Novel piperidine derivatives and pharmaceutical compositions comprising them for inhibiting autocrine motor factors

Abstract

This invention provides: novel piperidine derivative compounds, their hydrates, their solvates, or pharmaceutically acceptable salts thereof; and pharmaceutical compositions for the prevention or treatment of diseases associated with autocrine motor factor activity, said pharmaceutical compositions comprising, as active ingredients, the novel piperidine derivative compound, its hydrate, its solvate, or pharmaceutically acceptable salt thereof. The piperidine derivative compounds of this invention exhibit excellent inhibitory activity against autocrine motor factors and are therefore effective for the treatment and prevention of diseases associated with autocrine motor factor inhibition, such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastases, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

Description

Technical Field

[0001] This invention relates to novel piperidine derivatives, and more specifically, to novel piperidine derivatives and pharmaceutical compositions comprising them for inhibiting autocrine motor factors. Background Technology

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

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

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

[0005] Purpose of the invention

[0006] The problem to be solved by the present invention is to provide an inhibitory compound of autocrine motor factors with a novel structure that exhibits excellent inhibitory activity against autocrine motor factors.

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

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

[0009] Furthermore, the problem to be solved by the present invention is to provide an autocrine motor factor inhibitory compound with a novel structure for use in inhibiting autocrine motor factors and treating diseases caused by them.

[0010] The problems to be solved by this invention are not limited to those described above, and other technical problems not mentioned will be clearly understood by those skilled in the art from the following description. Summary of the Invention

[0011] To address the aforementioned problems, according to one aspect of the present invention, a piperidine derivative compound represented by formula 1, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof is provided:

[0012] <Formula 1>

[0013]

[0014] in:

[0015] X is aryl C 1-4 Alkyl; fused bicyclic ring, wherein an aromatic ring or a heteroaromatic ring having 1 to 3 N atoms is fused with a non-aromatic cycloalkyl ring; or fused bicyclic ring, wherein an aromatic ring is fused with a non-aromatic heterocyclic ring having 1 to 3 O atoms, wherein X is fused with one or more R atoms. 1 Replaced or not by one or more R 1 replace,

[0016] A is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O, and S.

[0017] L is C 1-6 Alkylene; -(CH2) a CO-; -(CH) a CO-; -(CH2) b O(CH2) c CO-; or a 5-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from N and O, wherein a, b, and c are independently integers from 1 to 5.

[0018] B is COOH; CH2COOH; CONHOH; SO2NH2; a 4- to 5-membered non-aromatic heterocycle having 1 to 3 heteroatoms selected from N and O; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N and O.

[0019] R 1 Is it halogen or C? 1-4 alkylsulfonyl,

[0020] R 2 It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, hydroxyl, oxo(O) or aryl C 1-4 alkyl,

[0021] R 3 It is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen,

[0022] R 4 Is it hydrogen, halogen, or C? 1-4 alkyl,

[0023] R 5 Is it hydrogen or C? 1-4 alkyl.

[0024] According to another aspect of the invention, a pharmaceutical composition is provided for the prevention or treatment of diseases associated with autocrine motor factor activity, comprising a piperidine derivative compound, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025] According to another aspect of the invention, a method is provided for inhibiting autocrine motor factors and treating or preventing diseases caused therefrom, said method using piperidine derivative compounds, their hydrates, their solvates, or their pharmaceutically acceptable salts.

[0026] According to another aspect of the invention, piperidine derivative compounds, their hydrates, their solvates, or pharmaceutically acceptable salts thereof are provided for use in inhibiting autocrine motor factors and in treating or preventing diseases caused by autocrine motor factors.

[0027] According to another aspect of the invention, a pharmaceutical composition comprising a piperidine derivative compound, its hydrate, its solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive is provided.

[0028] According to the present invention, the piperidine derivatives of the novel structure of the present invention have been found to exhibit excellent inhibitory activity against autocrine motor factors.

[0029] Therefore, the piperidine derivatives of the novel structure of the present invention can be used to treat and prevent diseases associated with inhibition of autocrine motor factors, such as fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0030] The effects of this invention are not limited to those described above, but should be understood to include all effects that can be inferred from the compositions of this invention as described in the detailed specification or claims. Detailed Implementation

[0031] In this invention, autocrine motor factor (ATX) is a secreted enzyme important in the production of lysophosphatidic acid (LPA), and is also referred to as exonucleotide pyrophosphatase / phosphodiesterase family member 2 (ENPP2). Autocrine motor factor exhibits lysophosphatase D activity, which converts lysophosphatidylcholine (LPC) to LPA. Therefore, LPA levels in plasma and ascites are correlated with ATX activity.

[0032] This invention provides piperidine derivative compounds represented by Formula 1, their hydrates, their solvates, or pharmaceutically acceptable salts thereof:

[0033] <Formula 1>

[0034]

[0035] in:

[0036] X is aryl C 1-4 Alkyl; fused bicyclic, wherein an aromatic ring or a heteroaromatic ring having 1 to 3 N atoms is fused with a non-aromatic cycloalkyl ring; or fused bicyclic, wherein an aromatic ring is fused with a non-aromatic heterocyclic ring having 1 to 3 O atoms, and X is fused with one or more R atoms. 1 Replaced or not by one or more R 1 replace,

[0037] A is a 5- to 6-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O, and S.

[0038] L is C 1-6 Alkylene; -(CH2) a CO-; -(CH) a CO-; -(CH2) b O(CH2) c CO-; or a 5-membered aromatic or non-aromatic heterocycle having 1 to 3 heteroatoms selected from N and O, wherein a, b, and c are independently integers from 1 to 5.

[0039] B is COOH; CH2COOH; CONHOH; SO2NH2; a 4- to 5-membered non-aromatic heterocycle having 1 to 3 heteroatoms selected from N and O; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N and O.

[0040] R 1 Is it halogen or C? 1-4 alkylsulfonyl,

[0041] R 2 It is hydrogen, C 1-4 Alkyl, C 1-4Halogenated alkyl, hydroxyl, oxo(O) or aryl C 1-4 alkyl,

[0042] R 3 It is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen,

[0043] R 4 Is it hydrogen, halogen, or C? 1-4 alkyl,

[0044] R 5 Is it hydrogen or C? 1-4 alkyl.

[0045] In one embodiment, X may be selected from benzyl, phenethyl, dihydroindenyl, dihydrocyclopentadiazinyl and benzo[a]dioxacyclopentenyl.

[0046] In one implementation, A may be selected from pyridine, pyrimidine, pyridazine, pyrazine, etc. One of diazole and thiadiazole.

[0047] In one implementation, L can be selected from -(CH2)3-, -(CH2)2CO-, -(CH2)3CO-, -(CH)2CO-, -CH2OCH2CO-, azole, isotonic azole, dihydroisocyanate azole and One of the diazoles.

[0048] In one embodiment, B may be selected from carboxyl, carboxymethyl, formamide, sulfonamide, aziridine, morpholine, etc. One of the following: diazole, imidazole, triazole, and tetraazole.

[0049] In one implementation, R 1 It can be selected from F, Cl, Br and methylsulfonyl.

[0050] In one implementation, R 2 It can be selected from one of hydrogen, methyl, difluoromethyl, trifluoromethyl, hydroxyl, oxo (O) and benzyl.

[0051] In one implementation, R 3 It can be selected from one of hydrogen, methyl, methoxy, and F.

[0052] In one implementation, R 4 It can be selected from hydrogen, Cl, and methyl.

[0053] In one implementation, R 5 It can be hydrogen or alkyl.

[0054] Representative examples of piperidine derivative compounds according to the present invention are as follows: [1]

[0056] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(2,3-dihydro)

[0057] -1H-inden-2-yl)pyrimidin-2-amine, [2]

[0059] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [3]

[0061] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [4]

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

[0065] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(5,6-difluoro)

[0066] -2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [6]

[0068] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(5,6-dichloro)

[0069] -2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [7]

[0071] N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopentan[b]pyrazin-6-amine, [8]

[0073] 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazin-3-amine, [9]

[0075] 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[10]

[0077] 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- (diazol-2-yl)pyrimidin-2-amine,

[11]

[0079] 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- (diazol-2-yl)pyrimidin-2-amine,

[12]

[0081] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine,

[13]

[0083] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine,

[14]

[0085] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine,

[15]

[0087] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine,

[16]

[0089] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine,

[17]

[0091] 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)prop-1-one,

[18]

[0093] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-1-one,

[19]

[0095] 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)but-1-one,

[20]

[0097] 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)but-1-one, [twenty one]

[0099] 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- (diazol-2-yl)but-1-one, [twenty two]

[0101] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- (diazol-2-yl)but-1-one, [twenty three]

[0103] 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)ethyl-1-one, [twenty four]

[0105] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine,

[25]

[0107] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine,

[26]

[0109] 5-(5-(4-(1,2,4- (diazol-3-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[27]

[0111] 5-(5-(4-(1,3,4- (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[28]

[0113] 5-(5-(4-(1H-tetrazol-1-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[29]

[0115] 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- (diazol-2-yl)pyrimidin-2-amine,

[30]

[0117] (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]

[0119] 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl) (azol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[32]

[0121] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine,

[33]

[0123] 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- (diazol-2-yl)pyrimidin-2-amine,

[34]

[0125] 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- (diazol-2-yl)pyrimidin-2-amine,

[35]

[0127] N-Indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine,

[36]

[0129] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[37]

[0131] N-(5,6-difluoroinden-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine,

[38]

[0133] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso (-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[39]

[0135] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-azolyl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[40]

[0137] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso (-5-azolyl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[41]

[0139] N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine,

[42]

[0141] N-Benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine,

[43]

[0143] N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine,

[44]

[0145] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine

[45]

[0147] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine,

[46]

[0149] N-(1,3-benzodioxacyclopenten-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]iso [Azol-5-yl]pyrimidin-2-amine,

[47]

[0151] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine,

[48]

[0153] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidin-2-amine,

[49]

[0155] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidin-2-amine

[50]

[0157] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[51]

[0159] 5-(3-(4-(5-(difluoromethyl)-1,3,4- (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[52]

[0161] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine,

[53]

[0163] N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano (Azol-5-yl)pyrimidin-2-amine,

[54]

[0165] 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- (diazol-2-yl)pyrimidin-2-amine,

[55]

[0167] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine

[56]

[0169] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine,

[57]

[0171] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine,

[58]

[0173] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine,

[59]

[0175] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine,

[60]

[0177] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[61]

[0179] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine,

[62]

[0181] 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]

[0183] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine,

[64]

[0185] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)piperidin-4-yl)azacyclobutane-3-ol,

[65]

[0187] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)piperidine-4-sulfonamide,

[66]

[0189] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)piperidin-4-yl)-1,3,4- diazole-2(3H)-one,

[67]

[0191] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)piperidine-4-carboxylic acid,

[68]

[0193] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- diazol-2-yl)piperidin-4-yl)acetic acid,

[69]

[0195] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- diazol-2-yl)-N-hydroxypiperidine-4-carboxamide,

[70]

[0197] 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- (diazol-2-yl)pyrimidine-2-amine, and

[71]

[0199] 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- (Diazol-2-yl)pyrimidine-2-amine.

[0200] Unless otherwise defined, the following definitions apply to compounds of formula 1 in this specification.

[0201] The term "alkyl" refers to a straight-chain or branched hydrocarbon group, preferably C1-C. 10 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0202] The term "alkylene" refers to a divalent functional group derived from an alkyl group, and preferably contains 1 to 10 carbon atoms, but is not limited thereto. Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0203] The term "cycloalkyl" refers to partially or fully saturated monocyclic or fused-ring hydrocarbons, preferably C3-C. 10 Cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

[0204] The term “hydroxyl” is defined as -OH, and unless otherwise defined, the term “alkoxy” means alkyloxy, in which the hydrogen atom of the hydroxyl group is replaced by one to ten alkyl groups.

[0205] The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0206] The terms “halogenated alkyl” and “halogenated alkoxy” refer to alkyl or alkoxy groups that have been substituted with one or more halogen atoms.

[0207] The term "heteroatoms" refers to N, O, or S.

[0208] The term "aryl" refers to aromatic hydrocarbons, including polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heterocyclic aromatic ring is fused with one or more other rings, preferably C5-C6. 12 Aryl, more preferably C5-C 10 Aryl groups. For example, aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, etc.

[0209] Additionally, aryl groups include heteroaromatic rings fused with cycloalkyl or non-aromatic heterocycles, such as dihydrocyclopentadiazinyl.

[0210] The terms "heteroaryl" or "aromatic heterocycle" refer to a 3- to 12-membered, more preferably 5- to 10-membered aromatic hydrocarbon forming a monocyclic or fused ring containing one or more heteroatoms selected from N, O, and S as ring atoms, and which may be fused with benzo[a] or C3-C8 cycloalkyl groups. For example, heteroaryl groups include, but are not limited to, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc. diazole group, iso Diazole, tetrazolium, indole, indazole, iso azole group, Azolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzo[] Azolyl, benzimidazole, quinolinyl, isoquinolinyl, etc.

[0211] Arylalkyl, alkylaryl, and heteroarylalkyl refer to groups formed by combining aryl and alkyl or heteroaryl and alkyl as defined above, and include, for example, benzyl, phenethyl, etc., but are not limited thereto.

[0212] The compounds represented by Formula 1 according to the present invention can be prepared and used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts to enhance in vivo absorption or improve solubility; therefore, prodrugs, hydrates, solvates, and pharmaceutically acceptable salts are also within the scope of the present invention. Furthermore, the compounds represented by Formula 1 have a chiral carbon, resulting in the existence of their stereoisomers, and these stereoisomers are also included within the scope of the present invention.

[0213] The term "prodrug" refers to a substance that is converted into a parent drug in vivo. Prodrugs are frequently used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not be. Prodrugs may also have increased solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug can be an in vivo hydrolyzable ester of a compound according to the invention and its pharmaceutically acceptable salt. Another example of a prodrug can be a short peptide (polyamino acid) in which the peptide is coupled to an acidic group and is metabolically converted to exhibit an active site.

[0214] The term "hydrate" refers to a compound or salt thereof of the present invention that contains a stoichiometric or nonstoichiometric amount of water bound together by noncovalent intermolecular forces.

[0215] The term "solvent" refers to a compound or salt thereof of the present invention, which contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Therefore, preferred solvents include volatile, non-toxic, and / or solvents suitable for human administration.

[0216] The term "isomer" refers to the compound of the present invention or its salts that have the same chemical formula or molecular formula but differ in structure or space. Such isomers include both structural isomers and stereoisomers, such as tautomers, and stereoisomers such as R or S isomers and geometric isomers (trans, cis) having an asymmetric carbon center. All such isomers and mixtures thereof are also included within the scope of the present invention.

[0217] The term "medicinal salt" refers to a salt form of a compound that does not cause severe irritation to the organism to which the compound is applied and does not impair the biological activity and physical properties of the compound. Medicinal salts include acid addition salts formed from acids containing a pharmaceutically acceptable anion and forming a non-toxic acid addition salt, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrogen iodide, etc.; organic carbonic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, malic acid, salicylic acid, etc.; and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylates include metal salts or alkaline earth metal salts formed from lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts like lysine, arginine, guanidine, etc.; and organic salts like dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of Formula 1 according to the present invention can also be converted into its salt by conventional methods.

[0218] In addition, the present invention provides a method for synthesizing compounds represented by Formula 1.

[0219] Schemes 1 to 26 are shown as methods for synthesizing compounds of Formula 1 according to the present invention, and the methods described below are not intended to be limited to methods for preparing compounds of Formula 1 according to the present invention. It is obvious that the methods described in Schemes 1 to 26 below are merely exemplary and can be readily modified by those skilled in the art based on specific substituents.

[0220] <Option 1>

[0221]

[0222] <Option 2>

[0223]

[0224] <Option 3>

[0225]

[0226] <Option 4>

[0227]

[0228] <Option 5>

[0229]

[0230] <Option 6>

[0231]

[0232] <Option 7>

[0233]

[0234] <Option 8>

[0235]

[0236] <Option 9>

[0237]

[0238] <Option 10>

[0239]

[0240] <Option 11>

[0241]

[0242] <Option 12>

[0243]

[0244] <Option 13>

[0245]

[0246] <Scheme 14>

[0247]

[0248] <Scheme 15>

[0249]

[0250] <Scheme 16>

[0251]

[0252] <Scheme 17>

[0253]

[0254] <Scheme 18>

[0255]

[0256] <Scheme 19>

[0257]

[0258] <Scheme 20>

[0259]

[0260] <Scheme 21>

[0261]

[0262] <Scheme 22>

[0263]

[0264] <Scheme 23>

[0265]

[0266] <Scheme 24>

[0267]

[0268] <Scheme 25>

[0269]

[0270] <Scheme 26>

[0271]

[0272] The present invention also provides pharmaceutical compositions for the prevention or treatment of diseases associated with autocrine motor factor activity, said pharmaceutical compositions comprising, as an active ingredient, a piperidine derivative compound, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof.

[0273] The present invention also provides a method for inhibiting autocrine motor factors and treating or preventing diseases caused therefrom, the method comprising administering a piperidine derivative compound, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof to a subject in need.

[0274] The present invention also provides piperidine derivative compounds, their hydrates, their solvates or pharmaceutically acceptable salts thereof, for inhibiting autocrine motor factors and for treating or preventing diseases caused by autocrine motor factors.

[0275] The inhibitory activity of the piperidine derivative compounds of the present invention against autotaxin was measured, and it was found that they exhibited excellent autotaxin inhibitory activity even at very low compound concentrations (nM levels), and therefore could be used to treat and prevent diseases related to autotaxin activity.

[0276] In one implementation, the diseases associated with autocrine motor factor activity can be selected from fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic and other forms of chronic pruritus, and acute or chronic organ transplant rejection.

[0277] Fibrotic diseases include, but are not limited to, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis, radiation-induced fibrosis, myocardial and vascular fibrosis, renal fibrosis, skin fibrosis, glomerular sclerosis, myocardial fibrosis, and vascular fibrosis.

[0278] 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.

[0279] Autoimmune diseases include, but are not limited to, multiple sclerosis and scleroderma.

[0280] Respiratory diseases include, but are not limited to, asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome (ARDS).

[0281] Cardiovascular diseases include, but are not limited to, arteriosclerosis, myocardial infarction, arterial and pulmonary hypertension, arrhythmia, stroke and other vascular injuries.

[0282] Metabolic diseases include, but are not limited to, obesity and diabetes.

[0283] Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and their progression and metastatic invasion.

[0284] Eye diseases include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery / vein occlusion, traumatic injury, and glaucoma.

[0285] The present invention also provides pharmaceutical compositions comprising piperidine derivative compounds, their hydrates, their solvates or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives.

[0286] Additives may contain pharmaceutically acceptable carriers or diluents, each of which can be formulated into oral preparations according to conventional methods, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols; external applications; suppositories; and sterile injectable solutions.

[0287] Pharmaceutically 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, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Pharmaceutically acceptable carriers also include diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, and surfactants. Oral solid dosage forms include tablets, pills, powders, granules, and capsules, which may contain at least one excipient, such as starch, calcium carbonate, sucrose, lactose, and gelatin, and may contain lubricants such as magnesium stearate and talc. Oral liquid preparations may include suspensions, oral solutions, emulsions, syrups, etc., and may contain diluents (e.g., water and liquid paraffin), wetting agents, sweeteners, flavoring agents, and preservatives. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations, and suppositories; non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable esters such as ethyl oleate. The base for suppositories can be Witepsol, polyethylene glycol, Tween 61, cocoa gum, lauryl gum, glycerin gelatin, etc.

[0288] The dosage of the active ingredient in the pharmaceutical composition of the present invention depends on the patient's condition and weight, the severity of the disease, the formulation of the active ingredient, the route of administration, and the duration of administration, and can be appropriately adjusted according to the patient. For example, the active ingredient can be administered at a dose of 0.0001 to 1000 mg / kg daily, preferably 0.01 to 100 mg / kg, and this dose can be administered once daily or in several divided doses. Furthermore, based on the total weight of the composition, the pharmaceutical composition of the present invention may contain 0.001% to 90% by weight of the active ingredient.

[0289] The pharmaceutical compositions of the present invention can be administered via various routes, such as orally, through the skin, intraperitoneally, rectally or intravenously, intramuscularly, subcutaneously, or through the endometrium. It can be administered via intracerebroventricular injection to mammals such as rats, mice, livestock, and humans.

[0290] The present disclosure is described in more detail below with reference to preparation examples, embodiments, and test examples. However, the following preparation examples, embodiments, and test examples are intended to illustrate the invention, and the scope of the invention is not limited thereto.

[0291] <Preparation Example 1> Synthesis of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl(3)

[0292]

[0293] Step 1: Synthesis of 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (2): 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (1, 1.05 g, 5.00 mmol), trimethylsilyl azide (5.5 mmol), and copper iodide (I) (0.25 mmol) were added to a mixture of N,N-dimethylformamide / methanol (9:1, 2 mL) under argon. The reaction mixture was heated at 100 °C for 12 hours under argon. 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 give the main compound (1.03 g, 81.3% yield) as a white solid.

[0294] 1 H NMR (400MHz, CDCl3) δ12.73 (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).

[0295] Step 2: Synthesis of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3): A solution of tert-butyl 4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylic acid (3.60 mmol) obtained from the above steps in dioxane (10 mL) was added to a 4.0 M hydrochloric acid solution in dioxane (2 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness to give the main compound as a white solid (quantitative).

[0296] 1 H NMR (400MHz, MeOD) δ8.37 (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).

[0297] <Preparation Example 2> Synthesis 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)

[0298]

[0299] Step 1: Synthesis 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)

[0300] 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 hour. 4-[(methanesulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol) was added to the reaction mixture under argon atmosphere. The reaction mixture was heated at 90 °C for 5 hours. 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 subject compound as a white solid.

[0301] 4-(1H-1,2,4-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Im15-1a) yield: 43.5%;

[0302] 1¹H 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, 2H), 1.95 (qd, J = 12.2, 4.5 Hz, 2H), 1.48 (s, 9H); C 12 H 21 N4O2[M+H] + The calculated MS(ESI, m / z) value is 253.15, and the measured value is also 253.15.

[0303] 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Im15-1b) yield 38.5%;

[0304] 1 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); C 13 H 23 N4O2[M+H] + The calculated MS(ESI, m / z) value is 267.15, and the measured value is also 267.15.

[0305] Step 2: Synthesis 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)

[0306] The 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 from the above steps was dissolved in 4M HCl in dioxane (5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness to give the subject compound as a white solid (quantitative).

[0307] 4-(1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2a) Yield: 97.8%; C7H 13 N4[M+H] +The calculated MS(ESI, m / z) value is 153.11, and the measured value is 153.10.

[0308] 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b). Yield: 95.7%; C8H 15 N4[M+H] + The calculated MS(ESI, m / z) value is 167.12, and the measured value is 167.15.

[0309] <Preparation Example 3> Synthesis of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e)

[0310]

[0311] Step 1: Synthesis of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b)

[0312] 3,4-Difluorophenylpropionic acid (925.8 mg, 4.97 mmol) was dissolved in DCM (20 mL). Oxaloyl chloride (9.94 mmol) and 1 drop of DMF were added to the reaction mixture. The resulting solution was stirred for 3 to 5 hours. After the reaction was complete, the solvent was removed under vacuum. Then, 3-(3,4-difluorophenyl)propionyl 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 minutes and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured onto ice and extracted with DCM (2 × 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 give the subject compound (yield: 78.0%).

[0313] 1 ¹H 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).

[0314] Step 2: Synthesis of (Z)-5,6-difluoro-2-(hydroxyimino)-2,3-dihydro-1H-inden-1-one (E3c)

[0315] Amyl nitrite (3.6 mmol) followed by concentrated HCl (1 mL) was added to a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (E3b, 3 mmol) in MeOH at 40 °C. The reaction mixture was stirred at 40 °C for 2 to 5 hours, cooled to room temperature, and water (50 mL) was added. The precipitate was collected by filtration and dried to give the subject compound (yield: 54.0%).

[0316] 1 H NMR (400MHz, DMSO-d6) δ12.77 (s, 1H), 7.82 (dd, J=9.3, 7.7Hz, 1H), 7.75 (dd, J=10.3, 7.0Hz, 1H), 3.76 (s, 2H).

[0317] Step 3: Synthesis of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (4e)

[0318] The 5,6-difluoro-2-(hydroxyimino)-2,3-dihydro-1H-indene-1-one (E3c, 1 mmol) obtained from the above steps was dissolved in acetic acid (37.5 mL) and sulfuric acid (1.5 mL). 10% palladium on carbon (10 wt%) was added. The reaction mixture was hydrogenated overnight. After filtration through a diatomaceous earth mat, 4N NaOH was added to pH approximately 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 give the subject compound (yield: 12.1%).

[0319] 1 H NMR (400MHz, CDCl3) δ6.98 (t, J=8.9Hz, 2H), 3.87 (tt, J=6.7, 4.9Hz, 1H), 3.12 (dd, J=15.8, 6.7Hz, 2H), 2.62 (dd, J=15.7, 4.9Hz, 2H), 1.40 (s, 2H); C9H 10 F2N[M+H] + The calculated MS(ESI, m / z) value is 170.07, and the measured value is 170.01.

[0320] <Preparation Example 4> Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-2-amine (4f)

[0321]

[0322] Step 1: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (F4b)

[0323] A catalytic amount of DMF was added to a solution of 4.56 mmol of 3-(3,4-dichlorophenyl)propionic acid in DCM, and excess oxalyl chloride was added dropwise under ice bath conditions. 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 conditions. The reaction mixture was refluxed for 1.5 h and cooled to room temperature. The crude mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were evaporated and purified by silica gel rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 75.4%).

[0324] 1 ¹H 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).

[0325] Step 2: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c)

[0326] 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 overnight at room temperature. The crude mixture was poured into DCM, washed with H2O (40 mL), and dried over MgSO4. The crude mixture was purified by silica gel rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 88.8%).

[0327] 1 ¹H NMR (400MHz, 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 (100MHz, chloroform-d) δ 145.26, 143.36, 132.22, 130.68, 126.81, 126.22, 75.72, 36.39, 29.41.

[0328] Step 3: Synthesis of 5,6-dichloro-1H-indene (F4d)

[0329] p-Toluenesulfonic acid (0.1 equivalent) was added to a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-ol (F4c, 1.92 mmol) in toluene, and the mixture was refluxed using a Dean-Stark separator for 2 hours. The resulting mixture was cooled to room temperature and the solvent was removed under vacuum. The crude mixture was purified by silica gel rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 65.5%).

[0330] 1 ¹H NMR (400MHz, chloroform-d) δ 7.55–7.48 (m, 1H), 7.45 (s, 1H), 6.79 (dtd, J = 5.5, 1.9, 0.7Hz, 1H), 6.61 (dt, J = 5.5, 2.0Hz, 1H), 3.38 (td, J = 2.0, 0.8Hz, 2H); 13 C NMR (100MHz, chloroform-d) δ 144.96, 143.44, 136.36, 130.95, 130.43, 128.56, 125.64, 122.50, 38.90.

[0331] Step 4: Synthesis of 3,4-dichloro-1a,6a-dihydro-6H-indeno[1,2-b]ethylene oxide (F4e)

[0332] 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 the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were evaporated and purified by silica gel rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 84.9%).

[0333] 1 ¹H 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 (100MHz, chloroform-d) δ 143.62, 141.21, 132.60, 130.30, 128.14, 127.15, 58.20, 58.03, 34.26.

[0334] Step 5: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f)

[0335] 2.5 M lithium aluminum hydride in THF (1.1 mmol) was slowly added to a solution of 3,4-dichloro-1a,6a-dihydro-6H-indeno[1,2-b]epoxy (F4e, 0.98 mmol) in THF 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 rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 86.3%).

[0336] 1 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 (100MHz, chloroform-d) δ 141.29, 130.54, 126.87, 73.32, 42.30.

[0337] Step 6: Synthesis of 5,6-dichloro-2,3-dihydro-1H-inden-2-amine (4f)

[0338] Phthalimide (1.7 mmol), triphenylphosphine (1.7 mmol), and diisopropyl azodicarboxylate (1.3 mmol) were added to a solution of 5,6-dichloro-2,3-dihydro-1H-inden-2-ol (F4f, 0.84 mmol) in THF 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 added to 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 rapid chromatography (dichloromethane / methanol) to give the subject compound (yield: 20.2%).

[0339] 1 ¹H 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 C10 NMR (100MHz, methanol-d4) δ 143.28, 131.29, 127.62, 41.35, 20.36; C9H 10 Cl2N[M+H] + The calculated MS(ESI, m / z) value is 202.02, and the measured value is 202.05.

[0340] <Preparation Example 5> 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4- Synthesis of diazole trifluoroacetate (im19)

[0341]

[0342] 4-(5-(difluoromethyl)-1,3,4- Diazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (23.5 mg, 0.103 mmol) was dissolved in 2 mL of DCM, followed by the addition of 600 μL of trifluoroacetic acid and stirring 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 under vacuum. The compound (im19) (17.8 mg, yield: 54%) was obtained in salt form without purification.

[0343] LCMS m / z 222[M+H] +

[0344] <Preparation Example 6> 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4- Synthesis of diazole (im20)

[0345]

[0346] Step 1: 4-(5-(difluoromethyl)-1,3,4- Synthesis of diazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (im20-1)

[0347] 4-(1H-tetrazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.395 mmol) and difluoroacetic anhydride (64 μL, 0.592 mmol) were dissolved in DCM (3.9 mL), and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated. The product was purified by column chromatography (DCM:MeOH) to give the main compound (im20-1) (77 mg, yield: 64.7%) as a colorless oil.

[0348] 1H NMR (400MHz, CDCl3) δ6.83 (t, J=51.8Hz, 2H), 4.12 (d, J=7.7Hz, 2H), 3.19-3.11 (m, 1H), 2.96 (t, J=13.2Hz, 2H), 2.09 (d, J=12.9Hz, 3H), 1.84 (ddd, J=24.6, 11.3, 4.1Hz, 3H), 1.47 (s, 9H).

[0349] Step 2: 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4- Synthesis of diazole (im20)

[0350] TFA (833 μL) was added to a solution of im20-1 (76 mg, 0.251 mmol) in DCM (2.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. 1 N NaOH was added to adjust the pH to 8-10, and the mixture was extracted with DCM. The organic layer was dried over Na2SO4 and filtered. The solvent was concentrated under vacuum. The subject compound (im20) was obtained as a yellow oil and was used in the following reaction (32 mg, yield: 63%) without purification.

[0351] <Preparation Example 7> Synthesis of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21)

[0352]

[0353] Step 1: Synthesis of tert-butyl 4-(prop-1-yn-1-yl)piperidine-1-carboxylic acid (im21-1)

[0354] 4-Ethynylpiperidin-1-carboxylic acid tert-butyl ester (1.0 g, 4.8 mmol) was dissolved in tetrahydrofuran (14 mL) under a nitrogen atmosphere and maintained at -78 °C. 2.5 M n-butyllithium (1.92 mL, 4.8 mmol) was added and the mixture was stirred for 30 min. The temperature was raised to room temperature, and then iodomethane (450 μL, 7.2 mmol) was added and the reaction was stirred for 12 h. After the reaction, ethyl acetate and H₂O were added and the mixture was extracted. The organic layer was dried over Na₂SO₄ and concentrated. The resulting residue was purified by silica gel column chromatography (0–5% MeOH in DCM) to obtain the subject compound (im21-1) (1.09 g, yield: 100%) as a brown liquid.

[0355] 1H NMR (400MHz, CDCl3) δ3.69 (d, J=11.7Hz, 2H), 3.18-3.06 (m, 2H), 2.49 (d, J=2.1H z, 1H), 1.79 (d, J=2.3Hz, 3H), 1.77-1.67 (m, 2H), 1.57-1.48 (m, 2H), 1.45 (s, 9H).

[0356] Step 2: Synthesis of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (im21-2)

[0357] im21-1 (170 mg, 0.75 mmol) and trimethylsilyl azide (150 μL, 1.16 mmol) were reacted in a microwave reactor at 200 °C for 2 h. The reaction solution was purified by silica gel column chromatography (0 to 5% MeOH in DCM) to obtain the main compound (im21-2) (30 mg, yield: 15%) as a yellow liquid.

[0358] 1 H NMR (400MHz, CDCl3) δ4.18 (m, 2H), 2.91-2.75 (m, 3H), 2.30 (s, 3H), 1.89-1.66 (m, 4H), 1.46 (s, 9H).

[0359] Step 3: Synthesis of 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine trifluoroacetate (im21)

[0360] 4-(4-methyl-1H-1,2,3-triazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.11 mmol) was dissolved in DCM (1.5 mL), and then trifluoroacetic acid (350 μL) was added at 0 °C. After raising the temperature to room temperature and reacting for 12 h, the reaction solution was concentrated to give the subject compound (im21), which was used in the following reaction without further purification (yield: 100%).

[0361] LCMS m / z 167 [M+H] +

[0362] <Preparation Example 8> Synthesis of 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25)

[0363]

[0364] 0.3 g (1.1844 mmol) of 4-(1H-tetrazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester and 3.9 mL of LTFA were dissolved in 30 mL of DCM, and the reaction mixture was stirred at room temperature. After the reaction was confirmed to be complete by TLC, it was concentrated and used in the following reaction without further purification (yield: 100%).

[0365] [Example 1] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a)

[0366]

[0367] Step 1: Synthesis of ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (5a)

[0368] A mixture of 2,3-dihydro-1H-indene-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 hours. After cooling, the solvent was evaporated and the crude product was extracted with ethyl acetate and subsequently 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 subject compound as a white solid (yield: 89.2%).

[0369] 1 H NMR (400MHz, CDCl3) δ8.90 (s, 1H), 8.75 (s, 1H), 7.25-7.15 (m, 4H), 6.00 (d, J=7.8Hz, 1H), 4.97-4.79 (m, 1H) C 16 H 18 N3O2[M+H] + The calculated MS(ESI, m / z) value is 284.14, and the measured value is 284.05.

[0370] Step 2: Synthesis of 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonylhydrazine (6a)

[0371] Compound 5a (5 mmol) and hydrazine monohydrate (50 mmol) were dissolved in EtOH and refluxed for 6 hours. After the reaction was complete, the reaction mixture was evaporated under vacuum to obtain the subject compound (yield: 93.4%).

[0372] 1 H NMR (400MHz, DMSO-d6) δ9.59 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.08 (d, J=6.9Hz, 1H), 7.27-7.08 (m, 4H), 4.66 (h, J=7.2Hz, 1H), 4.42 (s, 2H), 3.26 (dd, J=15.8, 7.6Hz, 2H), 2.91 (dd, J=15.8, 6.9Hz, 2H); C 14 H 16 N5O[M+H] + The calculated MS(ESI, m / z) value is 270.13, and the measured value is 270.05.

[0373] Step 3: 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazole-2(3H)-one (7a)

[0374] A mixture of compound 6a (0.1 mmol), TEA (0.5 mmol), and 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 hours. 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 give the subject compound (yield: 27.4%).

[0375] 1 H NMR (400MHz, chloroform-d) δ8.75 (s, 1H), 8.67 (s, 1H), 7.26-7.17 (m, 4H), 5.79 (d, J=7.9Hz, 1H), 4.92-4.83 (m, 1H), 3.42 (dd, J=16.0, 6.9Hz, 2H), 2.92 (dd, J=16.0, 4.9Hz, 2H); C 15 H 14 N5O2[M+H] + The calculated MS(ESI, m / z) value is 296.11, and the measured value is 296.05.

[0376] Step 4: 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8a)

[0377] The 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-yl prepared in Preparation Example 1 Diazol-2(3H)-one (7a, 1 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3, 1.2 mmol), DIEA (3 mmol), and BOP reagent (1.2 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. 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 give the subject compound as a white solid (yield: 46.1%).

[0378] 1 H NMR (400MHz, CDCl3) δ12.55 (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=7.7Hz, 1H), 4.93-4.83 (m, 1H), 4.21-4 .09(m, 2H), 3.42(dd, J=16.0, 7.0Hz, 2H), 3.33-3.22(m, 2H), 3.11-3.02(m , 1H), 2.92 (dd, J=16.0, 5.0Hz, 2H), 2.21-2.11 (m, 2H), 1.97-1.83 (m, 2H); C 22 H 24 N9O[M+H] + The calculated HRMS (ESI, m / z) value is 430.2098, and the measured value is 430.2103.

[0379] [Example 2] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8b)

[0380] The subject compound was synthesized according to the same steps as in Example 1 (yield: 83.0%), except that 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0381] 1 ¹H 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, 7.0Hz, 2H), 3.28 (ddd, J=13.1, 11.7, 2.9Hz, 2H), 3.07 (tt, J=11.5, 3.7 Hz, 1H), 2.88 (td, J=16.0, 5.2Hz, 2H), 2.16 (dd, J=13.6, 3.5Hz, 2H), 1.97-1.82 (m, 2H); C 22 H 23 FN9O[M+H] + The calculated HRMS (ESI, m / z) value is 448.2004, and the measured value is 448.2003.

[0382] [Example 3] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-chloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8c)

[0383] The subject compound was synthesized according to the same steps as in Example 1 (yield: 62.5%), except that 5-chloro-2,3-dihydro-1H-indene-2-amine (4c) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0384] 1¹H 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, 4.0Hz, 2H), 3.45-3.33 (m, 2H), 3.27 (ddd, J=13.2, 11.9, 2.9Hz, 2H), 3.07 (tt, J=11.4, 3.7Hz, 1H), 2.95-2.83(m, 2H), 2.21-2.11(m, 2H), 1.96-1.80(m, 2H); C 22 H 23 CIN9O[M+H] + The calculated MS(ESI, m / z) value is 464.1709, and the measured value is also 464.1709.

[0385] [Example 4] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8d)

[0386] The subject compound was synthesized according to the same steps as in Example 1 (yield: 38.0%), except that 5-bromo-2,3-dihydro-1H-indene-2-amine (4d) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0387] 1 H NMR (400MHz, CDCl3) δ8.79 (s, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J=8.0, 1.9Hz, 1H), 7.11 (d, J=8.0Hz, 1H), 5.70 (d, J=7.6Hz, 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, 3.8Hz, 1H), 2 .88 (ddd, J=20.9, 16.2, 5.1Hz, 2H), 2.21-2.10 (m, 2H), 1.98-1.81 (m, 2H); C 22 H 23 BrN9O[M+H] + The calculated MS(ESI, m / z) value is 508.1203, and the measured value is 508.1202.

[0388] [Example 5] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8e)

[0389] The subject compound was synthesized according to the same steps as in Example 1 (yield: 63.8%), except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0390] 1 H NMR (400MHz, chloroform-d) δ 13.08 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 7.02 (t, J = 8.8Hz, 2H), 6.03 (d, J = 7.6Hz, 1H), 4.89 (qt, J = 7.2, 5.2Hz, 1H), 4.14 ( C 22 H 22 F2N9O[M+H] + The calculated HRMS (ESI, m / z) value is 466.1910, and the measured value is 466.1913.

[0391] [Example 6] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (8f)

[0392] The subject compound was synthesized according to the same steps as in Example 1 (yield: 54.3%), except that 5,6-dichloro-2,3-dihydro-1H-indene-2-amine (4f) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0393] 1¹H 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, 7.3Hz, 2H), 3.28 (td, J=13.2, 2.9Hz, 2H), 3.06 (ddt, J=11.4, 7.4, 3 .7Hz, 1H), 2.88 (dd, J=16.3, 5.2Hz, 2H), 2.22-2.12 (m, 2H), 1.98-1.82 (m, 2H); C 22 H 22 Cl2N9O[M+H] + The calculated MS(ESI, m / z) value is 498.13, and the measured value is 498.15.

[0394] [Example 7] N-(5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopentan[d]pyrazine-6-amine (13)

[0395]

[0396] The subject compound was synthesized according to the same steps as in Example 1 (yield: 53.0%), except that 6,7-dihydro-5H-cyclopentan[b]pyrazine-6-amine (9) was used instead of 2,3-dihydro-1H-indene-2-amine (4a).

[0397] 1 H NMR (400MHz, methanol-d4) δ8.79 (s, 2H), 8.34 (s, 2H), 7.75-7.62 (m, 1H), 4.94 (tt, J=7.8, 5.7Hz, IH), 4.11 (dt, J=13.3, 3.7H z, 2H), 3.54 (dd, J=17.5, 7.9Hz, 2H), 3.35 (s, 2H), 3.19-3.04 (m, 3H), 2.19-2.08 (m, 2H), 1.86 (qd, J=12.2, 4.3Hz, 2H); C 20 H 22 N 11 O[M+H] + The calculated MS(ESI, m / z) value is 432.20, and the measured value is also 432.20.

[0398] [Example 8] 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyridazine-3-amine (14)

[0399]

[0400] The subject compound was synthesized according to the same steps as in Example 1 (yield: 42.0%), except that ethyl 6-chloropyridazine-3-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0401] 1 H NMR (400MHz, DMSO-d6) δ14.78 (s, 1H), 7.80 (d, J = 9.4Hz, 1H), 7.76 (d, J = 6.4Hz, 1H), 7.72(s, 1H), 7.30-7.24(m, 2H), 7.19-7.15(m, 2H), 6.94(d, J=9.4Hz, 1H), 4.77 (h, J=6.7, 6.1Hz, 1H), 4.04-3.96 (m, 2H), 3.30 (d, J=2.5Hz, 4H), 3.08-2.9 9 (m, 1H), 2.90 (dd, J=16.0, 5.4Hz, 2H), 2.09-2.02 (m, 2H), 1.80-1.67 (m, 2H).C 22 H 24 N9O(M+H) + The calculated HRMS(ESI) m / z value is 430.21; the measured value is 430.2107.

[0402] [Example 9] 5-(5-(4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (15a)

[0403]

[0404] The subject compound was synthesized according to the same steps as in Example 1 (yield: 65.2%), except that 4-(1H-1,2,4-triazol-1-yl)piperidine HCl (Im15-2a) obtained from Preparation Example 2 was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3).

[0405] 1H NMR (400MHz, CDCl3) δ8.76 (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=7.7Hz, 1H), 4.87(qt, J=7.2, 5.0Hz, 1H), 4.47(tt, J= 11.1, 4.1Hz, 1H), 4.29-4.17 (m, 2H), 3.52-3.35 (m, 3H), 3.30 (ddd, J=13.4, 11.7, 3.0Hz, 2H), 2.91 (dd, J=16.0, 5.0Hz, 2H), 2.37-2.27 (m, 2H), 2.27-2.13 (m, 2H); C 22 H 24 N9O[M+H] + The calculated HRMS (ESI, m / z) value is 430.2098, and the measured value is also 430.2098.

[0406] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine (15b)

[0407] The subject compound was synthesized according to the same steps as in Example 1 (yield: 57.4%), except that 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine·HCl (Im15-2b) obtained from Preparation Example 2 was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine HCl (3).

[0408] 1 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, 7.0Hz, 2H), 3.34-3.22 (m, 2H), 2.91 (dd, J=16.0, 5.0Hz, 2H) , 2.46 (d, J=45.0Hz, 3H), 2.38-2.24 (m, 2H), 2.26-2.13 (m, 1H), 2.09-1.99 (m, 1H); C 23 H 26 N9O[M+H] +The calculated HRMS(ESI, mz) value is 444.2255, and the measured value is also 444.2255.

[0409] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine (16)

[0410]

[0411] Step 1-1: Synthesis of tert-butyl 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine-1-carboxylic acid (M2)

[0412] The subject compound was synthesized according to the same steps as in step 1 of Preparation Example 1 (yield: 47.0%), except that 4-ethynyl-2-methylpiperidine-1-carboxylic acid tert-butyl ester was used instead of 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester.

[0413] 1 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, ¹H), 2.03–1.85 (m, 2H), 1.79 (dt, J = 13.0, 6.5 Hz, ¹H), 1.62–1.49 (m, ¹H), 1.47 (s, 9H), 1.26 (d, J = 7.0 Hz, 3H); C 13 H 23 N4O2[M+H] + The calculated MS(ESI, m / z) value is 267.18, and the measured value is 267.20.

[0414] Steps 1-2: Synthesis of 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (M3)

[0415] Using M2 obtained from the above steps, the subject compound was synthesized (quantitatively) according to the same steps as step 2 of Preparation Example 1.

[0416] C8H 14 N4[M+H] + The calculated MS(ESI, m / z) value is 166.12, and the measured value is 166.10.

[0417] Step 2: 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- Synthesis of diazol-2-yl)pyrimidine-2-amine (16)

[0418] The subject compound was synthesized according to the same steps as in Example 4 (yield: 11.2%), except that 2-methyl-4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (M3) obtained from the above steps was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0419] 1 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), 4.0 5-3.95 (m, 1H), 2.93 (ddd, J=21.7, 16.1, 6.3Hz, 2H), 2.14 (d, J=12.4Hz, 1H), 2.04-2 .02 (m, 2H), 1.80 (qd, J=13.0, 4.7Hz, 1H), 1.62-1.56 (m, 2H), 1.42 (d, J=6.9Hz, 3H); C 23 H 25 BrN9O[M+H] + The calculated MS(ESI, m / z) value is 522.13, and the measured value is 522.15.

[0420] [Example 12] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine (17a)

[0421]

[0422] Step 1: Synthesis of ethyl 6-chloronicotinate (A4a)

[0423] 6-Chloronicotinic acid (3.2 mmol) and 1,1'-carbonyldiimidazole (3.5 mmol) were added to THF at room temperature under Ar atmosphere. The reaction mixture was stirred at the same temperature for 3 hours. 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 rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 62.8%).

[0424] 1 ¹H NMR (400MHz, chloroform-d) δ 9.00 (dd, J = 2.4, 0.6Hz, 1H), 8.25 (dd, J = 8.3, 2.4Hz, 1H), 7.42 (dd, J = 8.3, 0.7Hz, 1H), 4.42 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H); C8H9ClNO2 [M+H] + The calculated MS(ESI, m / z) value is 186.03, and the measured value is 186.05.

[0425] Step 2: Synthesis of 6-((5-bromo-2,3-dihydro-1H-indene-2-yl)amino)nicotinic acid ethyl ester (A5a) The subject compound was synthesized according to the same steps as in Step 1 of Example 1 (yield: 12.4%), except that 5-bromo-2,3-dihydro-1H-indene-2-amine was used instead of 2,3-dihydro-1H-indene-2-amine and 6-chloronicotinic acid ethyl ester (A4a) was used instead of 2-chloropyrimidine-5-carboxylic acid ethyl ester.

[0426] 1 H NMR (400MHz, chloroform-d) δ8.75 (d, J=1.8Hz, 1H), 7.99 (dd, J=8.8, 2.2Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8.1Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 6.36 (d, J =8.8Hz, 1H), 5.30 (d, J = 8.1Hz, 1H), 4.78-4.59 (m, 1H), 4.33 (q, J = 7.1Hz, 2H), 3.42-3.25 (m, 2H), 2.93-2.74 (m, 2H), 1.36 (t, J = 7.1Hz, 3H); C 17 H 18 BrN2O2[M+H] + The calculated MS(ESI, m / z) value is 361.05, and the measured value is 361.00.

[0427] Step 3: Synthesis of 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)nicotinic acid hydrazide (A6a)

[0428] The subject compound was synthesized according to the same steps as in step 2 of Example 1 (yield: 84.1%), except that compound A5a was used instead of compound 5a.

[0429] 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.49 (d, J = 2.0Hz, 1H), 7.84-7.74 (m, 3H), 7.44 (s, 1H), 7.39-7.30 (m, C 15 H 16 BrN4O[M+H] + The calculated MS(ESI, m / z) value is 347.05, and the measured value is 347.05.

[0430] Step 4: 5-(6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)pyridin-3-yl)-1,3,4- Synthesis of diazole-2(3H)-one (A7a)

[0431] 1,1'-carbonyldiimidazole (0.22 mmol) and TEA (0.2 mmol) were added to a solution of compound A6a (0.2 mmol) in DMF at room temperature and the mixture was stirred for 3 hours. The DMF solvent was removed under vacuum and the crude mixture was purified by silica gel rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 84.0%).

[0432] 1 H NMR (400MHz, DMSO-d6) δ10.94-10.85 (m, 1H), 10.21 (dd, J=8.9, 2.4Hz, 1H), 10.13-10.07 (m, 1H), 9.95 (s, 1H), 9.87- C 16 H 14 BrN4O2[M+H] + The calculated MS(ESI, m / z) value is 373.03, and the measured value is 373.00.

[0433] Step 5: 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyridin-2-amine (17a)

[0434] The subject compound was synthesized according to the same steps as in step 4 of Example 1 (yield: 57.2%), except that compound A7a was used instead of compound 7a.

[0435] 1 H NMR (400MHz, chloroform-d) δ8.60 (dd, J=2.4, 0.7Hz, 1H), 7.98 (dd, J=8.8, 2.4Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.31 (dd, J=7.8, 1.9Hz, 1H), 7.11 (d, J=7.9Hz, 1H), 6.46 (dd, J=8.9, 0.8Hz, 1H ), 5.24 (d, J=7.5Hz, 1H), 4.74-4.62 (m, 1H), 4.19-4.09 (m, 2H), 3.45-3.20 (m, 4H), 3.06 (tt C 23 H 24 BrN8O[M+H] + The calculated MS(ESI, rm / z) value is 507.13, and the measured value is 507.15.

[0436] [Example 13] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazon-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)pyrazin-2-amine (17b)

[0437] The subject compound was synthesized according to the same procedure as in Example 12 (yield: 48.5%), except that 5-chloropyrazine-2-carboxylic acid was used instead of 6-chloronicotinic acid.

[0438] 1H NMR (400MHz, methanol-d4) δ8.60 (d, J=1.3Hz, 1H), 7.93 (d, J=1.5Hz, 1H), 7.68 (s, 1H), 7.4 0 (s, 1H), 7.30 (dd, J=8.1, 1.9Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 4.77 (tt, J=7.2, 3.6Hz , 2H), 4.13 (dt, J=13.3, 3.5Hz, 2H), 3.44-3.32 (m, 4H), 3.10 (ddt, J=11.6, 7.4, 3.7H z, 1H), 2.90 (ddd, J=19.0, 16.1, 5.4Hz, 2H), 2.18-2.08 (m, 2H), 1.93-1.76 (m, 2H); C 22 H 23 BrN9O[M+H] + The calculated MS(ESI, m / z) value is 508.12, and the measured value is 508.15.

[0439] [Example 14] 5-(5c(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine (18)

[0440]

[0441] Step 1: Synthesis of ethyl 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinate (A5c)

[0442] The subject compound was synthesized using ethyl 4,6-dichloronicotinate following the same procedure as compound A5a (yield: 64.2%).

[0443] 1 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, J = 16.6, 7.0 Hz, 2H), 2.92 (ddd, J = 20.7, 16.3, 4.8 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); C 17 H 17 BrClN2O2[M+H] +The calculated MS(ESI, m / z) value is 395.02, and the measured value is 395.05.

[0444] Step 2: Synthesis of 6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloronicotinic acid (A6c)

[0445] Lithium hydroxide (1.5 mmol) was added to a solution of compound A5c (0.50 mmol) in EtOH and water 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 rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 64.2%).

[0446] 1 H NMR (400MHz, DMSO-d6) δ8.61 (d, J=6.1Hz, 1H), 8.51 (s, 1H), 7.47 (s, 1H), 7.35 (dd, J=8.0, 1.9Hz, 1H), 7.23 (d, J=8.0H z, 1H), 6.90 (s, 1H), 4.49 (h, J=6.8Hz, 1H), 3.38 (ddd, J=20.2, 16.4, 7.0Hz, 2H), 2.84 (ddd, J=21.3, 16.3, 4.7Hz, 2H);

[0447] C 15 H 13 BrClN2O2[M+H] + The calculated MS(ESI, m / z) value is 366.98, and the measured value is 366.95.

[0448] Step 3: 5-(6-((5-bromo-2,3-dihydro-1H-inden-2-yl)amino)-4-chloropyridin-3-yl)-1,3,4- Synthesis of diazon-2(3H)-yl (A7c)

[0449] 1,1'-carbonyldiimidazole (0.27 mmol) was added to a solution of compound A6c (0.25 mmol) in THF at room temperature under Ar atmosphere 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 rapid chromatography (hexane / ethyl acetate) to give the subject compound (yield: 59.6%).

[0450] 1H NMR (400MHz, DMSO-d6) δ12.74 (s, 1H), 8.30 (s, 1H), 7.48 (s, 1H), 7.43-7.33 (m, 2H), 7.24 (d, J=8.0Hz, 1H), 7.04 (s, 1H), 4.65-4.53 (m, 1H), 3.49-3.36 (m, 2H), 2.91-2.76 (m, 2H); C 16 H 13 BrClN4O2[M+H] + The calculated MS(ESI, m / z) value is 406.99, and the measured value is 407.00.

[0451] Step 4: 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-chloropyridin-2-amine (18)

[0452] The subject compound was synthesized using compound A7c following the same steps as in step 4 of Example 1 (yield: 67.8%).

[0453] 1 H NMR (400MHz, DMSO-d6) δ14.73 (s, 1H), 8.49 (s, 1H), 8.12 (d, J = 6.9Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.37 (dd, J=8.0.2.0Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 7.02 (s, 1H), 4.60 (tt, J=6.9, 2.8Hz, 1H), 4.05-3.96 (m, 2H), 3.42 (ddd, =19.8, 16.3, 6.8Hz, 2H), 3.25 (td, J = 12.5, 2.7Hz, 2H), 3.01 (tt, J = 11. 5, 3.7Hz, 1H), 2.87 (ddd, J=20.8, 16.4, 4.1Hz, 2H), 2.06-1.96 (m, 2H), 1.70 (qd, J=12.6, 4.2Hz, 2H); C 23 H 23 BrClN8O[M+H] + The calculated MS(ESI, m / z) value is 541.09, and the measured value is 541.10.

[0454] [Example 15] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine (19a)

[0455]

[0456] The subject compound was synthesized according to the same steps as in Example 1 (yield: 48.7%), except that (3,5-dichlorophenyl)methylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0457] 1 H NMR (400MHz, DMSO-d6) δ8.84-8.67 (m, 2H), 8.46 (t, J=6.4Hz, 1H), 7.69 (s, 1H), 7.48 (t, J=2.0Hz, 1H), 7.36 (d, J=1.9Hz, 2H), 4. C 20 H 20 Cl2N9O[M+H] + The calculated MS(ESI, m / z) value is 472.12, and the measured value is 472.10.

[0458] [Example 16] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine (19b)

[0459] The subject compound was synthesized according to the same steps as in Example 1 (yield: 54.6%), except that diisopropylethylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0460] 1 H NMR (400MHz, DMSO-d6) δ8.73 (d, J=8.1Hz, 2H) ，7.97 (t, J=5.8Hz, 1H), 7.70 (s, 1H), 7.42 (t, J=1.9Hz, 1H), 7.32 (d, J=1.9Hz, 2H), 3.99 (dt, J=13.1, 3.6Hz, 2H), 3.59 (q, J=6.7Hz, 2H) C 21 H 22 Cl2N9O[M+H] + The calculated MS(ESI, m / z) value is 486.13, and the measured value is 486.15.

[0461] [Example 17] Synthesis 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)prop-1-one (20a)

[0462]

[0463] Step 1: Synthesis of (E)-3-(2-chloropyrimidin-5-yl)ethyl acrylate (imL14-1): A mixture of 5-bromo-2-chloropyrimidin (0.19 g, 1.00 mmol), ethyl acrylate (0.42 mL, 4.00 mmol), palladium(II) diacetate (8.98 mg, 0.04 mmol), and tris(o-tolyl)phosphine (30.43 mg, 0.10 mmol) in dimethylformamide (2 mL) and diisopropylethylamine (1 mL) was heated under reflux for 4 hours and then cooled to room temperature. The solvent was evaporated to dryness and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and then concentrated. The residue was separated by column chromatography (ethyl acetate / hexane) to give the subject compound (0.15 g, 71.2%) as a pale yellow solid.

[0464] 1 H NMR (400MHz, CDCl3) δ8.76 (d, J=0.6Hz, 2H), 7.59 (d, J=16.2Hz, 1H), 6.58 (d, J=16.2Hz, 1H), 4.30 (q, J=7.2Hz, 2H), 1.35 (t, J=7.1Hz, 3H).

[0465] Step 2: Synthesis of (E)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl acrylate (imL14-2)

[0466] The subject compound (0.11 g, 71.5%) as a white solid was synthesized using imL14-1 (0.11 g, 0.50 mmol) instead of ethyl 2-chloropyrimidine-5-carboxylate and using 2-aminoindane (0.80 g, 6.00 mmol) and triethylamine (1.01 g, 10 mmol) according to the same steps as in step 1 of Example 1.

[0467] 1 H NMR(400MHz, CDCl3)δ8.38(br s, 2H), 7.48 (d, J=16.1Hz, 1H), 7.26-7.14 (m, 4H), 6.29 (d, J=16.1Hz, 1H), 6.01 (s, 1H), 4.96-4.78 (m, 1H) , 4.26 (q, J=7.1Hz, 2H), 3.41 (dd, J=16.0, 7.0Hz, 2H), 2.90 (dd, J=16.0, 4.8Hz, 2H), 1.34 (t, J=7.1Hz, 3H).

[0468] Step 3: Synthesis of ethyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propionate (imL14-3)

[0469] In a round-bottom flask containing 20 mL of ethyl acetate / methanol / tetrahydrofuran (1:2:1) (92.81 mg, 0.30 mmol), 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 atmosphere for 6 hours. The mixture was filtered through a celite filter and the filtrate was concentrated. The residue was purified by column chromatography (ethyl acetate / hexane) to give the subject compound as a white solid (78.56 mg, 84.1%).

[0470] 1 H NMR (400MHz, CDCl3) δ8.10 (s, 2H), 7.25-7.13 (m, 4H), 5.65 (d, J=7.8Hz, 1H), 4.84-4.68 (m, 1H), 4.13 (q, J=7.2Hz, 2H), 3.38 (dd, J=16.0, 7.0Hz, 2H), 2.86 (dd, J=15.9, 5.0Hz, 2H), 2.74 (t, J=7.5Hz, 2H), 2.54 (t, J=7.3Hz, 2H), 1.25 (t, J=7.1Hz, 3H).

[0471] Step 4: Synthesis of 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)propionic acid (L14)

[0472] A solution of lithium hydroxide (5.00 mmol) in water (2 mL) was added to a solution of 1 μL 14-3 (1.00 mmol) in a mixture of tetrahydrofuran / methanol (18 mL: 2 mL). The reaction mixture was stirred at room temperature for 6 hours. The solvent was then evaporated and redissolved in water and acidified with 1 M 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 give the subject compound (60.33 mg, 84.4%) as a white solid.

[0473] Step 5: Synthesis 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)prop-1-one (20a)

[0474] 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) were added to a 10 mL vial containing 2 mL of N,N'-dimethylformamide. Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU) (45.51 mg, 0.12 mmol) was added to the stirred mixture. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by column chromatography (dichloromethane / methanol) to give the main compound as a white solid (36.95 mg, 88.5%).

[0475] 1 H NMR (400MHz, CDCl2) δ13.71 (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=7.6Hz, 1H), 4.83-4.70(m, 1H), 4.71-4.57(m, 1H), 3.9 4-3.81 (m, 1H), 3.37 (dd, J=16.0, 7.1Hz, 2H), 3.21-3.09 (m, 1H), 3.07-2.94 (m, 1H) , 2.91-2.73 (m, 5H), 2.60 (t, J=7.2Hz, 2H), 2.08-1.98 (m, 2H), 1.71-1.49 (m, 2H); C 23 H 28 N7O(M+H) +The calculated HRMS(ESI) m / z value is 418.24; the measured value is 418.2354.

[0476] [Example 18] Synthesis of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)prop-1-one (20b)

[0477] The subject compound was synthesized according to the same steps as in Example 17, except that (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%) in step 5.

[0478] 1 H NMR (400MHz, CDCl3) δ9.97 (s, 1H), 8.17 (s, 2H), 7.55 (d, J=1.2Hz, 1H), 7.25-7.19 (m, 2H ), 7.19-7.13(m, 2H), 6.74(s, 1H), 5.40(d, J=7.8Hz, 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, 7.0Hz, 2H), 3.16-3.07 (m, 1H), 2.89-2.77 ( m, 5H), 2.76-2.68 (m, 1H), 2.58 (t, J=7.4Hz, 2H), 2.09-1.98 (m, 2H), 1.60-1.44 (m, 2H); C 24 H 29 The calculated HRMS(ESI) m / z value of N6O(M+H)+ is 417.24, and the measured value is 417.2400.

[0479] [Example 19] Synthesis 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)but-1-one (21a)

[0480]

[0481] Step 1: Synthesis of 2-isocyanothio-2,3-dihydro-1H-indene (imL15-1)

[0482] Sulfogen phosgene (115.00 μL, 0.15 mmol) was added dropwise to a cooled mixture of 2-aminoindenhydride (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 hours, 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 main compound (0.173 g, 98.8%) as a light brown solid.

[0483] 1 H NMR (400MHz, CDCl3) δ7.26-7.19 (m, 4H), 4.53 (tt, J=6.9, 5.2Hz, 1H), 3.32 (dd, J=15.9, 7.0Hz, 2H), 3.16 (dd, J=15.8, 5.2Hz, 2H).

[0484] Step 2: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)hydrazine thioamide (imL15-2)

[0485] Hydrazine hydrate (200 μL) was added to a 1 μL 15⁻¹ solution (0.14 g, 0.08 mmol) in ethanol (5 mL). The reaction mixture was stirred overnight at room temperature. 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 subject compound (0.156 g, 94.3%) as a pale yellow solid.

[0486] 1 H NMR (400MHz, CDCl3) δ7.59 (s, 1H), 7.28-7.14 (m, 4H), 5.24-5.13 (m, 1H), 3.68 (s, 1 H), 3.43 (dd, J=16.2, 7.2Hz, 2H), 2.93 (dd, J=16.2, 4.7Hz, 2H), 1.37-1.16 (m, 2H).

[0487] Step 3: Synthesis of ethyl 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butyrate (imL15-3)

[0488] A solution of ethyl 4-cyanobutyrate (70.59 mg, 0.50 mmol) and 1 μL 15-2 (0.10 g, 0.50 mmol) was stirred overnight in trifluoroacetic acid (3 mL) at 80 °C. The mixture was cooled to 0 °C and quenched with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane / methanol) to give the main compound (0.10 g, 62.5%) as a white solid.

[0489] 1 H NMR (400MHz, CDCl3) δ7.26-7.13 (m, 4H), 6.01 (s, 1H), 4.42 (p, J=5.7Hz, 1H), 4.13 (q, J=7.1Hz, 2H), 3.38 (dd , J=16.1, 6.9Hz, 2H), 3.11-2.86 (m, 4H), 2.41 (t, J=7.4Hz, 2H), 2.05 (p, J=7.4Hz, 2H), 1.26 (t, J=7.1Hz, 3H).

[0490] Step 4: Synthesis of 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)butyric acid (L15)

[0491] The subject compound (68.90 mg, 75.7%) as a white solid was synthesized using imL15-3 (0.10 g, 0.30 mmol) following the same steps as in step 4 of Example 17.

[0492] Step 5: Synthesis 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)but-1-one (21a)

[0493] L15 (0.10 mmol), 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (0.12 mmol), and N,N-diisopropylethylamine (0.30 mmol) were added to a 10 mL vial containing 2 mL of N,N'-dimethylformamide. Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate (HBTU) (0.12 mmol) was added to the stirred mixture. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and the crude product was separated by column chromatography (dichloromethane / methanol) to give the subject compound as a white solid (19.34 mg, 44.2%).

[0494] 1H NMR (400MHz, CDCl3) δ7.47 (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); C 22 H 28 The calculated HRMS(ESI) m / z value of N7OS(M+H)+ is 438.21; the measured value is 438.2076.

[0495] [Example 20] Synthesis of 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-indene-2-yl)amino)-1,3,4-thiadiazol-2-yl)but-1-one (21b): The subject compound (38.24 mg, 68.0%) as a white solid was synthesized according to the same steps as in step 5 of Example 19, except that 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 (0.12 mmol).

[0496] 1 H NMR (400MHz, CDCl3) δ7.52 (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); C 23 H 29 The calculated HRMS(ESI) m / z value of N6OS(M+H)+ is 437.21; the measured value is 437.2126.

[0497] [Example 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- Synthesis of diazol-2-yl)but-1-one (22a)

[0498]

[0499] Step 1: Synthesis of tert-butyl 2-(5-methoxy-5-oxopentanoyl)hydrazide carboxylate (imL17-1)

[0500] N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.00 mmol) was added to a mixture containing methyl glutarate (5.00 mmol), tert-butyl hydrazinocarbamate (6.00 mmol), and 4-dimethylaminopyridine (0.025 mmol) in dichloromethane (2 mL). The reaction mixture was stirred overnight at room temperature. 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 give the subject compound (1.14 g, 87.6%) as a white solid.

[0501] Step 2: Synthesis of methyl 5-hydrazino-5-oxovalerate hydrochloride (imL17-2)

[0502] The subject compound (quantitative) was synthesized as a white solid using imL17-1 (0.52 g, 2.00 mmol) following the same steps as in step 2 of Preparation Example 1.

[0503] 1 H NMR (400MHz, MeOD) δ3.66 (s, 3H), 2.41 (t, J=7.3Hz, 2H), 2.36 (t, J=7.4

[0504] Hz, 2H), 1.94 (p, J=7.4Hz, 2H).

[0505] Step 3: 4-(5-oxo-4,5-dihydro-1,3,4-) Synthesis of diazol-2-yl)butyrate methyl ester (imL17-3)

[0506] A solution of 4.0 M hydrochloric acid (2 mL) in dioxane was added to a solution of im17-2 (0.52 g, 2.00 mmol) in dioxane (10 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness to give the subject compound as a white solid (quantitative).

[0507] 1H NMR (400MHz, MeOD) δ3.66 (s, 3H), 2.41 (t, J=7.3Hz, 2H), 2.36 (t, J=7.4Hz, 2H), 1.94 (p, J=7.4Hz, 2H).

[0508] Step 4: 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- Synthesis of diazol-2-yl)butyrate methyl ester (imL17-4)

[0509] The subject compound (0.12 g, 50.2%) as a white solid was synthesized using imL17-3 (0.149 mg, 0.80 mmol) and 2-aminoindene (0.13 g, 0.96 mmol) according to the same steps as in step 4 of Example 1.

[0510] 1 H NMR (400MHz, CDCl3) δ7.27-7.15 (m, 4H), 5.34 (s, 1H), 4.51 (qt, J=6.9, 4.6Hz, 1H), 3.67 (s, 3H), 3.36 (dd, J=16. 1, 6.9Hz, 2H), 2.97 (dd, J=16.1, 4.6Hz, 2H), 2.74 (t, J=7.3Hz, 2H), 2.43 (t, J=7.3Hz, 2H), 2.03 (p, J=7.3Hz, 2H).

[0511] Step 5: 4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- Synthesis of diazol-2-yl)butyric acid (L17)

[0512] The subject compound (0.11 g, 96.8%) was synthesized as a white solid according to the same steps as in step 4 of Example 17, except that imL17-4 (0.12 g, 0.40 mmol) was used instead of imL14-3.

[0513] 1 H NMR (400MHz, CDCl3) δ8.42 (br s, 1H), 7.25-7.14 (m, 4H), 6.09 (br s, 1H), 4.47 (tt, J=7.0, 5.2Hz, 1H), 3.35 (dd, J=16.0, 7.0Hz, 2H), 2.95 (dd, J=16. 0, 5.2Hz, 2H), 2.77 (t, J=7.3Hz, 2H), 2.43 (t, J=7.1Hz, 2H), 2.02 (p, J=7.2Hz, 2H).

[0514] Step 6: 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- Synthesis of diazol-2-yl)but-1-one (22a)

[0515] The subject compound (28.37 mg, 67.3%) as a white solid was synthesized 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) according to the same steps as in step 5 of Example 19.

[0516] 1 H NMR (400MHz, CDCl3) δ13.51 (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); C 22 H 28 The calculated HRMS(ESI) m / z value for N7O2(M+H)+ is 422.2299; the measured value is 422.2300.

[0517] [Example 22] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4- Synthesis of diazol-2-yl)but-1-one (22b)

[0518] The subject compound was synthesized according to the same steps as in Example 21 (yield: 69.4%), except that 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 in step 6.

[0519] 1H NMR (400MHz, CDCl3) δ7.50 (d, J=1.2Hz, 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), 3.38-3.3 0(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, 1H), 2.48-2.36(m, 2H), 2.10-1.91(m, 4H), 1.70-1.52(m, 2H); C 23 H 29 The calculated HRMS (EsI) m / z (M+H) of N6O2 is 421.2347; the measured value is 421.2348.

[0520] [Example 23] Synthesis 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)acetone (23)

[0521]

[0522] Step 1: Synthesis of methyl 2-(cyanomethoxy)acetate (imL18-1)

[0523] Sodium hydride 60% (0.24 g, 6.00 mmol) was slowly added to a solution of methyl glycolate (0.45 g, 5.00 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred continuously at room temperature for 1 hour until bubbling ceased. Bromoacetonitrile (0.72 g, 6.00 mmol) was added to the mixture and the reaction mixture was stirred overnight at room temperature. 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 give the main compound (0.395 g, 61.2%) as a colorless oil.

[0524] 1 H NMR (400MHz, CDCl3) δ4.46 (s, 2H), 4.25 (s, 2H), 3.80 (s, 3H).

[0525] Step 2: Synthesis of methyl 2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetate (imL18-2)

[0526] A mixture of 1 μL 15-2 (0.41 g, 2.00 mmol) and 1 μL 18-1 (0.26 g, 2.00 mmol) was heated overnight at 80 °C in trifluoroacetic acid (3 mL). The mixture was cooled to 0 °C and quenched with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (dichloromethane / methanol) to give the subject compound (0.29 g, 62.5%) as a white solid.

[0527] 1 H NMR (400MHz, CDCl3) δ7.26-7.16(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, 6.8Hz, 2H), 2.99 (dd, J=16.1, 4.7Hz, 2H).

[0528] Step 3: Synthesis of 2-((5-((2,3-dihydro-1H-inden-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)acetic acid (L18)

[0529] The subject compound was synthesized using imL18-2 (0.32 g, 1.00 mmol) following the same steps as in step 4 of Example 17 (yield: 91.3%).

[0530] 1 H NMR (400MHz, DMSO-d6) δ8.09 (d, J=6.2Hz, 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, 7.1Hz, 2H), 2.89 (dd, J=16.1, 5.1Hz, 2H).

[0531] Step 4: Synthesis 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)acetone (23)

[0532] The subject compound, as a white solid (yield: 60.2%), was synthesized 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) following the same steps as in step 5 of Example 17.

[0533] 1 H NMR (400MHz, CDCl3) δ7.46 (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- C 21 H 25 HRMS(ESI) m / z(M+H) of N7O2S + Calculated value = 462.1863; Measured value = 462.1686.

[0534] [Example 24] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0535] The subject compound was synthesized according to the same steps as in Example 1 (14.7 mg, yield: 30%), except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-2-amine (4a), and 2-(piperidin-4-yl)-5-(trifluoromethyl)-1,3,4- Diazole trifluoroacetate (im19) replaces 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0536] 1 H NMR (400MHz, CDCl3): δ8.79 (s, 2H), 7.03 (t, J=8.7Hz, 2H), 5.71 (d, J=7.6Hz, 1H), 4.94-4.84 (m, 1H), 4.14 (d, J=13.6Hz, 2H), 3.49 (d , J=4.7Hz, 1H), 3.43-3.25 (m, 5H), 2.86 (dd, J=16.0, 5.2Hz, 2H), 2.30 (dd, J=13.7, 3.0Hz, 2H), 2.17-2.02 (m, 2H); LCMSm / z535[M+H] + .

[0537] [Example 25] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(difluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0538] The subject compound (32.5 mg, yield: 62.4%) was synthesized according to the same steps as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-2-amine (4a), and 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4- Diazole (im20) replaces 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0539] 1 H NMR (400MHz, CDCl3): δ8.78 (s, 2H), 7.03 (t, J=8.8Hz, 2H), 6.72-6.98 (t, J=52Hz, 1H), 5.77 (d, J=7.4Hz, 7H), 4.89 (m, 1H), 4.13 (d, J=13.5H LCMS m / z 517[M+H] + .

[0540] [Example 26] 5-(5-(4-(1,2,4-) (diazol-3-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0541] The subject compound (12.6 mg, yield: 29.8%) was synthesized according to the same steps as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-2-amine (4a), and 3-(piperidin-4-yl)-1,2,4- Diazole replaced 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0542] 1H NMR (400MHz, DMSO-d6): δ9.53 (s, 1H), 8.75 (s, 2H), 8.25 (d, J=6.7Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 4.69 (dd, J=13.8, 7.2Hz, 1H), 3.96 (d, J=13.1H z, 2H), 3.24 (dd, J=16.1, 7.6Hz, 4H), 3.17 (dd, J=9.0, 6.4Hz, 1H), 2.88 (dd, J=16.1, 6.5Hz, 2H), 2.06 (d, J=11.1Hz, 2H), 1.83-1.70 (m, 2H); LCMS m / z 467[M+H] + .

[0543] [Example 27] 5-(5-(4-(1,3,4-) (diazol-2-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0544] The subject compound (7.6 mg, yield: 6.7%) was synthesized according to the same steps as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-2-amine (4a), and 2-(piperidin-4-yl)-1,3,4- Diazole replaced 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0545] 1 H NMR (400MHz, DMSO-d6): δ9.17 (s, 1H), 8.76 (d, J=11.8Hz, 2H), 8.26 (d, J=8.0Hz, 1H), 7.28 (t, J=9.1Hz, 2H), 4.69 (dd, J=15.0, 7.9Hz, 1H), 3. 95 (d, J=12.5Hz, 2H), 3.24 (dd, J=18.0, 9.2Hz, 5H), 2.88 (dd, J=16.3, 6.2Hz, 2H), 2.12 (d, J=13.3Hz, 2H), 1.81 (dd, J=22.6, 9.9Hz, 2H); LCMS m / z 467[M+H] + .

[0546] [Example 28] 5-(5-(4-(1H-tetrazol-1-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0547] The subject compound (20.9 mg, yield: 54.4%) was synthesized according to the same steps as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-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).

[0548] 1 H NMR (400MHz, DMSO-d6): (DMSO-d6) δ9.00 (s, 1H), 8.77 (d, J=10.6Hz, 2H), 8.27 (d, J= 6.7Hz, 1H), 7.28 (t, J=9.4Hz, 2H), 5.21 (dd, J=14.3, 8.5Hz, 1H), 4.68 (dd, J=14.1, 6 .9Hz, 1H), 4.02 (d, J=13.5Hz, 2H), 3.39 (t, J=11.3Hz, 2H), 3.24 (dd, J=16.2, 7.6Hz, 2H), 2.88 (dd, J=16.0, 6.3Hz, 2H), 2.31 (d, J=9.8Hz, 2H), 2.20-2.06 (m, 2H); LCMSm / z 467[M+H] + .

[0549] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0550] The subject compound (3.7 mg, yield: 20%) was synthesized according to the same steps as in Example 1, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2,3-dihydro-1H-indene-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).

[0551] 1H NMR (400MHz, CDCl3): δ8.79 (s, 2H), 7.02 (t, J=8.8Hz, 2H), 5.90 (d, J=7.7Hz, 1H), 4.88 (dd, J=12.6, 5.4Hz, 1H), 4.16 (d, J=12.9Hz, 2H), 3.36 (d d, J=16.0, 7.0Hz, 2H), 3.30-3.20 (m, 2H), 2.88 (d, J=5.1Hz, 1H), 2.84 (d, J=5.0Hz, 1H), 2.33 (s, 3H), 2.06-1.90 (m, 2H), 1.52-1.39 (m, 2H); LCMS m / z 480[M+H] + .

[0552] [Example 30] Synthesis 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

[0553] Step 1: Synthesis of (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)ethyl acrylate (imL22-1)

[0554] A mixture of im L14-1 (0.249 g, 1.17 mmol), 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (0.160 g, 0.585 mmol), diisopropylethylamine (1.5 g, 11.7 mmol), and n-BuOH (1.2 mL) was stirred in a microwave reactor at 150 °C for 2 h. The reaction mixture was concentrated under vacuum and subsequently purified by column chromatography (hexane / ethyl acetate) to give the main compound (0.132 g, 65.3%) as a brown solid.

[0555] 1 H NMR (400MHz, DMSO-d6) δ 8.67 (s, 2H), 8.09 (d, J = 6.8Hz, 1H), 7.48 (d, J = 16.1Hz, 1H), 7.26 (t, J = 9.3Hz, 2H), 6.51 (d, J = 16.1Hz, 1H), 4.66 (dd, LCMSm / z 346[M+HJ + .

[0556] Step 2: Synthesis of (E)-3-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)acrylic acid (L22)

[0557] The subject compound (0.90 g, 97.0%) was synthesized as a pale yellow solid according to the same steps as in step 4 of Example 17, except that imL22-1 was used instead of imL14-3.

[0558] 1 H NMR (400MHz, DMSO-d6) δ12.17 (bs, 1H), 8.64 (s, 2H), 8.05 (d, J = 7.2Hz, 1H), 7.41 (d, J = 16.0Hz, 1H), 7.26 (t, J = 9.3Hz , 2H), 6.41 (d, J=16.2Hz, 1H), 4.66 (dd, J=14.0, 6.8Hz, 1H), 3.26-3.19 (m, 2H), 2.86 (dd, J=16.1, 6.6Hz, 2H); LCMSm / z 318[M+H] + .

[0559] Step 3: Synthesis 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)

[0560] The subject compound (0.019 g, 29.3%) was synthesized as a yellow solid according to the same steps as in step 5 of Example 17, except that L22 was used instead of L14.

[0561] 1 H NMR (400MHz, DMSO-d6): δ8.71 (s, 2H), 8.06 (s, 1H), 7.67 (s, 1H), 7.35 (d, J=1 5.3Hz, 1H), 7.26 (t, J=9.2Hz, 2H), 7.21 (d, J=15.5Hz, 1H), 4.69-4.63 (m, 1H) , 4.39 (dd, J=62.1, 11.5Hz, 4H), 3.23 (dd, J=16.0, 7.5Hz, 2H), 3.00 (dd, J=18 .4, 7.4Hz, 1H), 2.86 (dd, J=16.2, 6.6Hz, 2H), 1.95 (s, 2H), 1.51 (s, 2H); LCMS m / z452[M+H] + .

[0562] [Example 31] 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl) Synthesis of (31)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0563]

[0564] Step 1-1: Synthesis of 4-ethynylpiperidine hydrochloride (imL23-1)

[0565] 4-Ethynylpiperidin-1-carboxylic acid tert-butyl ester (12.0 g, 57.4 mmol) was dissolved in Et₂O (100 mL) and cooled to 0 °C. HCl (4 M, 100 mL) was added to Et₂O and the mixture was stirred for 20 hours. Et₂O was evaporated and PE was added. The solid was then filtered and washed with PE and Et₂O to give the main compound (imL23-1) (8.3 g, yield: 99.4%) as a white solid.

[0566] LCMS m / z 110[M+H] +

[0567] Steps 1-2: Synthesis of tert-butyl (2-(4-ethynylpiperidin-1-yl)-2-oxoethyl)carbamate (imL23-2)

[0568] EDCI (13.1 g, 68.5 mmol) and HOBt (9.2 g, 68.5 mmol) were added to a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (10.0 g, 57.1 mmol) in DMF (50 mL) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. imL23-1 (8.3 g, 57.1 mmol, HCl salt) and TEA (17.3 g, 171.3 mmol) were added and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with EA, washed with water and NaCl, dried over Na2SO4, filtered, and concentrated. The main compound (imL23-2) (15.1 g, yield: 99.7%) was given as a yellow oil.

[0569] LCMS m / z 267[M+H] +

[0570] Steps 1-3: Synthesis of 2-amino-1-(4-ethynylpiperidin-1-yl)acetone hydrochloride (imL23-3)

[0571] imL23-2 (15.1 g, 57.1 mmol) was dissolved in Et2O (100 mL) and cooled to 0 °C. HCl (4 M, 70 mL) was added to the Et2O and the mixture was stirred for 20 hours. The Et2O was evaporated and PE was added. The solid was then filtered and washed with PE and Et2O to give the main compound (imL23-3) (17.7 g, yield: 100%) as a white solid.

[0572] LCMS m / z 167 [M+H] +

[0573] Step 2-1: Synthesis of 2-chloropyrimidine-5-carbonyl chloride (imL23-4)

[0574] Oxaloyl dichloride (48.0 g, 378 mmol) and 6 drops of DMF were slowly added to a solution of 2-chloropyrimidine-5-carboxylic acid (30.0 g, 189 mmol) in DCM (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness to give the main compound (imL23-4) (33 g, yield: 99.8%) as a white solid, which was used in the following reaction without purification.

[0575] Step 2-2: Synthesis of 2-chloro-N-(2-(4-ethynylpiperidin-1-yl)-2-oxoethyl)pyrimidine-5-carboxamide (imL23-5)

[0576] TEA (52.7 g, 522 mmol) and DMAP (600 mg) were added to a solution of imL23-3 (17.7 g, 87.0 mmol) in DCM (400 mL). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 °C. ImL23-4 (16.9 g, 95.7 mmol) was added and stirred overnight at room temperature. The reaction mixture was extracted with DCM, washed with water and NaCl, dried over Na2SO4, filtered, and concentrated. The product was purified by column chromatography (DCM:MeOH = 100:1 to 20:1) to give the main compound (imL23-5) as a yellow solid (15.8 g, yield: 59.4%).

[0577] LCMS m / z 307[M+H] +

[0578] Steps 2-3: 2-(2-chloropyrimidin-5-yl)-5-(4-ethynylpiperidin-1-yl) Synthesis of azole (imL23-6)

[0579] After cooling to 0°C under Ar atmosphere, perchloroethane (46.5 g, 193.9 mmol) was added to a solution of PPh3 (51.0 g, 193.9 mmol) in DCM (400 mL). The mixture was stirred at 0 to 20°C for 0.5 h. After cooling to 0°C again, 1 μL 23-5 (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 the mixture to pH 9 to 10 and stirred overnight at room temperature. The reaction mixture was extracted with DCM, washed with water and NaCl, followed by saturated Na2CO3, and then dried over Na2SO4, filtered, and concentrated. The P(O)Ph3 solid was removed by dilution with Et2O, the filtrate was concentrated, and purified by Al2O3 column (PE:EA = 20:1 to 10:1 to DCM:EA = 100:0 to 20:1) to give 7.3 g of yellow solid (crude product, 88% purity). The solid was purified again using an Al2O3 column (0.1% TEA) (PE:EA = 50:1 to 1:1) to give 5.3 g of yellow solid. The yellow solid was then purified with PE to give the main compound (imL23-6) (5.2 g, yield: 36.9%), which is the yellow solid.

[0580] 1 H NMR (400MHz, CDCl3): δ9.04 (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] + .

[0581] Steps 2-4: N-(2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl) Synthesis of (L23)-azolo-2-yl)pyrimidin-2-amine

[0582] A mixture of 2-aminoindenhydride (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 at 100 °C for 1 hour. After cooling, the solvent was evaporated and the product was purified by column chromatography (hexane / ethyl acetate) to give the main compound (0.190 g, 14.2%) as a brown solid.

[0583] Steps 2-5: 5-(5-(4-(1-benzyl-1H-1,2,3-triazol-5-yl)piperidin-1-yl) Synthesis of (31)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0584] A solution of L23 (0.145 g, 0.376 mmol) in DMF / MeOH (3.4 mL / 0.38 mL) was added with 0.5 M benzyl azide solution (502 μL, 0.564 mmol), CuI (0.115 g, 0.602 mmol), and DIPEA (128 μL, 0.564 mmol) in DCM, and stirred at 40 °C for 1 h. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give the main compound (1.3 mg, 6.7%) as a brown solid.

[0585] 1 H NMR (400MHz, DMSO-d6): δ8.71 (s, 2H), 8.01 (d, J=6.8Hz, 1H), 7.99 (s, 1H), 7 .37-7.26(m, 5H), 7.16(d, J=21.5Hz, 4H), 6.23(s, 1H), 5.53(s, 2H), 3.57(d , J=12.6Hz, 1H), 3.24 (dd, J=15.1, 7.8Hz, 4H), 2.91 (d, J=7.8Hz, 2H), 2.87 ( t, J=7.0Hz, 3H), 2.00 (d, J=12.8Hz, 2H), 1.69 (dd, J=13.4, 4.6Hz, 2H); LCMS m / z519[M+H] + .

[0586] [Example 32] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine

[0587]

[0588] Step 1: 5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)(methyl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazole-2(3H)-one (L26)

[0589] NaH (60%) (7.2 mg, 0.181 mmol) was added to a solution of 7e (20 mg, 0.060 mmol) in DMF (0.6 mL) at 0 °C and stirred at 0 °C for 30 min. CH3I (11 μL, 0.181 mmol) was added and stirred overnight at room temperature. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by column chromatography (DCM / MeOH) to give the subject compound (L26) (9.9 mg, yield: 47.5%) as a white solid.

[0590] LCMS m / z 346 [M+H] +

[0591] Step 2: 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-N-methylpyrimidin-2-amine (32)

[0592] 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, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by column chromatography (DCM / MeOH) to give the subject compound (32) (1.5 mg, yield: 13.3%) as a white solid.

[0593] 1 H NMR (400MHz, DMSO-d6): δ8.81 (s, 2H), 7.69 (s, 1H), 7.31 (t, J=9.2Hz, 2H), 5.75 (dt, J=15.4, 7.9Hz, 1H), 3.97 (d, J=13.2H z, 2H), 3.27-3.10 (m, 5H), 3.05 (d, J=6.9Hz, 2H), 3.01 (s, 3H), 2.02 (d, J=11.9Hz, 2H), 1.69 (dd, J=22.4, 11.0Hz, 2H); LCMS m / z480[M+H] + .

[0594] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0595]

[0596] Step 1-1: Synthesis of neopentanoic acid azidomethyl ester (im27-1)

[0597] NaN3 (0.648 g, 9.96 mmol) was added to a solution of methyl chloropentanoate (1 g, 6.64 mmol) in H2O (1.7 mL), and the mixture was stirred overnight at 90 °C. The reaction mixture was diluted with water, extracted with EA, dried over Na2SO4, filtered, and concentrated. The main compound (im27-1) (1 g, yield: 96%) was obtained as a colorless liquid and used in the following reactions without purification.

[0598] Steps 1-2: Synthesis of 4-(1-((neovaleroxy)methyl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester (im27-2)

[0599] CuOAc (78.0 mg, 0.636 mmol) and NaOAc (1.7 g, 19.1 mmol) were added to a solution of im27-1 (1 g, 6.36 mmol) and 4-ethynyl-1-piperidinic acid tert-butyl ester (1.3 g, 6.36 mmol) in THF / H2O (12.7 mL), and the mixture was 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 residue obtained was purified by column chromatography (DCM / MeOH) to give the subject compound (im27-2) (1.18 g, yield: 51%) as a light green oil.

[0600] 1 H NMR (400MHz, CDCl3): δ7.53 (s, 1H), 6.20 (s, 2H), 4.15 (s, 2H), 2.88 (dd, J=26.4, 1 3.4Hz, 2H), 2.02 (d, J=13.1Hz, 2H), 1.65-1.56 (m, 3H), 1.46 (s, 9H), 1.18 (s, 9H).

[0601] Steps 1-3: Synthesis of (4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)neoplastate methyl ester trifluoroacetate (im27)

[0602] TFA (6.0 mL) was added to a solution of im27-2 (0.658 g, 1.80 mmol) in DCM (17.9 mL) at 0 °C and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the main compound (im27) (0.493 g, yield: 74.9%) as a white solid, which was used in the following reaction without purification.

[0603] Step 2-1: (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)neopentanoic acid methyl ester (L27)

[0604] Im27 (0.494 g, 1.35 mmol) was added to a solution of 7e (0.374 mg, 1.13 mmol) in DMF (5.6 mL), and the mixture was 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 overnight at room temperature. The reaction mixture was extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by column chromatography (DCM / MeOH) to give the subject compound (L27) as a yellow solid (0.344 g, yield: 52.61%).

[0605] LC / MS m / z 580[M+H] +

[0606] Step 2-2: 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- Synthesis of diazol-2-yl)pyrimidine-2-amine (33)

[0607] L27 (0.25 g, 0.431 mmol) and MeOTf (57 μL, 0.518 mmol) were dissolved in DCM (500 μL) and stirred overnight at room temperature. The reaction mixture was dissolved in MeOH (2.2 mL), K2CO3 (0.119 g, 1.24 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, washed with DCM, and the filtrate was concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to give the subject compound (33) as a yellow solid (17.7 mg, yield: 6.9%).

[0608] 1 H NMR (400MHz, DMSO-d6): δ 8.76 (s, 2H), 8.25 (d, J = 6.8Hz, 1H), 7.57 (s, 1H), 7.27 (t, J = 9.4Hz, 2H), 4.69 (dd, J = 12.8, 5.5Hz, 1H), 4.03 (d, J = 12.5Hz, 1H) LCMS m / z 480[M+H] + .

[0609] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0610]

[0611] Step 1: N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynylpiperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)pyrimidine-2-amine (L28)

[0612] Add 0.150 g, 0.724 mmol of 4-ethynylpiperidine trifluoroacetate to a solution of 7e (0.2 g, 0.603 mmol) in DMF (3.1 mL), cool to 0 °C, and add DIPEA (308 μL, 1.81 mmol). Stir the mixture at 0 °C for 30 min, then add BOP reagent (0.320 g, 0.724 mmol) and stir at room temperature for 3 h. Extract the reaction mixture with EA, wash the organic layer with brine, dry with Na2SO4, filter, and concentrate. Purify the residue by column chromatography (DCM / MeOH) to give the subject compound (L28) as a white solid (0.101 g, yield: 39.6%).

[0613] LCMS m / z 423[M+H] +

[0614] Step 2: 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- Synthesis of diazol-2-yl)pyrimidine-2-amine (34)

[0615] 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 overnight at room temperature. 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 overnight at room temperature. 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 give the subject compound (34) (1.6 mg, yield: 1.4%) as a yellow solid.

[0616] 1 H NMR (400MHz, DMSO-d6): δ8.75 (s, 2H), 8.24 (d, J=6.8Hz, 1H), 7.87 (s, 1H), 7.27 (t, J=9.4Hz, 2H), 4.68 (dd, J=13.8, 6.9Hz, 1H), 3.97 (s, 5H), 3.2 4 (dd, J=15.9, 7.3Hz, 4H), 2.96 (d, J=11.0Hz, 1H), 2.88 (dd, J=16.2, 6.5Hz, 2H), 2.00 (d, J=11.5Hz, 2H), 1.66 (dd, J=20.0, 11.1Hz, 2H); LCMSm / z 480[M+H] + .

[0617] [Example 35] N-Indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]+4,5-dihydroisocyano Synthesis of [azol-5-yl]pyrimidin-2-amine (35)

[0618]

[0619] Step 1: Synthesis of N-(2,3-dihydro-1H-inden-2-yl)-5-vinylpyrimidine-2-amine (imL24-1)

[0620] 2-Aminoindane (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 h. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated. The resulting residue was then adsorbed onto silica gel and purified by silica gel column chromatography (15% EA in hexane) to give the subject compound (imL24-1) as a white solid (0.837 g, yield: 47%).

[0621] LCMS m / z 238[M+H] +

[0622] Step 2: 5-(3-bromo-4,5-dihydroisocyanate) Synthesis of (L24)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0623] After dissolving 1,1-dibromoformaldehyde oxime (0.960 g, 6.742 mmol) in DMF (7 mL) and cooling to -10 °C, a solution of imL24-1 (0.8 g, 3.371 mmol) and KHCO3 (0.843 g, 8.428 mmol) in H2O (7 mL) was slowly added dropwise to the reaction mixture and 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 resulting residue was adsorbed onto silica gel and purified by silica gel column chromatography (25% EA in hexane) to give the subject compound (L24) (0.905 g, yield: 74.8%) as a yellow solid.

[0624] 1 H NMR (400MHz, CDCl3): δ8.28 (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, 9.4Hz, 1H), 2.92-2.83 (m, 2H); LCMS m / z 360[M+H] + .

[0625] Step 3: N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyanuric acid Synthesis of [azol-5-yl]pyrimidin-2-amine (35)

[0626] 5-(3-bromo-4,5-dihydroisocyanate) (L24)-N-(2,3-dihydro-1H-indene-2-yl)pyrimidin-2-amine (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 t-BuOH and reacted in a microwave reactor for 1 h. After confirming the completion of the reaction by TLC, the mixture was filtered and washed with a solution of 10% MeOH in DCM. The residue obtained by concentrating the filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (5% MeOH in DCM) to give the subject compound (35) as a yellow solid (10.8 mg, yield: 45.1%).

[0627] 1 H NMR (400MHz, CDCl3): δ8.31 (s, 2H), 7.65 (s, 1H), 7.58 (d, J=7.0Hz, 1H), 7.15 (td, J=8.3, 3.2Hz, 4H), 5.25 (t, J=9.4Hz, 1H), 4.62- 4.55 (m, 1H), 3.59 (d, J = 14.2Hz, 2H), 3.25-3.10 (m, 4H), 2.99-2.81 (m, 5H), 1.91 (d, J = 14.6Hz, 2H), 1.62 (d, J = 9.0Hz, 2H); LCMSm / z 431[M+H] + .

[0628] [Example 36] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso Synthesis of (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0629] N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-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, it was diluted with EA, 10% Na2S2O4 was added, and the mixture was stirred for 10 min. 1N NaOH was added to the reaction mixture to adjust the pH to 8 to 10, and the reaction mixture was 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 purified by silica gel column chromatography (2% MeOH in DCM) to give the subject compound (36) (12.8 mg, yield: 44.3%) as a white solid.

[0630] 1 H NMR (400MHz, DMSO-d6): δ8.68 (s, 2H), 8.12 (d, J=6.3Hz, 1H), 7.22-7.10 (m, 4H), 6.73 (s, 1H), 4.66 (d, J=6.8Hz, 1H), 3.71 (d, J=13.0 Hz, 2H), 3.25 (dd, J=15.9, 7.6Hz, 3H), 3.00 (d, J=12.1Hz, 2H), 2.90 (dd, J=15.8, 7.0Hz, 2H), 1.95 (s, 2H), 1.67 (d, J=9.8Hz, 2H); LCMS m / z 429[M+H] + .

[0631] [Example 37] N-(5,6-difluoroinden-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]+4,5-dihydroisocyano Synthesis of [azol-5-yl]pyrimidine-2-amine

[0632] The subject compound (7.3 mg, yield: 30.9%) was synthesized according to the same procedure as in Example 35, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2-aminoindene.

[0633] 1H NMR (400MHz, DMSO-d6): δ8.31 (s, 1H), 7.66-7.60 (m, 2H), 7.25 (t, J=9.2Hz, 2 H), 5.26 (t, J=9.2Hz, 1H), 4.61 (dd, J=14.0, 7.3Hz, 1H), 3.59 (d, J=13.2Hz, 2 H), 3.20 (dd, J=15.9, 7.3Hz, 2H), 3.17-3.09 (m, 2H), 2.98-2.88 (m, 3H), 2.83 (dd, J=15.9, 6.8Hz, 2H), 1.91 (d, J=11.7Hz, 2H), 1.62 (d, J=13.4Hz, 2H); LCMS m / z467[M+H] + .

[0634] [Example 38] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso Synthesis of (-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0635] The subject compound (9.2 mg, 71.6% yield) was synthesized according to the same steps as in Example 36, except that N-(5,6-difluoroindan-2-yl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyanuric acid was used. [Azol-5-yl]pyrimidin-2-amine (Example 37) replaces N-indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyanuric acid [Azol-5-yl]pyrimidin-2-amine (35).

[0636] 1 H NMR (400MHz, DMSO-d6): δ8.67 (s, 1H), 8.13 (d, J=6.7Hz, 1H), 7.64 (d, J=23.5Hz, 1H), 7.27 (t, J=9.2Hz, 2H), 6.73 (s, 1H), 4.68 (dd, J=13.8, 6.9Hz, 1H), 3.71 (d, J=12.9Hz, 2H), 3.24 (dd, J=16.2, 7.5Hz, 2H), 3.02-2.94 (m, 2H), 2. 87 (dd, J=16.2, 6.5Hz, 2H), 1.97 (d, J=12.5Hz, 3H), 1.72-1.60 (m, 2H); LCMS m / z465[M+H] + .

[0637] [Example 39] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0638] The subject compound (3.1 mg, yield: 17.5%) was synthesized according to the same steps as in Example 35, except that 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) was used instead of 2-aminoindene.

[0639] 1 H NMR (400MHz, CDCl3): δ8.35 (s, 2H), 7.53 (s, 1H), 7.11-7.19 (m, 1H), 6.82-6.97 (m, 2H), 5.49 (d, J=6.8Hz, 1H), 5.40 (t, J=8.9Hz, 1H), 4.87-4.77 LCMS m / z 449[M+H] + .

[0640] [Example 40] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso Synthesis of (-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0641] The subject compound (20.3 mg, yield: 58%) was synthesized according to the same steps as in Example 36, except that 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate was used. (5-Azol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-indene-2-yl)pyrimidin-2-amine (Example 39) instead of N-indene-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyanuric acid [Azol-5-yl]pyrimidin-2-amine (35).

[0642] 1H NMR (400MHz, DMSO-d6): δ8.65 (s, 2H), 8.02 (d, J=6.7Hz, 1H), 7.57 (s, 1H), 7.16-7.23 (m, 1H), 6.97 (d, J=8.3Hz, 1H), 6.89 (t, J=8.7Hz, 1H), 6.60 (s, 1H), 4.81-4.66 (m, 1H), 3.78 (d, J=12.8Hz, 2H), 3.42-3.21 (m, 3H), 2.96 (m, 2H), 2.02 (d, J=10.9Hz, 2H), 1.75 (m, 2H); LCMS m / z 447[M+H] + .

[0643] [Example 41] N-[(3,5-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano Synthesis of [azol-5-yl]pyrimidine-2-amine

[0644] The subject compound (8.3 mg, yield: 18.2%) was synthesized according to the same steps as in Example 35, except that (3,5-difluorophenyl)methylamine was used instead of 2-aminoindane.

[0645] 1 H NMR (400MHz, DMSO-d6): δ 8.30 (s, 2H), 7.89 (t, J = 6.5Hz, 1H), 7.65 (bs, 1H), 7.04 (t, J = 9.6Hz, 1H), 6.97 (d, J = 6.7Hz, 2H), 5.24 (t, J = 9.1Hz, 1H), 4.49 ( d, J=6.2Hz, 2H), 3.57 (d, J=12.8Hz, 2H), 3.13 (dd, J=15.9, 9.3Hz, 2H), 2.9 6-2.87 (m, 3H), 1.90 (d, J=12.6Hz, 2H), 1.61 (dd, J=23.3, 14.4Hz, 2H); LCMS m / z 441[M+H] + .

[0646] [Example 42] N-Benzyl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano Synthesis of [azol-5-yl]pyrimidine-2-amine

[0647] The subject compound (6.2 mg, yield: 12.8%) was synthesized according to the same steps as in Example 35, except that phenylmethylamine was used instead of 2-aminoindane.

[0648] 1H NMR (400MHz, DMSO-d6): δ8.28 (s, 2H), 7.82 (t, J=6.4Hz, 1H), 7.64 (bs, 1H), 7.27 (d, J=4.3Hz, 4H), 7.19 (dd, J=8.5, 4.2Hz, 1H), 5.23 (t, J=9.4Hz, 1H), 4. 48 (d, J=6.4Hz, 2H), 3.57 (d, J=12.9Hz, 2H), 3.12 (dd, J=15.9, 9.2Hz, 2H), 2. 97-2.86 (m, 3H), 1.90 (d, J=11.6Hz, 2H), 1.61 (dd, J=21.2, 11.8Hz, 2H); LCMS m / z 405[M+H] + .

[0649] [Example 43] N-[(3,4-difluorophenyl)methyl]-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano Synthesis of [azol-5-yl]pyrimidine-2-amine

[0650] The subject compound (9.7 mg, yield: 20.3%) was synthesized according to the same steps as in Example 35, except that (3,4-difluorophenyl)methylamine was used instead of 2-aminoindane.

[0651] 1 H NMR (400MHz, DMSO-d6): δ8.29 (s, 2H), 7.85 (t, J=6.3Hz, 1H), 7.64 (s, 1H), 7.3 2 (dt, J=17.3, 7.3Hz, 2H), 7.12 (s, 1H), 5.24 (t, J=9.2Hz, 1H), 4.45 (d, J=6.1H z, 2H), 3.57 (d, J=12.7Hz, 2H), 3.12 (dd, J=15.6, 9.4Hz, 2H), 2.91 (dd, J=24.4 , 11.8Hz, 3H), 1.90 (d, J=12.0Hz, 2H), 1.61 (dd, J=20.6, 10.6Hz, 2H); LCMSm / z 441[M+H] + .

[0652] [Example 44] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(3,5-dichlorobenzyl)pyrimidin-2-amine

[0653] The subject compound (4.8 mg, yield: 10.2%) was synthesized according to the same steps as in Example 35, except that (3,5-dichlorophenyl)methylamine was used instead of 2-aminoindane.

[0654] 1 H NMR (400MHz, DMSO-d6): δ8.30 (s, 2H), 7.90 (t, J=6.4Hz, 1H), 7.62 (bs, 1H), 7.43 (s, 1H), 7.32 (s, 2H), 5.24 (t, J=9.2Hz, 1H), 4.48 (d, J=6.4Hz, 2H LCMS m / z 474[M+H] + .

[0655] [Example 45] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine

[0656] The subject compound (5.1 mg, yield: 10.7%) was synthesized according to the same procedure as in Example 35, except that benzo[d][1,3]m-dioxacyclopenten-5-ylmethylamine was used instead of 2-aminoindane.

[0657] 1 H NMR (400MHz, DMSO-d6): δ8.28 (s, 2H), 7.76 (t, J=6.2Hz, 1H), 7.62 (bs, 1H), 6 .85-6.78 (m, 2H), 6.75 (d, J=7.7Hz, 1H), 5.94 (s, 2H), 5.23 (t, J=9.0Hz, 1H), 4 .37 (d, J=6.1Hz, 2H), 3.57 (d, J=12.8Hz, 2H), 3.12 (dd, J=15.9, 9.3Hz, 2H), 2 .96-2.88 (m, 3H), 1.90 (d, J=12.8Hz, 2H), 1.61 (dd, J=19.9, 10.1Hz, 2H); LCMS m / z 449[M+H] + .

[0658] [Example 46] N-(1,3-benzodioxacyclopenten-5-ylmethyl)-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]iso Synthesis of [azol-5-yl]pyrimidine-2-amine

[0659] The subject compound (3.4 mg, yield: 21%) was synthesized according to the same steps as in Example 36, except that 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate was used. (5-azolyl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine (Example 45) instead of N-indan-2-yl-5-[3-[4-(1H-triazolyl-5-yl)-1-piperidinyl]-4,5-dihydroisocyanuric acid [Azol-5-yl]pyrimidin-2-amine (35).

[0660] 1 H NMR (400MHz, DMSO-d6): δ8.64 (s, 2H), 8.25 (t, J=5.9Hz, 1H), 6.87-6.80 (m, 2H), 6.77 (d, J=8.3Hz, 1H), 6.71 (s, 1H), 5.95 (s, 2H), 4.4 3(d, J=6.5Hz, 2H), 3.70 (d, J=12.5Hz, 2H), 3.48 (s, 1H), 3.02-2.93 (m, 3H), 1.96 (d, J=9.8Hz, 2H), 1.66 (dd, J=20.8, 12.7Hz, 2H); LCMS m / z 447[M+H] + .

[0661] [Example 47] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine

[0662] The subject compound (5.8 mg, yield: 12.4%) was synthesized according to the same steps as in Example 35, except that 2-(3,5-dichlorophenyl)ethyl-1-amine was used instead of 2-aminoindane.

[0663] 1H NMR (400MHz, DMSO-d6): δ8.28 (s, 2H), 7.99 (s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.29 (s, 2H), 5.24 (t, J=9.4Hz, 1H), 3.49 (dd, J=12.0 , 6.3Hz, 4H), 3.17-3.11 (m, 2H), 2.95 (d, J=12.9Hz, 2H), 2.83 (t, J=6.6Hz, 2H), 1.91 (d, J=17.4Hz, 3H), 1.62 (d, J=10.8Hz, 2H); LCMS m / z 487[M+H] + .

[0664] [Example 48] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(3-(methylsulfonyl)benzyl)pyrimidine-2-amine

[0665] The subject compound (15.3 mg, yield: 32.6%) was synthesized according to the same steps as in Example 35, except that (3-(methylsulfonyl)phenyl)methylamine was used instead of 2-aminoindane.

[0666] 1 H NMR (400MHz, DMSO-d6): δ8.30 (s, 2H), 7.96 (t, J=6.5Hz, 1H), 7.85 (s, 1H), 7.76 (d, J=7 .5Hz, 1H), 7.63 (d, J=8.1Hz, 2H), 7.57 (d, J=7.6Hz, 1H), 5.24 (t, J=9.2Hz, 1H), 4.58 (d , J=6.1Hz, 2H), 3.57 (d, J=12.8Hz, 2H), 3.31 (dd, J=15.6, 9.1Hz, 1H), 3.17 (s, 3H), 2.9 1 (dd, J=22.5, 10.5Hz, 4H), 1.90 (d, J=11.3Hz, 2H), 1.61 (dd, J=23.4, 13.5Hz, 2H); LCMS m / z 483[M+H] + .

[0667] [Example 49] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(4-(methylsulfonyl)benzyl)pyrimidine-2-amine

[0668] The subject compound (13.2 mg, yield: 28.1%) was synthesized according to the same steps as in Example 35, except that (4-(methylsulfonyl)phenyl)methylamine was used instead of 2-aminoindane.

[0669] 1 H NMR (400MHz, DMSO-d6): δ8.29 (s, 2H), 7.97 (dd, J=9.6, 3.2Hz, 1H), 7.83 (d, J=8.3Hz, 2H), 7.63 (bs, 1H), 7.52 (d, J=8.2Hz, 2H), 5.23 (t, J=9.2Hz, 1H), 4.61-4.54 (m, 2H), 3. 57(d, J=12.8Hz, 2H), 3.31(dd, J=15.9, 9.3Hz, 2H), 3.15(d, J=2.1Hz, 3H), 3.13-3.08( m, 1H), 2.96-2.88 (m, 2H), 1.90 (d, J=12.3Hz, 2H), 1.61 (dd, J=21.0, 12.2Hz, 2H); LCMS m / z 483[M+H] + .

[0670] [Example 50] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0671] The subject compound (15.7 mg, yield: 65.4%) was synthesized according to the same steps 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).

[0672] 1 H NMR (400MHz, DMSO-d6): δ8.31 (s, 2H), 7.59 (d, J=6.5Hz, 1H), 7.15 (d, J=20.3Hz, 4H), 5.26 (t, J=9.6Hz, 1H), 4.62-4.57 (m, 1H), 4.08 (s, 1H), 3.59 (d, J=12.9Hz, 1H), 3.20 (dd, J=14.3, 6.8Hz, 3H), 3.15 (s, 2H), 3.02-2.93 (m, 2 H), 2.89-2.82 (m, 2H), 1.95 (t, J=11.6Hz, 2H), 1.74 (d, J=13.6Hz, 2H); LCMS m / z 432[M+H] + .

[0673] [Example 51] 5-(3-(4-(5-(difluoromethyl)-1,3,4- (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0674] The subject compound (3.7 mg, yield: 13.8%) was synthesized according to the same steps as in Example 35, except that 2-(difluoromethyl)-5-(piperidin-4-yl)-1,3,4- Diazole (im20) replaces 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0675] 1 H NMR (400MHz, DMSO-d6): δ8.31(s, 1H), 7.59(t J=134.0Hz, 1H), 7.59 (J=6.6Hz, 1H), 7.20-7.10 (m, 4H), 5.26 (t, J=9.4Hz, 1H), 4.59 (d, J=7.1Hz, 1H), 3.58 (d, J=13.1Hz, 2H), 3.26-3.11 (m, 5H), 3.05-2.95 (m, 2H), 2.86 (dd, J=15.7, 6.6Hz, 2H), 2.01 (dd, J=25.3, 16.9Hz, 3H), 1.77 (d, J=9.4Hz, 1H); LCMS m / z 482[M+H] + .

[0676] [Example 52] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (-5-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0677] The subject compound (18.7 mg, yield: 79%) was synthesized according to the same steps as in Example 35, except that 5,6-difluoro-2,3-dihydro-1H-indene-2-amine (4e) was used instead of 2-aminoindene in step 1, and 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) in step 3.

[0678] 1H NMR (400MHz, DMSO-d6): δ8.32 (s, 2H), 7.62 (d, J=6.5Hz, 1H), 7.25 (t, J=9.5Hz, 2H), 5.26 (t, J=9.4Hz, 1H), 4.61 (d, J=6.9Hz, 1H), 3.59 (d, J=12. 8Hz, 2H), 3.20 (dd, J=16.2, 7.8Hz, 5H), 3.01-2.93 (m, 2H), 2.83 (dd, J=15.8, 7.0Hz, 2H), 1.98-1.91 (m, 2H), 1.73 (dd, J=22.3, 13.3Hz, 2H); LCMS m / z 468[M+H] + .

[0679] [Example 53] N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (azol-5-yl)pyrimidine-2-amine

[0680] Step 1: 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate Synthesis of (-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine

[0681] The subject compound (15.4 mg, yield: 46%) was synthesized according to the same steps as in Example 35, except that 5-fluoro-2,3-dihydro-1H-indene-2-amine (4b) was used instead of 2-aminoindene in step 1, and 4-(1H-tetrazol-5-yl)piperidine trifluoroacetate (im25) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3) in step 3.

[0682] LCMS m / z 450[M+H] +

[0683] Step 2: N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-5-(3-(4-(5-(trifluoromethyl)-1,3,4-) (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano Synthesis of (azol-5-yl)pyrimidine-2-amine

[0684] 5-(3-(4-(1H-tetrazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyano (9.3 mg, 0.021 mmol)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (5-azol-5-yl)-N-(5-fluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (5.3 mg, 0.021 mmol) was dissolved in DCM, and then trifluoroacetic anhydride (6.5 mg, 0.031 mmol) was added dropwise at 0 °C. The temperature was raised to room temperature, and the mixture was stirred overnight. Trifluoroacetic anhydride (0.1 mL) was added, and the mixture was stirred for another 2 hours. The reaction mixture was then extracted with DCM, and the organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine. After drying with MgSO4, filtration, and concentration, the residue was purified by Prep-TLC (5% MeOH in DCM) to give the subject compound (0.5 mg, yield: 4.7%).

[0685] 1 H NMR (400MHz, CDCl3): δ8.33 (s, 2H), 7.15 (m, 1H), 6.97-6.81 (m, 2H), 5.42 (m, 2H), 4.81 (m, 1H), 3.73 (d, J=13.6Hz, 2H), 3.3 5 (s, J=6Hz, 2H), 3.22 (m, 1H), 3.13-2.94 (m, 4H), 2.84 (td, J=16.2, 5.5Hz, 2H), 2.27-2.14 (m, 2H), 2.08-1.92 (m, 2H); LCMS m / z 518[M+H] + .

[0686] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0687] The subject compound was synthesized according to the same steps as in Example 11 (yield: 8%), except that 7e was used instead of 7d.

[0688] 1¹H 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, 3.1Hz, 1H), 3.41-3.34 (m, 3H), 3.31-3.24 (m, 1H), 2.86 (dd, J=16.0, 5.3Hz, 2 H), 2.03 (d, J=4.4Hz, 2H), 1.81 (dd, J=12.9, 4.8Hz, 1H), 1.40 (d, J=6.9Hz, 3H); C 23 H 24 F2N9O[M+H] + The calculated MS(ESI, m / z) value is 480.21, and the measured value is 480.15.

[0689] [Example 55] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine

[0690] The subject compound was synthesized according to the same steps as in Example 1 (yield: 46%), except that benzo[d][1,3]-dioxacyclopenten-5-ylmethylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0691] 1 H NMR (400MHz, CDCl3) δ12.36 (s, 1H), 8.79 (s, 2H), 7.54 (s, 1H), 6.86-6.75 (m, 3H), 5.95 (s, 2H), 4.60 (d, J=5.9Hz, 2H), 4.14 (dt , J=13.6, 3.7Hz, 2H), 3.27 (ddd, J=13.2, 11.8, 2.9Hz, 2H), 3.06 (tt, J=11.4, 3.7Hz, 1H), 2.19-2.13 (m, 2H), 1.95-1.84 (m, 2H); 13 C NMR (100MHz, CDCl3) δ163.93, 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; C21 H 22 N9O3[M+H] + The calculated HRMS (ESI, m / z) value is 448.1840, and the measured value is 448.1841.

[0692] [Example 56] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,4-dichlorobenzyl)pyrimidin-2-amine

[0693] The subject compound was synthesized according to the same steps as in Example 1 (yield: 36%), except that (3,4-dichlorophenyl)methylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0694] 1 H NMR (400MHz, CDCl3) δ8.80 (s, 2H), 7.54 (s, 1H), 7.47-7.38 (m, 2H), 7.21-7.17 (m, 1H), 5.88 (t, J=6.2Hz, 1H), 4.67 C 20 H 20 Cl2N9O[M+H] + The calculated HRMS (ESI, m / z) value is 472.1162, and the measured value is also 472.1162.

[0695] [Example 57] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,5-difluorobenzyl)pyrimidin-2-amine

[0696] The subject compound was synthesized according to the same steps as in Example 1 (yield: 40%), except that (3,4-difluorophenyl)methylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0697] 1H NMR (400MHz, CD3OD) δ8.78 (s, 2H), 7.52 (s, 1H), 6.92-6.87 (m, 2H), 6.71 (tt, J=8.9, 2.3Hz, 1H), 4.67 (s, 2H), 4.14-4 .09 (m, 2H), 3.29 (ddd, J=13.2, 11.9, 2.9Hz, 2H), 3.07 (tt, J=11.5, 3.6Hz, 1H), 2.20-2.14 (m, 2H), 1.92-1.82 (m, 2H); 13 C NMR (100MHz, CD3OD) δ163.99, 163.39 (q, J=12.8Hz), 162.41, 156.13, 156.05, 149.06, 143.21, 128.77-1 27.05 (m), 110.17 (dd, J=11.9, 7.0Hz), 102.74 (t, J=25.4Hz), 46.45, 44.57 (d, J=2.3Hz), 32.49, 30.86; C 20 H 20 F2N9O[M+H] + The calculated HRMS (ESI, m / z) value is 440.1753, and the measured value is 440.1755.

[0698] [Example 58] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,4-difluorobenzyl)pyrimidin-2-amine

[0699] The subject compound was synthesized according to the same steps as in Example 1 (yield: 43.4%), except that (3,4-difluorophenyl)methylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0700] 1 H NMR (400MHz, CD3OD) δ8.77 (s, 2H), 7.51 (s, 1H), 7.22-7.07 (m, 3H), 4.64 (s, 2H), 4.12 (dLJ=13.3, 3.5Hz, 2H ), 3.32-3.25 (m, 2H), 3.07 (ddt, J=11.5, 7.8, 3.7Hz, 1H), 2.20-2.14 (m, 2H), 1.87 (td, J=12.0, 7.8Hz, 2H); 13C NMR (100MHz, CD3OD) δ163.96, 162.32, 156.11, 156.00, 151.38 (dd, J=74.0, 12.7Hz), 149.02, 148.91 (dd, J=60.1, 12.7Hz), 135.93 (dd C 20 H 20 F2N9O + [M+H] + The calculated HRMS (ESI, m / z) value is 440.1753, and the measured value is 440.1754.

[0701] [Example 59] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(3,5-dibromobenzyl)pyrimidin-2-amine

[0702] The subject compound was synthesized according to the same steps as in Example 1 (yield: 31.7%), except that (3,5-dibromophenyl)methylamine was used instead of 2,3-dihydro-1H-indene-2-amine.

[0703] 1 H NMR (400MHz, CD3OD) δ8.78 (s, 2H), 7.57 (t, J=1.8Hz, 1H), 7.52 (s, 1H), 7.45 (d, J=1.7Hz, 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).; 13 C NMR (100MHz, CD3OD) δ163.99, 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; C 20 H 20 Br2N9O + [M+H] + HRMS (ESI, m / z)

[0704] Calculated value: 560.0152; Measured value: 560.0132.

[0705] [Example 60] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5-bromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0706] The subject compound was synthesized according to the same steps as in Example 1 (yield: 52%), except that 5-bromo-2,3-dihydro-1H-indene-2-amine (4d) was used instead of 2,3-dihydro-1H-indene-2-amine, and ethyl 2-chloro-4-methylpyrimidine-5-carboxylate was used instead of 2-chloropyrimidine-5-carboxylate.

[0707] 1 H NMR (400MHz, CD3OD) δ8.61 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=1.8Hz, 1H), 7.30 (dd, J=8.0, 1.9Hz, 1H), 7.12 (d, J=8.0Hz, 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, 3.7Hz, 1H), 2.95-2.84(m, 2H), 2.68(s, 3H), 2.20-2.13(m, 2H), 1.94-1.83(m, 2H); 13 C NMR (100MHz, CD3OD) δ167.27, 163.85, 161.29, 157.08, 143.75, 140.30, 129.94, 12 8.07, 126.46.120.51, 108.11, 52.82, 46.46, 39.90, 39.52, 32.52, 30.89, 24.59; C 23 H 25 BrN9O[M+H] + The calculated HRMS (ESI, m / z) value is 522.1360, and the measured value is 522.1359.

[0708] [Example 61] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)-N-(5,6-dibromo-2,3-dihydro-1H-inden-2-yl)-4-methylpyrimidin-2-amine

[0709] The subject compound was synthesized according to the same steps as in Example 1 (yield: 50%), except that 5,6-dibromo-2,3-dihydro-1H-indene-2-amine was used instead of 2,3-dihydro-1H-indene-2-amine, and ethyl 2-chloro-4-methylpyrimidine-5-carboxylate was used instead of ethyl 2-chloropyrimidine-5-carboxylate.

[0710] 1 H NMR (400MHz, CDCl3) δ11.96 (s, 1H), 8.63 (s, 1H), 7.54 (s, 1H), 7.49 (s, 2H), 5.65 (d, J = 7.5Hz, 1H), 4.89 (d, J = 6.6Hz, 1H), 4.16-4.11 (m, 2H) C 23 H 24 BrN9O[M+H] + The calculated MS(ESI, m / z) value is 600.04, and the measured value is 600.05.

[0711] [Example 62] Synthesis of 5-(3-(4-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)propyl)-N-(2,3-dihydro1H-inden-2-yl)pyrimidin-2-amine

[0712] 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)prop-1-one (Example 17, 0.47 mmol) was dissolved in DMF and cooled to 0 °C, then lithium aluminum hydride (LiAl4, 0.10 mmol) in ACN was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and then quenched with 1N HCl. The pH was adjusted to 7-8 with an aqueous solution of Na2CO3, and the mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the subject compound (yield: 45%).

[0713] 1H NMR (400MHz, CD3OD): δ8.17 (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, 2 H), 3.14-3.08(m, 2H), 2.94-2.84(m, 3H), 2.58-2.50(m, 4H), 2.33(t, J=11.7Hz, 2H), 2.12-2.06(m, 2H), 1.90-1.78(m, 4H); 13 C C 23 H 30 N7 + [M+H] + The calculated MS(ESI, m / z) value is 404.26, and the measured value is 404.30.

[0714] [Example 63] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-morpholinopiperidin-1-yl)-1,3,4- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0715] The subject compound (14.8 mg, yield: 33.8%) was synthesized as a white solid according to the same steps as in Example 1, except that 4-(piperidin-4-yl)morpholine was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidin·HCl (3).

[0716] 1H NMR (400MHz, DMSO-d6): δ8.73 (s, 2H), 8.24 (d, J=6.5Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 4. 68 (dd, J=13.7, 7.0Hz, 1H), 3.93 (d, J=13.0Hz, 2H), 3.59-3.48 (m, 4H), 3.24 (dd, J=16. 1, 7.6Hz, 2H), 3.06 (t, J=11.4Hz, 2H), 2.87 (dd, J=16.1, 6.5Hz, 2H), 2.46-2.35 (m, 4H) , 1.84 (d, J=11.0Hz, 2H), 1.46 (ddd, J=16.3, 12.8, 4.8Hz, 2H), 1.19-1.11 (m, 1H); LCMS m / z 484[M+H] + .

[0717] [Example 64] 1-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidin-4-yl)azacyclobutane-3-ol

[0718] The subject compound (25.1 mg, yield: 59%) as a grayish-white solid was synthesized according to the same steps as in Example 1, except that 1-(piperidin-4-yl)azacyclobutane-3-ol (1-(piperidin-4-yl)azacyclobutane-3-ol) was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0719] 1 H NMR (400MHz, DMSO-d6): δ8.73 (s, 2H), 8.23 ​​(d, J=6.8Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 5.31 (d, J= 3.2Hz, 1H), 4.68 (dd, J=14.0, 7.2Hz, 1H), 4.23-3.99 (m, 2H), 3.74 (dd, J=7.7, 5.4Hz, 2H), 3.52 (t, J=6.2Hz, 2H), 3.30 (s, 2H), 3.23 (dd, J=16.1, 7.5Hz, 2H), 3.19-3.12 (m, 2H), 2.87 (dd, J=15 .9, 6.5Hz, 2H), 2.74 (s, 1H), 2.25 (s, 1H), 1.71 (d, J = 10.5Hz, 2H), 1.23 (d, J = 12.6Hz, 2H); LCMS m / z470[M+H] + .

[0720] [Example 65] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidine-4-sulfonamide

[0721] The subject compound (20.7 mg, yield: 47.9%) was synthesized as a white solid according to the same steps as in Example 1, except that piperidine-4-sulfonamide was used instead of 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl (3).

[0722] 1 H NMR (400MHz, DMSO-d6): δ8.76 (d, J=12.8Hz, 2H), 8.26 (d, J=6.9Hz, 1H), 7.27 (t, J=9.4Hz, 2H), 6.82 (s, 2H), 4.68 (dd, J=14.1, 7.0Hz, 1H), 4.04 (d, J=12.9 Hz, 2H), 3.24 (dd, J=16.1, 7.5Hz, 2H), 3.13 (t, J=11.4Hz, 3H), 2.87 (dd, J=16 .0, 6.5Hz, 2H), 2.08 (d, J=12.4Hz, 2H), 1.64 (qd, J=12.6, 4.5Hz, 2H); LCMSm / z 478[M+H] + .

[0723] [Example 66] 5-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-2-yl)piperidin-4-yl)-1,3,4- Synthesis of diazon-2(3H)-one

[0724] The subject compound (10.9 mg, yield: 24.9%) was synthesized as a white solid following the same steps as in Example 1, except that 5-(piperidin-4-yl)-1,3,4- Diazol-2(3H)-one replaces 4-(1H-1,2,3-triazol-5-yl)piperidine·HCl(3).

[0725] 1 H NMR (400MHz, DMSO-d6): δ12.14 (s, 1H), 8.75 (d, J=9.9Hz, 2H), 8.26 (d, J

[0726] =4.1Hz, 1H), 7.28 (t, J = 8.8Hz, 2H), 4.68 (d, J = 4.9Hz, 1H), 3.92 (d, J = 13.0Hz, 2H), 3.21 (t, J = 12.3Hz , 4H), 2.83 (dd, J=34.8, 13.5Hz, 3H), 1.99 (d, J=11.4Hz, 2H), 1.68 (dd, J=23.7, 12.3Hz, 2H); LCMSm / z 483[M+H] + .

[0727] [Example 67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidine-4-carboxylic acid

[0728] Step 1: Synthesis of piperidine-4-carboxylic acid methyl ester trifluoroacetate (im29)

[0729] TFA (2.7 mL) was added to a solution of methyl 1-(tert-butoxycarbonyl)-4-piperidinecarboxylate (0.2 g, 0.822 mmol) in DCM (8.2 mL) at 0 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the main compound (im29) (0.181 g, yield: 91.5%) as a white solid, which was used in the following reaction without purification.

[0730] 1 H NMR (400MHz, DMSO-d6): δ8.43 (bs, 1H), 3.61 (s, 3H), 3.23 (d, J=12.9Hz, 2H), 2.91 (td, J=12.6, 3.0Hz, 2H), 2.66 (dd, J=12.9, 9.0Hz, 1H), 1.96 (d, J=14.5Hz, 2H), 1.67 (td, J=15.0, 4.0Hz, 2H).

[0731] Step 2: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidine-4-carboxylic acid methyl ester (L29)

[0732] Add im29 (52.2 mg, 0.217 mmol) to a solution of 7e (60 mg, 0.181 mmol) in DMF (0.9 mL) and cool to 0 °C. Add DIPEA (52 μL, 0.543 mmol) to the reaction mixture and stir at the same temperature for another 30 minutes, then add BOP reagent (96.1 mg, 0.217 mmol) and stir overnight at room temperature. Extract the reaction mixture with EA, wash the organic layer with brine, dry with Na2SO4, filter, and concentrate. Purify the obtained residue by column chromatography (DCM / MeOH) to give the main compound (L29) (60.6 mg, 73.3%) as a pale yellow solid.

[0733] 1 H NMR (400MHz, DMSO-d6): δ8.74 (s, 2H), 8.24 (d, J=6.5Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 4.68 (dd, J=14.0, 6.8Hz, 1H), 3.87 (d, J=13.0Hz, 2H), 3.61 (s, 3H), 3.24 (dd , J=16.1, 7.4Hz, 2H), 3.15 (t, J=11.0Hz, 2H), 2.87 (dd, J=15.9, 6.5Hz, 2H), 2.7 9 (d, J=10.7Hz, 1H), 1.92 (d, J=10.6Hz, 2H), 1.62 (dd, J=20.8, 11.1Hz, 2H); LCMS m / z 457[M+H] + .

[0734] Step 3: 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidine-4-carboxylic acid (67)

[0735] To a solution of L29 (10 mg, 0.022 mmol) in THF (0.1 mL), 1 N NaOH (55 μL, 0.055 mmol) was added and stirred overnight at room temperature. 3 N HCl was added to the reaction mixture to adjust the pH to 2-4, and the reaction mixture was extracted with EA. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated. The main compound was given as a white solid (8.6 mg, 88.7%).

[0736] 1H NMR (400MHz, DMSO-d6) δ12.30 (bs, 1H), 8.74 (s, 2H), 8.24 (d, J=6.8Hz, 1H), 7. 27 (t, J=9.3Hz, 2H), 4.68 (dd, J=13.7, 6.9Hz, 1H), 3.86 (d, J=12.9Hz, 2H), 3.24 (dd, J=16.1, 7.6Hz, 2H), 3.14 (t, J=11.0Hz, 2H), 2.87 (dd, J=15.9, 6.4Hz, 2H), 1.91 (d, J=13.5Hz, 2H), 1.59 (d, J=9.4Hz, 2H), 1.18 (d, J=24.2Hz, 1H); LCMSm / z 443[M+H] + .

[0737] [Example 68] 2-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)piperidin-4-yl)acetic acid

[0738] The subject compound (5.6 mg, 38.5%) as a grayish-white solid was synthesized according to the same steps as in Example 67, except that 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester was used instead of 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid methyl ester.

[0739] [Example 69] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- Synthesis of diazol-2-yl)-N-hydroxypiperidine-4-carboxamide

[0740] To 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- A solution of diazol-2-yl)piperidine-4-carboxylic acid (Example 67) (68 mg, 0.154 mmol) in THF (0.5 mL) was mixed with CDI (37.4 mg, 0.231 mmol) and stirred at room temperature for 1 hour. Then, NH₂OH-HCl (21.4 mg, 0.307 mmol) was added and stirred overnight. The reaction mixture was extracted with EA, the organic layer was collected, washed with brine, dried over MgSO₄, filtered, and concentrated. The resulting residue was purified by column chromatography (DCM / MeOH) to give the subject compound (2.5 mg, 3.6%) as a white solid.

[0741] 1H NMR (400MHz, DMSO-d6): δ10.49 (s, 1H), 8.74 (s, 2H), 8.24 (d, J = 7.1Hz, 1H), 7.27 (t, J = 9.5Hz, 2H), 4.68 (d, J = 7.1Hz, 1H), 3.94 (d, J = 13.1Hz, 2 LCMSm / z 458[M+H] + .

[0742] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0743] (4-(1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-yl) was synthesized according to the same steps as in steps 1-1 to 2-1 of Example 33. Methyl diazol-2-yl)-4-fluoropiperidin-4-yl)-1H-1,2,3-triazol-1-yl)neovalerate (L30) (90 mg, yield: 65%), differing in that 4-ethynyl-4-fluoropiperidin-1-carboxylic acid tert-butyl ester is used instead of 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester.

[0744] 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 8.25 (d, J=6.7Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 6.31 (s, 2H), 4.69 (dd, J=14.0, 7.1 Hz, 1H), 3.78 (m, 2H), 3.51 (m, 2H), 3.24 (dd, J=16.1, 7.5Hz, 2H), 2.93-2.82 (m, 4H), 2.32 (m, 2H), 1.11 (s, 9H); LCMSm / z 598[M+H] + .

[0745] K₂CO₃ (37 mg, 0.27 mmol) was added to a solution of L30 (80 mg, 0.13 mmol) in MeOH (1 mL) and stirred overnight at room temperature. The residue obtained by concentrating the reaction mixture was purified by column chromatography (DCM / MeOH) to give the subject compound (70) as a white solid (20 mg, yield: 31%).

[0746] 1 H NMR (400MHz, DMSO-d6) δ 8.74 (s, 2H), 8.24 (d, J = 6.7Hz, 1H), 7.27 (t, J = 9.3Hz, 2H), 4.68 (dd, J = 13.8, 6.8Hz, 1H), 3.60 (s, 2H), 3. 49 (m, 2H), 3.24 (dd, J=15.9, 7.5Hz, 2H), 2.95 (s, 3H), 2.88 (dd, J=15.9, 6.6Hz, 2H), 2.16 (m, 2H), 2.06 (m, 2H); LCMSm / z496[M+H] + .

[0747] [Example 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- Synthesis of diazol-2-yl)pyrimidine-2-amine

[0748] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-ethynyl-4-fluoropiperidin-1-yl)-1,3,4- Diazol-2-yl)pyrimidin-2-amine (L31) (55 mg, yield: 83%) differs in that 4-ethynyl-4-fluoropiperidine trifluoroacetate is used instead of 4-ethynylpiperidine trifluoroacetate.

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 2H), 8.26 (d, J=6.7Hz, 1H), 7.27 (t, J=9.3Hz, 2H), 4.68 (m, 1H), 4.0 2(d, J=5.2Hz, 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] + .

[0750] L31 (50 mg, 0.11 mmol), trimethylsilyl azide (18 μL, 0.14 mmol), and copper iodide (I) (2.4 mg, 0.013 mmol) were added to a solution of N,N-dimethylformamide / methanol (9:1, 2 mL) and heated at 100 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subsequently purified by column chromatography (dichloromethane / methanol) to give the subject compound (71) (12 mg, yield: 23%) as a white solid.

[0751] 1 H NMR (400MHz, DMSO-d6) δ8.75 (s, 2H), 8.26 (d, J=6.8Hz, 1H), 7.27 (t, J=9.4Hz, 2H), 4.74-4.62 ( LCMS m / z 484[M+H] + .

[0752] Test Example: Evaluation of the inhibitory activity of human autocrine motor factor protein

[0753] (1) Method

[0754] Solutions of the synthesized compounds (80 μM, 100% dimethyl sulfoxide) were sequentially diluted 5-fold with dimethyl sulfoxide to prepare six concentrations. Each concentration was diluted twice with 1× test buffer (50 mM Tris-Cl (pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 140 mM NaCl, deionized water, 1 mg / mL BSA), and 1 μL (1.25% dimethyl sulfoxide) of this diluted mixture was dispensed into each well of a 96-well clear round-bottom plate. 9 μL of 1× test buffer was added to each well, followed by 20 μL of 240 nM human autocrine motor factor protein (buffer: 50 mM Tris-HCl, pH 8.0, containing 150 mM sodium chloride and 20% glycerol). 10 μL of acoustically treated 360 μM 18:1 LysoPC (diluted with 1× test buffer) was added to each well. The reaction was carried out in a shaking incubator at 37°C for 2 hours, and a second reaction mixture (choline assay kit, KA1662) was prepared (65 μL 1× test buffer: 1 μL choline oxidase: 1 μL dye probe). 60 μL of the second reaction mixture was added to the reaction plate and reacted on a shaker for 30 minutes. Absorbance was measured at 570 nm using a SpectraMax iD3 microplate reader. The percentage of inhibitory activity (%inhibition) was calculated using the following formula: (1 - absorbance) 测试组 Absorbance 对照组 )×100.

[0755] (2) Results

[0756] The percentage of inhibitory activity of the compounds of Examples 1 to 71 against autocrine motor factor proteins was calculated and is shown in Table 1 below.

[0757] Table 1

[0758]

[0759]

[0760] All the synthesized compounds in Examples 1 to 71 showed excellent inhibitory activity against human autocrine motor factor protein.

[0761] The foregoing description of the present invention is for illustrative purposes only, and it will be apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the spirit or essential characteristics of the invention. Therefore, it should be understood that the above embodiments are for illustrative purposes only and are not intended to limit the scope of the invention in any way. For example, components described as a single form may also be implemented in a distributed manner, and similarly, components described as distributed may also be implemented in a combined form.

[0762] The scope of this invention is indicated by the appended patent claims. The meaning and scope of the patent claims, as well as all modifications or variations derived therefrom, are considered to fall within the scope of this invention.

Claims

1. Selected from the following piperidine derivatives or their pharmaceutically acceptable salts: [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- diazol-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- (diazol-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- (diazol-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- (diazol-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- (diazol-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- (diazol-2-yl)pyrimidin-2-yl)-6,7-dihydro-5H-cyclopentan[b]pyrazine-6-amine [8] 6-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (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- (diazol-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- (diazol-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- (diazol-2-yl)pyrimidin-2-amine, [12] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-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- (diazol-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- diazol-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- diazol-2-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine [17] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)prop-1-one, [18] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-3-(2-((2,3-dihydro-1H-indene-2-yl)amino)pyrimidin-5-yl)prop-1-one, [19] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-indene-2-yl)amino)-1,3,4-thiadiazol-2-yl)but-1-one, [20] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-indene-2-yl)amino)-1,3,4-thiadiazol-2-yl)but-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- (diazol-2-yl)but-1-one, [22] 1-(4-(1H-imidazol-5-yl)piperidin-1-yl)-4-(5-((2,3-dihydro-1H-indene-2-yl)amino)-1,3,4- (diazol-2-yl)but-1-one, [23] 1-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-2-((5-((2,3-dihydro-1H-indene-2-yl)amino)-1,3,4-thiadiazol-2-yl)methoxy)ethyl-1-one, [24] N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-5-(5-(4-(5-(trifluoromethyl)-1,3,4- (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-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- (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)pyrimidin-2-amine, [26] 5-(5-(4-(1,2,4- (diazol-3-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine, [27] 5-(5-(4-(1,3,4- (diazol-2-yl)piperidin-1-yl)-1,3,4- (diazol-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- (diazol-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- (diazol-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- (diazol-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- (diazol-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- (diazol-2-yl)pyrimidin-2-amine, [35] N-Indan-2-yl-5-[3-[4-(1H-triazol-5-yl)-1-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine, [36] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso (-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-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine, [38] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)iso (-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-dihydroisocyanate (5-Azol-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)iso (5-Azol-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-piperidinyl]-4,5-dihydroisocyano [Azol-5-yl]pyrimidin-2-amine, [44] 5-(3-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-4,5-dihydroisocyanate (-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-dihydroisocyanate (-5-yl)-N-(3,5-dichlorophenylethyl)pyrimidin-2-amine [51] 5-(3-(4-(5-(difluoromethyl)-1,3,4- (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano (-5-yl)-N-(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-) (diazol-2-yl)piperidin-1-yl)-4,5-dihydroisocyano (Zol-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- (diazol-2-yl)pyrimidin-2-amine, [55] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- (diazol-2-yl)-N-(benzo[d][1,3]m-dioxacyclopenten-5-ylmethyl)pyrimidin-2-amine [56] 5-(5-(4-(1H-1,2,3-triazol-5-yl)piperidin-1-yl)-1,3,4- diazol-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- diazol-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- diazol-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- diazol-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- (diazol-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- (diazol-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-indene-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- (diazol-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- (diazol-2-yl)piperidin-4-yl)azacyclobutane-3-ol [65] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-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- (diazol-2-yl)piperidin-4-yl)-1,3,4- diazole-2(3H)-one, [67] 1-(5-(2-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4- (diazol-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- diazol-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- diazol-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- (diazol-2-yl)pyrimidine-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- (Diazol-2-yl)pyrimidine-2-amine.

2. Use of the piperidine derivative compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting autocrine motor factors.

3. The use as described in claim 2, characterized in that... The drug is used to prevent or treat diseases selected from the following: fibrotic diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, metabolic diseases, cancer and cancer metastasis, eye diseases, cholestatic chronic pruritus, and acute or chronic organ transplant rejection.

4. The use as described in claim 2, characterized in that... The drug is used to prevent or treat diseases selected from the following: fibrotic diseases selected from idiopathic pulmonary fibrosis, interstitial lung disease, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis, renal fibrosis, cutaneous fibrosis, glomerular sclerosis, myocardial fibrosis, and vascular fibrosis; inflammatory diseases selected from rheumatoid arthritis, osteoarthritis, atopic dermatitis, inflammatory bowel disease, chronic obstructive pulmonary disease, and asthma; autoimmune diseases selected from multiple sclerosis and scleroderma; and respiratory diseases selected from asbestos-induced pulmonary fibrosis and acute respiratory distress syndrome. Cardiovascular diseases selected from arteriosclerosis, myocardial infarction, pulmonary hypertension, arrhythmia, and stroke; metabolic diseases selected from obesity and diabetes; cancers selected from breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver cancer, gastrointestinal cancer, pancreatic cancer, and their progressive and metastatic cancers; ocular diseases selected from proliferative and non-proliferative retinopathy, dry and wet age-related macular degeneration, macular edema, central arterial / vein occlusion, traumatic injury, and glaucoma; cholestatic chronic pruritus; and acute or chronic organ transplant rejection.

5. The use as described in claim 2, characterized in that... The drug is used to prevent or treat diabetic retinopathy.

6. The use as described in claim 2, characterized in that... The drug is used to prevent or treat radiation-induced fibrosis.

7. The use as described in claim 2, characterized in that... The drug is used to prevent or treat inflammatory airway diseases.

8. A pharmaceutical composition comprising the piperidine derivative compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

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