Hz, 2H), 1.59 (d, J = 9.4 Hz, 2H), 1.18 (d, J = 24.2 Hz, 1H); LCMS m / z 443[M+H] + [Example 68] Preparation of 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid The title compound was obtained as an orange solid (5.6 mg, 38.5%) by the same procedure as in Example 67, except that tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate was used instead of methyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylate.

[0232] [Example 69] Preparation of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-N-hydroxypiperidine-4-carboxamide To a solution of 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid (Example 67) (68 mg, 0.154 mmol) in THF (0.5 mL), CDI (37.4 mg, 0.231 mmol) was added and stirred at room temperature for 1 hour, and then NH2OH-HCl (21.4 mg, 0.307 mmol) was added and stirred overnight. The reaction mixture was extracted with EA, and the organic layer was collected and washed with brine, then dried over MgSO4, filtered and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound as a white solid (2.5 mg, 3.6%).

[0233] 1 H NMR (400 MHz, DMSO-d6): δ10.49 (s, 1H), 8.74 (s, 2H), 8.24 (d, J = 7.1 Hz, 1H), 7.27 (t, J = 9.5 Hz, 2H), 4.68 (d, J = 7.1 Hz, 1H), 3.94 (d, J = 13.1 Hz, 2H), 3.26 - 3.21 (m, 2H), 3.12 - 3.01 (m, 2H), 2.88 (dd, J = 15.1, 8.0 Hz, 2H), 2.19 - 2.13 (m, 1H), 1.68 - 1.61 (m, 2H), 0.83 (t, J = 6.4 Hz, 2H); LCMS m / z 458[M+H] + [Example 70] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-methoxy-4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (L30) was prepared in the same manner as in step 1-1 to step 2-1 of Example 33, except that tert-butyl 4-ethynylpiperidine-1-carboxylate was used instead of tert-butyl 4-ethynylpiperidine-1-carboxylate (90 mg, yield: 65%).

[0234] 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.25 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 6.31 (s, 2H), 4.69 (dd, J = 14.0, 7.1 Hz, 1H), LCMS m / z 598[M+H] + To a solution of L30 (80 mg, 0.13 mmol) in MeOH (1 mL), K2CO3 (37 mg, 0.27 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (DCM / MeOH) to obtain the title compound (70) as a white solid (20 mg, yield: 31%).

[0235] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.24 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (dd, J = 13.8, 6.8 Hz, 1H), 3.60 (s, 2H), LCMS m / z 496[M+H] + [Example 71] Preparation of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-fluoro-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynyl-4-fluoropiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (L31) was prepared in the same manner as in step 1 of example 34, except that 4-ethynyl-4-fluoropiperidine trifluoroacetate was used instead of 4-ethynylpiperidine trifluoroacetate (55 mg, yield: 83%).

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 8.26 (d, J = 6.7 Hz, 1H), 7.27 (t, J = 9.3 Hz, 2H), 4.68 (m,1H), 4.02 (d, J = 5.2 Hz, 1H), 3.68 - 3.48 (m, 4H), 3.29 - 3.17 (m, 2H), 2.94 - 2.81 (m, 2H), 2.15 - 2.00 (m, 4H); LCMS m / z 441[M+H] + L31 (50 mg, 0.11 mmol), trimethylsilyl azide (18 μL, 0.14 mmol) and copper(I) iodide (2.4 mg, 0.013 mmol) were added to a mixed solution of N,N-dimethylformamide / methanol (9:1, 2 mL) and heated at 100° C. for 2 hours. The reaction mixture was concentrated and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by column chromatography (dichloromethane / methanol) to obtain the title compound (71) as a white solid (12 mg, yield: 23%).

[0237] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.26 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 9.4 Hz, 2H), 4.74 - 4.62 (m, 1H), 3.78 (m, 2H), 3.51 (m, LCMS m / z 484[M+H] + Test example: Evaluation of the inhibitory activity of human autotaxin protein (1) Experimental method Solutions of each compound synthesized (80 μM, 100% Dimethylsorbocside) was diluted 5-fold with dimethyl sulfoxide to prepare six concentrations. Each concentration of 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 sonicated 360 μM 18:1 LysoPC (diluted with 1× test buffer) was added. The reaction was carried out for 2 hours in a 37°C shaking incubator, and a secondary reaction mixture (Choline Assay Kit, KA1662) (65 μL of 1× test buffer: 1 μL of choline oxidase chloride: 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 for 30 minutes on a shaker. The absorbance was measured at a wavelength of 570 nm using a SpectraMax® iD3 microplate reader. (1-Absorbance 試験群 / absorbance value 対照群 The percentage of inhibitory activity (inhibition %) was calculated using the formula: Percentage of inhibitory activity (%) × 100.

[0238] (2) Results The autotaxin protein inhibitory activity percentages (inhibition %) measured for the compounds of Examples 1 to 71 are shown in Table 1 below.

[0239] [Table 1] All of the synthesized compounds of Examples 1 to 71 exhibited excellent inhibitory activity against human autotaxin protein.

[0240] The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. Therefore, it should be understood that the above-described embodiment is illustrative in all respects and is not limiting. For example, each component described as a single type can be implemented separately, and similarly, the separated components can be implemented in a combined form.

[0241] The scope of the present invention is defined by the claims set forth below, and all modifications and variations that fall within the meaning and scope of the claims and their equivalent concepts should be construed as being included in the scope of the present invention.

Claims

1. A piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof, represented by the following chemical formula 1: 【Chemistry 1】 In Chemical Formula 1, X is an aryl C １－４ alkyl; a bicyclic fused ring formed by fusing an aryl ring with a non-aromatic cycloalkyl ring; or a bicyclic fused ring formed by fusing a heteroaryl ring having 1-3 N with a non-aromatic cycloalkyl ring, and X is one or more R １ or not replaced by, A is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O, and S; L is -(CH ２ ) ３ -;-(CH ２ ) ａ CO-; -(CH 2 CO-; or a 5-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of N and O, wherein a is an integer of 1 to 5; B is COOH; CH ２ COOH; CONHOH; a 4- or 5-membered non-aromatic heterocycle having 1 to 3 heteroatoms selected from the group consisting of N and O; or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from the group consisting of N and O, with the proviso that B is COOH; CH ２ R for COOH;CONHOH; ２ is not replaced by R １ is a halogen, R ２ is hydrogen, C １－４ Alkyl, C １－４ haloalkyl, hydroxy or oxo(O); R ３ is hydrogen, C １－４ Alkyl, C １－４ alkoxy or halogen; R ４ is hydrogen or C １－４ is alkyl, R ５ is hydrogen or C １－４ It is an alkyl.

2. 2. The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein X is one selected from the group consisting of benzyl, phenethyl, dihydroindenyl, and dihydrocyclopentapyrazinyl.

3. The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein A is one selected from the group consisting of pyridine, pyrimidine, pyrazine, oxadiazole, and thiadiazole.

4. The L is -(CH ２ ) ３ -, -(CH ２ ) ２ CO-, -(CH ２ ) ３ CO-, -(CH) ２ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, which is one selected from the group consisting of CO-, isoxazole, dihydroisoxazole, and oxadiazole.

5. The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein B is one selected from the group consisting of carboxyl, carboxymethyl, carboxamide, azetidine, oxadiazole, imidazole, triazole, and tetrazole.

6. The R １ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein is one selected from the group consisting of F, Cl, and Br.

7. The R ２ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein is one selected from the group consisting of hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxy, and oxo (O).

8. The R ３ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein is one selected from the group consisting of hydrogen, methyl, methoxy, and F.

9. The R ４ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein is one selected from the group consisting of hydrogen and methyl.

10. The R ５ The piperidine derivative compound, its hydrate, its solvate, or its pharma- ceutically acceptable salt according to claim 1, wherein is hydrogen or methyl.

11. The piperidine derivative compound is [1] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [2] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [3] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [4] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [5] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [6] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [7] N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-6-amine, [9] 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [10] N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [11] N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [12] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine, [13] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine, [15] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine, [16] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine, [17] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [18] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propan-1-one, [19] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butan-1-one, [21] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-oxadiazol-2-yl)butan-1-one, [24] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [25] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [26] 5-(5-(4-(1,2,4-oxadiazol-3-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [27] 5-(5-(4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [28] 5-(5-(4-(1H-tetrazol-1-yl)piperidin-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-(4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [30] (E)-1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-2-en-1-one, [32] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine, [33] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol -2-yl)pyrimidin-2-amine, [34] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [35] N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [36] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [37] N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [38] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [39] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [40] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)isoxazol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [41] N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidyl]-4,5-dihydroisoxazol-5-yl]pyrimidin-2-amine, [44] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine, [47] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisoxazol-5-yl)-N-(3,5-dichlorophenethyl)pyrimidin-2-amine, [54] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, [56] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine, [57] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine, [58] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine, [59] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine, [60] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine, [61] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine, [62] 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [64] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)azetidin-3-ol, [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)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one, [67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-4-carboxylic acid, [68] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)acetic acid, [69] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)-N-hydroxypiperidine-4-carboxamide, [70] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-methoxy-4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, and [71] The piperidine derivative compound according to claim 1, which is any one compound selected from the group consisting of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-fluoro-4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine, its hydrate, its solvate, or its pharma- ceutically acceptable salt.

12. [55] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4-oxadiazol-2-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine, and [63] A piperidine derivative compound, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof, which is any one compound selected from the group consisting of N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine.

13. A pharmaceutical composition for preventing or treating radiation-induced fibrosis, comprising the piperidine derivative compound according to any one of claims 1 to 12, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof.

14. A pharmaceutical composition for preventing or treating cancer and cancer metastasis, comprising the piperidine derivative compound according to any one of claims 1 to 12, a hydrate thereof, a solvate thereof, or a pharma- ceutically acceptable salt thereof.

15. The piperidine derivative compound according to any one of claims 1 to 12, its hydrate, its solvate, or its pharma- ceutically acceptable salt is used for the treatment of a fibrotic disease selected from among idiopathic pulmonary fibrosis (IPF), interstitial lung disease, hepatic fibrosis, hepatic sclerosis, non-alcoholic steatohepatitis, myocardial and vascular fibrosis, renal fibrosis, dermal fibrosis, glomerulosclerosis, myocardial and vascular fibrosis; an inflammatory disease selected from among rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, inflammatory airway disease, chronic obstructive pulmonary disease (COPD) and asthma; an autoimmune disease selected from among multiple sclerosis and scleroderma; a respiratory disease selected from among asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS). diseases; cardiovascular diseases selected from among arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias, stroke and other vascular damage; metabolic diseases selected from among obesity and diabetes; cancer and cancer metastasis selected from among breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatocarcinoma, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion; ocular diseases selected from among proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial / venous occlusion, traumatic injury, and glaucoma; cholestatic and other forms of chronic pruritus; and acute or chronic organ transplant rejection.

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