Novel pyrimidine derivative compound and use thereof

Abstract

The present invention relates to a novel pyrimidine derivative compound and a use thereof. In auditory cells, the compound has a protective effect through treatment (or alleviation) and prevention of auditory dysfunctions such as ototoxic hearing loss, noise-induced hearing loss, sudden hearing loss, age-related hearing loss, hereditary hearing loss, autoimmune hearing loss, tinnitus, and Meniere's disease, which cause hearing loss by inhibiting homeostasis of auditory organs, and thus can be usefully utilized as a pharmaceutical product.

Description

Novel pyrimidine derivative compounds and uses thereof

[0001] The present invention provides a novel pyrimidine derivative compound and its use.

[0002] Hearing loss is the most common sensorineural disorder worldwide. More than 80% of all hearing loss is sensorineural, resulting from damage to the inner ear's hair cells and auditory nerves. The prevalence of acquired hearing loss, caused by aging and environmental factors (such as noise and drugs), is rapidly increasing, placing a growing social and economic burden on individuals. Furthermore, research has shown that hearing loss reduces the transmission of sound stimuli to the brain, leading to cognitive and memory decline and a two- to five-fold increased risk of dementia compared to the general population. Given the global trend toward a hyper-aging society, hearing loss is expected to become a significant social and economic problem in the future. Acquired hearing loss, in particular, is known to be caused by environmental factors (such as drugs and noise) and the degeneration of the auditory organs due to aging. The current pathogenesis explains that hearing loss occurs due to a breakdown in homeostasis caused by increased oxidative stress caused by reactive oxygen species, which damages the biochemical systems of the cochlea. Specifically, cisplatin enters cells via diffusion or transporters and hydrates, lowering intracellular chloride concentrations and releasing chloride ions. The hydrated form of cisplatin cross-links with nucleotides in nuclear and mitochondrial DNA to form adducts, inhibiting the unrestricted replication of cancer cells. This allows its use as an anticancer agent. However, cisplatin's use is limited due to its side effects, including nephrotoxicity, neurotoxicity, and ototoxicity.Cisplatin-induced ototoxicity, in particular, can cause irreversible sensorineural hearing loss, a serious problem, particularly in children. Although the underlying molecular mechanisms of cisplatin-induced ototoxicity are not fully understood, previous studies have shown that cisplatin activates the death receptor pathway, the endoplasmic reticulum-stress pathway, and the mitochondrial reactive oxygen species (ROS)-generating pathway in normal cells, ultimately leading to cell death. Excessive ROS production is considered a major cause of cisplatin-induced ototoxic hearing loss and is also thought to be a direct attack of cisplatin on DNA. In particular, the organ of Corti, spiral ganglion, and lateral wall within the cochlea have been proposed to be major targets of cisplatin for potent ROS production, and research is ongoing to address this issue.

[0003] The purpose of the present invention is to provide a compound selected from a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof.

[0004] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hearing loss, comprising as an active ingredient a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0005] Another object of the present invention is to provide a health functional food composition for preventing or improving hearing loss, which comprises as an active ingredient a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0006] To achieve the above purpose, the present invention provides a compound selected from a pyrimidine derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:

[0007] [Chemical Formula 1]

[0008]

[0009] In the above chemical formula 1, R 1 is one of hydrogen, cyano and (C1-C5)alkyl, and R 2 is hydrogen, (C1-C5)alkoxy, -SR 21 , -SO2-(C1-C5)alkyl and (C3-C6)cycloalkyl, and the R 21 is (C1-C5)alkyl or -CH2COOCH3, and M is -NR 4 - or -O-, and the above R 4 is hydrogen, (C3-C6)cycloalkyl and One of them, Ar 1 is an unsubstituted or substituted (C5-C10)aryl or an unsubstituted or substituted 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or substituted 5 to 10-membered heteroaryl is selected from the group consisting of halogen, (C1-C5)alkyl, (C3-C6)cycloalkyl, (C1-C5)alkoxy, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and At least one selected from the group consisting of is substituted, n and m may be the same or different, are 0 or 1, and K is -NR 5- and the above R 5 is hydrogen or (C1-C5)alkyl, and L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” may be the same or different, and are hydrogen or (C1-C5)alkyl, and Ar 2 Is , , , and One of the above R 3 is an unsubstituted or substituted heteroaryl having 5 to 10 atoms, which comprises at least one heteroatom selected from the group consisting of (C1-C5)alkyl, (C3-C6)cycloalkyl, unsubstituted or substituted (C5-C10)aryl, N, O and S; and and the substituted (C5-C10)aryl or substituted heteroaryl of 5 to 10 atoms is (C1-C5)alkyl, (C1-C5)alkoxy, amine, nitro, -COOCH3, COOH, -CONHOH and At least one selected from the group consisting of is substituted, wherein p is 0 or 1, and wherein A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 may be the same or different, and are hydrogen or (C1-C5)alkyl, and the above R 33 Silver hydrogen, (C1-C5)alkyl, (C1-C5)alkoxy, halogen, amine, nitro, -COOCH3, COOH, -CONHOH and It could be one of them.

[0010] In addition, the present invention provides a pharmaceutical composition for preventing or treating hearing loss, comprising a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0011] In addition, the present invention provides a health functional food composition for preventing or improving hearing loss, comprising as an active ingredient a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0012] The present invention relates to a compound selected from a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, which has a protective effect through treatment (or improvement) and prevention of hearing function, such as ototoxic hearing loss, noise-induced hearing loss, sudden hearing loss, age-related hearing loss, hereditary hearing loss, autoimmune hearing loss, tinnitus, and Meniere's disease, which cause hearing loss by disrupting the homeostasis of the auditory organ, and thus can be usefully utilized as a pharmaceutical.

[0013] Hereinafter, the present invention will be described in more detail.

[0014] The present invention provides a compound selected from a pyrimidine derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1, R 1 is one of hydrogen, cyano and (C1-C5)alkyl, and R 2 is hydrogen, (C1-C5)alkoxy, -SR 21 , -SO2-(C1-C5)alkyl and (C3-C6)cycloalkyl, and the R 21 is (C1-C5)alkyl or -CH2COOCH3, and M is -NR 4 - or -O-, and the above R 4 is hydrogen, (C3-C6)cycloalkyl and One of them, Ar 1is an unsubstituted or substituted (C5-C10)aryl or an unsubstituted or substituted 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or substituted 5 to 10-membered heteroaryl is selected from the group consisting of halogen, (C1-C5)alkyl, (C3-C6)cycloalkyl, (C1-C5)alkoxy, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and At least one selected from the group consisting of is substituted, n and m may be the same or different, are 0 or 1, and K is -NR 5 - and the above R 5 is hydrogen or (C1-C5)alkyl, and L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” may be the same or different, and are hydrogen or (C1-C5)alkyl, and Ar 2 Is , , , and One of the above R 3 is an unsubstituted or substituted heteroaryl having 5 to 10 atoms, which comprises at least one heteroatom selected from the group consisting of (C1-C5)alkyl, (C3-C6)cycloalkyl, unsubstituted or substituted (C5-C10)aryl, N, O and S; and and the substituted (C5-C10)aryl or substituted heteroaryl of 5 to 10 atoms is (C1-C5)alkyl, (C1-C5)alkoxy, halogen, amine, nitro, -COOCH3, COOH, -CONHOH and At least one selected from the group consisting of is substituted, wherein p is 0 or 1, and wherein A 1 is N or CH, and the above A 2 is O or NR 33 and the above R31 and R 32 may be the same or different, and are hydrogen or (C1-C5)alkyl, and the above R 33 Silver hydrogen, (C1-C5)alkyl, (C1-C5)alkoxy, amine, nitro, -COOCH3, COOH, -CONHOH and It could be one of them.

[0018] In the above chemical formula 1, R 1 is one of hydrogen, cyano and methyl, and R 2 is hydrogen, (C1-C3)alkoxy, -SR 21 , -SO2CH3 and cyclopropyl, and the R 21 is methyl or -CH2COOCH3, and M is -NR 4 - or -O-, and the above R 4 is hydrogen, cyclopropyl and One of them, Ar 1 is an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 6 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O, wherein the substituted (C6-C10)aryl or substituted 6 to 10-membered heteroaryl is selected from the group consisting of fluorine, chlorine, (C1-C3)alkyl, cyclopropyl, methoxy, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and One to three selected from the group consisting of are substituted, and K is -NR 5 - and the above R 5 is hydrogen or (C1-C3)alkyl, and L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” may be the same or different, and are hydrogen or methyl, and Ar 2 Is , , , and One of the above R 3 is an unsubstituted or substituted heteroaryl having 6 to 10 atoms, which comprises at least one heteroatom selected from the group consisting of (C1-C3)alkyl, cyclohexyl, unsubstituted or substituted (C6-C10)aryl, N or O; and and the substituted (C6-C10)aryl or substituted heteroaryl of 6 to 10 atoms is (C1-C3)alkyl, methoxy, fluorine, chlorine, amine, nitro, -COOCH3, COOH, -CONHOH and One or two selected from the group consisting of are substituted, wherein p is 0 or 1, and wherein A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 may be the same or different, and are hydrogen or methyl, and the R 33 can be hydrogen or (C1-C5)alkyl.

[0019] In the above chemical formula 1, R 2 is hydrogen, ethoxy, -SR 21 , -SO2CH3 and cyclopropyl, and the R 21 is methyl or -CH2COOCH3, and Ar 1 is a substituted phenyl, an unsubstituted or methoxy substituted naphthyl and an unsubstituted or substituted 6, 9 or 10 membered heteroaryl containing nitrogen, wherein the substituted phenyl is substituted with one to three selected from the group consisting of amine, methoxy, trifluoromethyl, fluorine and chlorine, and the substituted 6, 9 or 10 membered heteroaryl is fluorine, isopropyl, cyclopropyl, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and One or two selected from the group consisting of are substituted, and K is -NR 5 - and the above R 5is hydrogen or ethyl, and L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” is hydrogen or methyl, and Ar 2 Is , , , and One of the above R 3 isopropyl, cyclohexyl, methoxy substituted phenyl, methoxy substituted naphthyl, unsubstituted or substituted 6 or 10-membered heteroaryl containing nitrogen, and and the substituted 6 or 10-membered heteroaryl is methyl, methoxy, fluorine, chlorine, amine, nitro, -COOCH3, COOH, -CONHOH and One or two selected from the group consisting of are substituted, wherein p is 0 or 1, and wherein A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 is hydrogen or methyl, and the above R 33 can be one of hydrogen, methyl, and ethyl.

[0020] The compound represented by the above chemical formula 1 may be selected from the following group of compounds:

[0021] (1) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine;

[0022] (2) Methyl 2-((4-((1H-indazol-5-yl)amino)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-2-yl)thio)acetate;

[0023] (3) 5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)oxy)-1H-indazole;

[0024] (4) N-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0025] (5) 4-((1H-indazol-5-yl)amino)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidine-5-carbonitrile;

[0026] (6) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0027] (7) N-(5-methyl-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0028] (8) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0029] (9) N,1-Dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0030] (10) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0031] (11) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0032] (12) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine;

[0033] (13) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-6-amine;

[0034] (14) 1-Isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine;

[0035] (15) N-(2-(methylsulfonyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0036] (16) N-(2-ethoxy-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0037] (17) N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0038] (18) N-(6-(4-(5-aminopyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0039] (19) Methyl 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylate;

[0040] (20) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0041] (21) Methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate;

[0042] (22) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid;

[0043] (23) 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide;

[0044] (24) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide;

[0045] (25) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5 -carboxamide;

[0046] (26) 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)nicotinic acid;

[0047] (27) 6-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxynicotinamide;

[0048] (28) 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxynicotinamide;

[0049] (29) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine;

[0050] (30) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine;

[0051] (31) 1-Isopropyl-N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine;

[0052] (32) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine;

[0053] (33) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine;

[0054] (34) N-(6-(4-cyclohexylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine;

[0055] (35) N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0056] (36) N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0057] (37) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0058] (38) N 4 -(5-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine;

[0059] (39) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(5-(piperazin-1-yl)pyridin-2-yl)pyrimidine-4,6-diamine;

[0060] (40) N 4 -(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine;

[0061] (41) N 4-(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0062] (42) 1-Isopropyl-N 5 -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine;

[0063] (43) 1-Isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine;

[0064] (44) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine;

[0065] (45) 1-Cyclopropyl-3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0066] (46) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine;

[0067] (47) 2-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine;

[0068] (48) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyrimidin-2-yl)-1H-indol-5-amine;

[0069] (49) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indol-5-amine;

[0070] (50) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indazol-5-amine;

[0071] (51) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-N-(pyrimidin-2-yl)-1H-indazol-5-amine;

[0072] (52) 3-Fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine;

[0073] (53) N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0074] (54) N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine;

[0075] (55) 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine;

[0076] (56) N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide;

[0077] (57) N 4 -Ethyl-N 6 -(1H-indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0078] (58) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0079] (59) N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0080] (60) N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0081] (61) N-(2-(methylthio)-6-morpholinopyrimidin-4-yl)-1H-indazol-5-amine;

[0082] (62) N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine;

[0083] (63) N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0084] (64) N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0085] (65) N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine;

[0086] (66) 2-(methylthio)-6-(4(pyridin-2-yl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine;

[0087] (67) 2-(Methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine;

[0088] (68) N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)pirerazin-1-yl)pyrimidin-4-amine;

[0089] (69) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine;

[0090] (70) 2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine;

[0091] (71) N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine;

[0092] (72) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-amine;

[0093] (73) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine;

[0094] (74) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0095] (75) N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0096] (76) N 4 -Ethyl-N 6 -(Indolin-5-yl)-2-(methylthio0)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0097] (77) N 4 -(Indolin-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0098] (78) N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine;

[0099] (79) N-(6-(4-(6-methoxynaphthalen-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0100] (80) 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0101] (81) 2-(methylthio)-N 4 -(1-(1-(pyrimidin-2-yl)piperidin-4-yl)ethyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine;

[0102] (82) 1-Isopropyl-N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine;

[0103] (83) N-(6-(4-(isoquinolin-8-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine;

[0104] (84) N-(2-(methylthio)-6-(4-(quinazolin-8-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine;

[0105] (85) N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide;

[0106] (86) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)pyrimidine-4,6-diamine;

[0107] (87) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine;

[0108] (88) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine;

[0109] (89) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine;

[0110] (90) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine;

[0111] (91) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)isoquinolin-6-amine;

[0112] (92) 6-(4-(isoquinolin-5-yl)piperazin-1-yl)-N-(6-methoxynaphthalen-2-yl)-2-(methylthio)pyrimidin-4-amine;

[0113] (93) 2-(methylthio)-N 4 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine;

[0114] (94) N 4 -(6-methoxynaphthalen-2-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine;

[0115] (95) 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0116] (96) 5-((6-(4-(8-aminoisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0117] (97) 5-((6-(4-(3-methylisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0118] (98) 5-((6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0119] (99) 5-((6-(4-(8-chloroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide;

[0120] (100) 5-((6-(4-(8-methoxyisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; and

[0121] (101) N-(6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine.

[0122]

[0123] In addition, the present invention provides a pharmaceutical composition for preventing or treating hearing loss, comprising a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0124] The above hearing loss disease may be one or more selected from the group consisting of noise-induced hearing loss, ototoxic hearing loss, presbycusis, traumatic hearing loss, infectious hearing loss, Meniere's disease, autoimmune hearing loss, sudden hearing loss, and hereditary hearing loss diseases, but is not limited thereto.

[0125] The above ototoxic hearing loss may be ototoxic hearing loss caused by a drug that causes an abnormality in hearing function, and preferably, the drug that causes an abnormality in hearing function may be at least one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, amikacin, gentamicin, kanamycin, tobramycin, capreomycin, biomycin, chloramphenicol, vancomycin, erythromycin, chloroquinone, furosemide, bumetanide, and acetaminophen, but is not limited thereto.

[0126] The above pyrimidine derivative compound is preferably N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; 3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N,1-dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6-((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; 1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; 1-isopropyl-N 5-(2-(Methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine; 1-Isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine; 2-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indol-5-amine; 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indazol-5-amine; 3-Fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6-(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide; N 4 -Ethyl-N 6-(1H-Indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine; 2-(methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; 2-(Methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine; N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine; N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; and N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine;

[0127] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, glidants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0128] Specifically, carriers, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspending agents can be propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases can include witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin.

[0129] According to one embodiment of the present invention, the pharmaceutical composition can be administered to a subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes.

[0130] The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and degree of the disease, the drug form, the route and period of administration, and may be appropriately selected by a person skilled in the art, and the daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. Administration may be once a day or divided into several times, and the scope of the present invention is not limited thereby.

[0131]

[0132] In addition, the present invention provides a health functional food composition for preventing or improving hearing loss, comprising as an active ingredient a compound selected from the pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0133] The above health functional food may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0134] In addition, it may contain fruit pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. Furthermore, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol, and vitamin complex.

[0135] In addition, the above health functional food may additionally contain food additives, and its suitability as a “food additive” is determined by the specifications and standards for the relevant item in accordance with the general provisions and general testing methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise provided.

[0136] Examples of items listed in the above "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kohlrabi pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0137] At this time, the content of the effective ingredient added to the food during the process of manufacturing the health functional food can be appropriately increased or decreased as needed, and preferably, it can be added so that it is included in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0138] Hereinafter, to aid understanding of the present invention, examples and other embodiments will be described in detail. However, the following examples and other embodiments merely illustrate the content of the present invention and are not intended to limit the scope of the present invention. The examples and other embodiments of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0139]

[0140] <Preparation Example> Analysis and Purification Conditions

[0141] (1) HPLC analysis conditions (A)

[0142] Device name: Thermo Scientific Ultimate 3000RSLC

[0143] Column: Kinetex 2.6 νM Biphenyl 100ÅA, 100x2.1mm

[0144] Mobile phase: 5% -> 100% acetonitrile / H2O+0.1%TFA,

[0145] Analysis time: 4.5 min, flow rate: 1.2 ml / min

[0146] UV detector: 254nm

[0147]

[0148] (2) HPLC analysis conditions (B)

[0149] Device name: Shimadzu

[0150] Column: YMC-pack pro C18, 150x4.6mm ID, 5 νm, 40℃

[0151] Mobile phase: 5% -> 100% acetonitrile / H2O+0.1%TFA,

[0152] Analysis time: 9 minutes, flow rate: 1 ml / min

[0153] UV detector: 254nm

[0154]

[0155] (3) LC-MS analysis conditions

[0156] Device name: Shimadzu LCMS-2020

[0157] Column: ACE Excel2 C18, 75x2.1 mm

[0158] Mobile phase: Acetonitrile / H2O+0.1%TFA

[0159] Flow rate: 0.5 mL / min

[0160] UV detector: 254 nm

[0161]

[0162] (4) MPLC purification conditions

[0163] Device Name: CombiFlash Rf+

[0164] UV detector: 254 nm

[0165]

[0166] (5) Prep-HPLC purification conditions

[0167] Device Name: Gilson GX-281, 321 pump, UV / VIS-155

[0168] Column: Luna 10 νM C18 (2) 100 Å, 250x21.2 mm

[0169] Mobile phase: Acetonitrile / 0.1% TFA H2O

[0170] Flow rate: 18 mL / min

[0171] UV detector: 254 nm

[0172]

[0173] (6) 1 HNMR

[0174] Device Name: Bruker Avance (400 MHz)

[0175] Device Name: Bruker Avance (500 MHz)

[0176]

[0177] <Example 1> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine

[0178]

[0179] Step 1: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine

[0180]

[0181] 4,6-Dichloro-2-(methylthio)pyrimidine (3 g, 15.38 mmol) and 1H-benzo[d]imidazol-5-amine (2.15 g, 16.15 mmol) were dissolved in DMF (20 mL), DIPEA (3.21 mL, 18.45 mmol) was added, and the mixture was stirred at 120 °C for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to obtain the target compound (2.6 g, 57%, white solid). LC / MS (ESI) m / z: 292 [M+H] +

[0182] Step 2: Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine

[0183]

[0184] N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine (100 mg, 0.34 mmol), 1-(pyridin-2-yl)piperazine (58 mg, 0.36 mmol) and DIPEA (0.072 mL, 0.41 mmol) prepared in Step 1 above were dissolved in DMF (1.5 mL) and reacted at 100 °C for 15 h. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer residue was dried over anhydrous sodium sulfate, filtered, concentrated and purified by MPLC to produce the target compound (100 mg, 69%, yellow solid). LC / MS(ESI) m / z: 419 [M+H] +

[0185]

[0186] <Example 2> Preparation of methyl 2-((4-((1H-indazol-5-yl)amino)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-2-yl)thio)acetate

[0187]

[0188] Step 1: Preparation of methyl 2-((4,6-dichloropyrimidin-2-yl)thio)acetate

[0189]

[0190] Methyl bromoacetate (2.91 mL, 30.8 mmol) was added to 4,6-dichloro-2-(methylthio)pyrimidine (1 g, 5.13 mmol). 2,2,2-Trifluoroethanol (5.53 mL, 5.53 mmol) was added at room temperature, and the mixture was stirred at 100 °C for 3 days. After completion of the reaction, the mixture was concentrated, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to obtain the target compound (250 mg, 19%, white solid). LC / MS (ESI) m / z: 254 [M+H] +

[0191] Step 2: Preparation of methyl 2-((4-((1H-indazol-5-yl)amino)-6-chloropyrimidin-2-yl)thio)acetate

[0192]

[0193] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 350 [M+H] +

[0194] Step 3: Preparation of methyl 2-((4-((1H-indazol-5-yl)amino)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-2-yl)thio)acetate

[0195]

[0196] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 477 [M+H] +

[0197]

[0198] <Example 3> Preparation of 5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)oxy)-1H-indazole

[0199]

[0200] Step 1: Preparation of 5-((6-chloro-2-(methylthio)pyrimidin-4-yl)oxy)-1H-indazole

[0201]

[0202] 4,6-Dichloro-2-(methylthio)pyrimidine (1 g, 5.13 mmol) and 1H-indazol-5-ol (0.72 g, 5.38 mmol) were dissolved in DMF (10 mL), K2CO3 (1.06 g, 7.69 mmol) was added, and the mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (0.67 g, 44%, white solid). LC / MS (ESI) m / z: 293 [M+H] +

[0203] Step 2: Preparation of 5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)oxy)-1H-indazole

[0204]

[0205] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 420 [M+H] +

[0206]

[0207] <Examples 4 to 7> Preparation of N-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine, 4-((1H-indazol-5-yl)amino)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidine-5-carbonitrile, N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine and N-(5-methyl-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0208] As in Example 1, Example 4, N-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; Example 5, 4-((1H-indazol-5-yl)amino)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidine-5-carbonitrile; Example 6, N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; And Example 7, N-(5-methyl-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine was prepared.

[0209]

[0210] <Example 8> Preparation of 3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0211]

[0212] Step 1: Preparation of 3-fluoro-5-nitro-1H-indazole

[0213]

[0214] 5-Nitro-1H-indazole (5 g, 30.6 mmol) was dissolved in acetonitrile (30 mL) and acetic acid (3 mL), tetrafluoroborate (11.07 g, 61.3 mmol) was added, and the mixture was stirred at 130°C for 30 h in a sealed tube. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (1.35 g, 24%, ivory solid). LC / MS (ESI) m / z: 182 [M+H] +

[0215] Step 2: Preparation of 3-fluoro-5-nitro-1H-indazole

[0216]

[0217] The prepared 3-fluoro-5-nitro-1H-indazole (1.35 g, 7.45 mmol) was dissolved in methanol (20 mL) and degassed with a nitrogen balloon. 10 wt% Pd / c (0.238 g, 2.23 mmol) was added, degassed with a nitrogen balloon, and hydrogenation was performed using a hydrogen balloon at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated and purified by MPLC to obtain the target compound (0.9 g, 90%, orange solid). LC / MS (ESI) m / z: 152 [M+H] +

[0218] Step 3: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-fluoro-1H-indazol-5-amine

[0219]

[0220] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 310 [M+H] +

[0221] Step 4: Preparation of 3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0222]

[0223] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 437 [M+H] +

[0224]

[0225] <Example 9> Preparation of N,1-dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0226]

[0227] N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine (40 mg, 0.09 mmol) prepared in Example 6 was dissolved in dichloroethane (1 mL), and then Na2CO3 (20 mg, 0.19 mmol), Cu(OAc)2 (17 mg, 0.09 mmol), 2,2'-bipyridylbipyridine (14 mg, 0.09 mmol), and cyclopropylboronic acid (16 mg, 0.19 mmol) were added. The mixture was stirred at 80 °C for 15 hours. After the reaction was completed, the residue was filtered and concentrated, and then purified by MPLC to obtain the target compound (21 mg, 44%, white solid). LC / MS(ESI) m / z: 499 [M+H] +

[0228]

[0229] <Example 10> Preparation of 1-cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0230] Step 1: Preparation of 1-cyclopropyl-5-nitro-1H-indazole

[0231]

[0232] The target compound was prepared by performing the same method as in Example 9. LC / MS (ESI) m / z: 203 [M+H] +

[0233] Step 2: Preparation of 1-cyclopropyl-1H-indazol-5-amine

[0234]

[0235] The target compound was prepared by performing the same method as step 2 of Example 8 above. LC / MS (ESI) m / z: 174 [M+H] +

[0236] Step 3: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-cyclopropyl-1H-indazol-5-amine

[0237]

[0238] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 332 [M+H] +

[0239] Step 4: Preparation of 1-cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0240]

[0241] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 459 [M+H] +

[0242]

[0243] <Example 11> N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0244]

[0245] Step 1: Preparation of tert-butyl 4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate

[0246]

[0247] The intermediate N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine (1 g, 3.43 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.80 g, 3.77 mmol) prepared in Example 6 were dissolved in DMF (5 mL), K2CO3 (0.94 g, 6.85 mmol) was added, and the mixture was stirred at 120°C for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (400 mg, 24%, white solid). LC / MS(ESI) m / z: 470 [M+H] +

[0248] Step 2: Preparation of N4-(1H-indazol-5-yl)-2-(methylthio)-N6-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0249]

[0250] The above-mentioned tert-butyl 4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate (0.4 g, 0.85 mmol) was dissolved in DMF (3 mL), trifluoroacetic acid (1.5 mL, 3.77 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was neutralized with aqueous sodium bicarbonate solution, diluted with dichloromethane, and washed with water and brine. The residue of the organic layer was filtered and concentrated to prepare the target compound (315 mg, 100%). LC / MS(ESI) m / z: 370 [M+H] +

[0251] Step 3: N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0252]

[0253] The above manufactured N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(Piperidin-4-ylmethyl)pyrimidine-4,6-diamine (50 mg, 0.13 mmol) was dissolved in DMF (1 mL), 2-bromopyridine (42 mg, 0.27 mmol) and K2CO3 (56 mg, 0.40 mmol) were added, and the mixture was stirred in a microwave at 140 °C for 1 hour. After the reaction was completed, the mixture was neutralized with aqueous sodium bicarbonate solution, diluted with ethyl acetate, and washed with water and brine. The organic layer was filtered and concentrated, and then purified by MPLC to produce the target compound (20 mg, 33%, yellow solid). LC / MS(ESI) m / z: 447 [M+H] +

[0254]

[0255] <Examples 12 and 13> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine and N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-6-amine

[0256] N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine, Example 12; and N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-6-amine, Example 13; were prepared by performing the same procedure as in Example 3.

[0257]

[0258] <Example 14> Preparation of 1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indole-5-amine

[0259]

[0260] The intermediate N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indole-5-amine prepared in Example 35 was used and the same method as step 2 of Example 1 was performed to prepare the target compound. LC / MS (ESI) m / z: 460 [M+H] +

[0261]

[0262] <Example 15> Preparation of N-(2-(methylsulfonyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0263] The target compound (41%, yellow solid) was prepared as in Example 3 above.

[0264]

[0265] <Example 16> Preparation of N-(2-ethoxy-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0266]

[0267]

[0268] <Example 17> Preparation of N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0269]

[0270] N-(2-(methylsulfonyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine (45 mg, 0.10 mmol) prepared in Example 15 was dissolved in THF (1.5 mL), 0.7 M cyclopropylmagnesium bromide (THF aqueous solution, 1 mL, 0.69 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was neutralized with sodium bicarbonate aqueous solution, diluted with dichloromethane, and washed with water and brine. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (7 mg, 16%, white solid). LC / MS(ESI) m / z: 413 [M+H] +

[0271]

[0272] <Example 18> Preparation of N-(6-(4-(5-aminopyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0273]

[0274] Step 1: Preparation of N-(2-(methylthio)-6-(piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0275]

[0276] The intermediate N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine (0.5 g, 1.71 mmol) and piperazine (0.44 g, 5.14 mmol) prepared in Example 6 were dissolved in methanol (10 mL), TEA (0.71 mL, 5.14 mmol) was added, and the mixture was stirred at 90°C for 24 hours. After the reaction was completed, the mixture was concentrated and purified by MPLC to prepare the target compound (0.43 g, 74%, brown solid). LC / MS(ESI) m / z: 342 [M+H] +

[0277] Step 2: Preparation of N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0278]

[0279] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 464 [M+H] +

[0280] Step 3: Preparation of N-(6-(4-(5-aminopyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0281]

[0282] N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine (50 mg, 0.10 mmol) prepared in the above step 2 was dissolved in ethyl acetate (1 mL) and tin chloride dihydrate (0.12 g, 0.53 mmol) was added. Hydrogenation reaction was performed at room temperature for 16 h. After completion of the reaction, the mixture was concentrated and purified by MPLC to prepare the target compound (27 mg, 57%, brown solid). LC / MS(ESI) m / z: 434 [M+H] +

[0283]

[0284] <Example 19> Preparation of methyl 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylate

[0285]

[0286] The target compound was prepared using the intermediate N-(2-(methylthio)-6-(piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine prepared in step 1 of the above Example 18 and the same method as step 3 of Example 11. LC / MS (ESI) m / z: 478 [M+H] +

[0287]

[0288] <Examples 20 and 21> N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine and methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate

[0289] N, which is Example 20, was performed as in Example 11 above. 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; and Example 21, methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate; were prepared.

[0290]

[0291] <Example 22> Preparation of 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid

[0292]

[0293] Methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate (40 mg, 0.07 mmol) prepared in Example 21 was dissolved in THF (1 mL), methanol (0.5 mL), and water (0.5 mL), and then lithium hydroxide monohydrate (3 mg, 0.07 mmol) was slowly added and stirred at room temperature for 15 hours. After the reaction was completed, the mixture was neutralized with aqueous ammonium chloride solution, diluted with dichloromethane, and washed with water and brine. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (30 mg, 77%, white solid). LC / MS(ESI) m / z: 492 [M+H] +

[0294]

[0295] <Example 23> Preparation of 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide

[0296]

[0297] Step 1: Preparation of 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylic acid

[0298]

[0299] The target compound was prepared using methyl 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylate prepared in Example 19 and the same method as in Example 22. LC / MS (ESI) m / z: 464 [M+H] +

[0300] Step 2: Preparation of 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide

[0301]

[0302] The prepared 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylic acid (100 mg, 0.21 mmol) was dissolved in DMF (1 mL), and EDCI (41 mg, 0.21 mmol), HOBt (33 mg, 0.21 mmol), and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (12 mg, 0.10 mmol) were added, and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (Mixture, white solid). LC / MS(ESI) m / z: 563 [M+H] +

[0303] Step 3: Preparation of 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide

[0304]

[0305] The above-mentioned 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide (60 mg, 0.10 mmol) was dissolved in DCM (3 mL), trifluoroacetic acid (1 mL, 12.98 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and purified by MPLC to obtain the target compound (7 mg, 13%, white solid). LC / MS(ESI) m / z: 479 [M+H] +

[0306]

[0307] <Example 24> Preparation of 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide

[0308]

[0309] The target compound was prepared using 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid prepared in Example 22 above and the same method as Step 1 of Example 23. LC / MS (ESI) m / z: 591 [M+H] +

[0310]

[0311] <Example 25> Preparation of 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide

[0312]

[0313] The target compound was prepared using 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide prepared in Example 24 above and the same method as Step 2 of Example 23 was performed. LC / MS (ESI) m / z: 507 [M+H] +

[0314]

[0315] <Example 26> Preparation of 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)nicotinic acid

[0316] The target compound (78%, ivory solid) was prepared as in Example 22 above.

[0317]

[0318] <Example 27> Preparation of 6-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxynicotinamide

[0319] The target compound (51%, yellow solid) was prepared as in Example 23 above.

[0320]

[0321] <Example 28> Preparation of 6-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxynicotinamide

[0322] The target compound (68%, beige solid) was prepared as in Example 25 above.

[0323]

[0324] <Example 29> Preparation of N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine

[0325]

[0326] Step 1: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine

[0327]

[0328] The target compound was prepared by performing the same method as step 1 of Example 3 above. LC / MS (ESI) m / z: 291 [M+H] +

[0329] Step 2: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine

[0330]

[0331] N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine (73 mg, 0.25 mmol), TEA (0.14 mL, 1.00 mmol), and DMAP (30 mg, 0.25 mmol) prepared above were dissolved in DCM (1 mL), and trifluoroacetic anhydride (0.12 mL, 0.75 mmol) was slowly added dropwise at 0 °C and stirred for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (22 mg, 20%, white solid). LC / MS(ESI) m / z: 423 [M+H] +

[0332] Step 3: Preparation of N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine

[0333]

[0334] The target compound was prepared using the above-mentioned N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine and the same method as step 2 of Example 1. LC / MS (ESI) m / z: 551 [M+H] +

[0335]

[0336] <Example 30> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine

[0337] The target compound (6%, brown solid) was prepared as in Example 29 above.

[0338]

[0339] <Example 31> Preparation of 1-isopropyl-N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine

[0340]

[0341] Step 1: Preparation of 1-isopropyl-5-nitro-1H-indole

[0342]

[0343] 5-Nitro-1H-indole (2 g, 12.33 mmol) was dissolved in DMF (41 mL), and sodium hydride (60 wt%, 0.7 g, 18.50 mmol) was slowly added at 0 °C. After 30 min, trifluoromethanesulfonyl chloride (1.44 mL, 13.57 mmol) was slowly added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer residue was filtered and concentrated, and purified by MPLC to produce the target compound (2 g, 55%, yellow solid). LC / MS (ESI) m / z: 205 [M+H] +

[0344] Step 2: Preparation of 1-isopropyl-1H-indole-5-amine

[0345]

[0346] The above-mentioned 1-isopropyl-5-nitro-1H-indole (2 g, 6.80 mmol) was dissolved in ethanol (22 mL) and degassed with a nitrogen balloon. Pd / c (10 wt%, 0.21 g, 2.03 mmol) was added and degassed with a nitrogen balloon. Then, hydrogenation was performed using a hydrogen balloon at room temperature for 16 h. After the reaction was completed, the residue was concentrated and purified by MPLC to obtain the target compound (0.68 g, 37%, white solid). LC / MS (ESI) m / z: 175 [M+H] +

[0347] Step 3: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine

[0348]

[0349] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 333 [M+H] +

[0350] Step 4: Preparation of 1-isopropyl-N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine

[0351]

[0352] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 465 [M+H] +

[0353]

[0354] <Examples 32 to 34> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine, N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine and N-(6-(4-cyclohexylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine of Example 34

[0355] As in Example 31, Example 32 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; Example 33 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; and Example 34 N-(6-(4-cyclohexylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine were prepared.

[0356]

[0357] <Example 35> N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0358]

[0359] Step 1: Preparation of tert-butyl 4-(((6-((1-isopropyl-1H-indol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate

[0360]

[0361] The target compound was prepared using N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indole-5-amine prepared in step 3 of Example 31 and the same method as step 1 of Example 11. LC / MS (ESI) m / z: 511 [M+H] +

[0362] Step 2: Preparation of N4-(1-isopropyl-1H-indol-5-yl)-2-(methylthio)-N6-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0363]

[0364] The target compound was prepared by performing the same method as step 2 of Example 11 above. LC / MS (ESI) m / z: 411 [M+H] +

[0365] Step 3: Preparation of N4-(1-isopropyl-1H-indol-5-yl)-2-(methylthio)-N6-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0366]

[0367] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 495 [M+H] +

[0368]

[0369] <Example 36> N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0370] The target compound was manufactured by performing the same procedure as in Example 35 above.

[0371]

[0372] <Example 37> N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6Preparation of -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0373]

[0374] Intermediate N prepared in step 2 of the above Example 11 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(Piperidin-4-ylmethyl)pyrimidine-4,6-diamine was used and the target compound was prepared by the same method as step 3 of Example 11. LC / MS (ESI) m / z: 454 [M+H] +

[0375]

[0376] <Example 41> N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0377]

[0378] Intermediate N prepared in step 5 of the above Example 35 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -(Piperidin-4-ylmethyl)pyrimidine-4,6-diamine was used and the target compound was prepared by the same method as step 3 of Example 11. LC / MS (ESI) m / z: 489 [M+H] +

[0379]

[0380] <Example 42> 1-Isopropyl-N 5 Preparation of -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine

[0381]

[0382] Step 1: Preparation of 1-isopropyl-5-nitro-1H-indazol-3-amine

[0383]

[0384] 2-Fluoro-5-nitrobenzonitrile (2 g, 12.04 mmol) was dissolved in DMF (20 mL), isopropylhydrazine hydrochloride salt (2.66 g, 24.08 mmol), and K2CO3 (4.99 g, 36.10 mmol) were added, and the mixture was stirred at 90 °C for 15 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with 0.5 N HCl and water. The organic layer was filtered and concentrated, and then purified by MPLC to produce the target compound (2 g, 75%, orange solid). LC / MS (ESI) m / z: 221 [M+H] +

[0385] Step 2: Preparation of tert-butyl(1-isopropyl-5-nitro-1H-indazol-3-yl)carbamate

[0386]

[0387] The above-mentioned 1-isopropyl-5-nitro-1H-indazol-3-amine (0.5 g, 2.27 mmol) was dissolved in acetonitrile (3 mL), di-tert-butyldicarbonate (0.5 g, 2.29 mmol) and K2CO3 (4.99 g, 36.10 mmol) were added, and the mixture was stirred at 100°C for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (0.41 g, 56%). LC / MS (ESI) m / z: 321 [M+H] +

[0388] Step 3: Preparation of tert-butyl(5-amino-1-isopropyl-1H-indazol-3-yl)carbamate

[0389]

[0390] The target compound was prepared by performing the same method as step 2 of Example 32 above. LC / MS (ESI) m / z: 291 [M+H]+

[0391] Step 4: Preparation of tert-butyl (5-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)-1-isopropyl-1H-indazol-3-yl)carbamate

[0392]

[0393] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 449 [M+H] +

[0394] Step 5: Preparation of tert-butyl (1-isopropyl-5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperidin-1-yl)pyrimidin-4-yl)amino)-1H-indazol-3-yl)carbamate

[0395]

[0396] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 575 [M+H] +

[0397] Step 6: 1-Isopropyl-N 5 Preparation of -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine

[0398]

[0399] Tert-butyl (1-isopropyl-5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperidin-1-yl)pyrimidin-4-yl)amino)-1H-indazol-3-yl)carbamate (43 mg, 0.07 mmol) prepared in the above step 5 was dissolved in DCM (1 mL), trifluoroacetic acid (0.5 mL, 0.07 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and purified by MPLC to obtain the target compound (27 mg, 76%, khaki solid). LC / MS(ESI) m / z: 475 [M+H]+

[0400]

[0401] <Example 43> Preparation of 1-isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indole-5-amine

[0402]

[0403] The intermediate N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indole-5-amine prepared in step 3 of the above Example 35 was used and the same method as step 2 of the above Example 1 was performed to prepare the target compound. LC / MS (ESI) m / z: 510 [M+H] +

[0404]

[0405] <Example 44> Preparation of 1-isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indole-5-amine

[0406] The target compound (23%, ivory solid) was prepared as in Example 10 above.

[0407]

[0408] <Example 45> Preparation of 1-cyclopropyl-3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0409]

[0410] The target compound was prepared using 3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine prepared in Example 8 and the same method as in Example 9. LC / MS (ESI) m / z: 477 [M+H] +

[0411]

[0412] <Example 52> Preparation of 3-fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine

[0413]

[0414] Step 1: Preparation of 3-fluoro-1-isopropyl-5-nitro-1H-indole

[0415]

[0416] The target compound was prepared using the 1-isopropyl-5-nitro-1H-indole prepared in step 1 of Example 35 and the same method as step 1 of Example 8. LC / MS (ESI) m / z: 223 [M+H] +

[0417] Step 2: Preparation of 3-fluoro-1-isopropyl-1H-indole-5-amine

[0418]

[0419] The target compound was prepared by performing the same method as step 2 of Example 32 above. LC / MS (ESI) m / z: 193 [M+H] +

[0420] Step 3: Preparation of N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-fluoro-1-isopropyl-1H-indol-5-amine

[0421]

[0422] The target compound was prepared by performing the same method as step 1 of Example 1 above. LC / MS (ESI) m / z: 351 [M+H] +

[0423] Step 4: Preparation of 3-fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine

[0424]

[0425] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 478 [M+H] +

[0426]

[0427] <Example 53> N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0428]

[0429] Step 1: Preparation of tert-butyl 4-((ethylamino)methyl)piperidine-1-carboxylate

[0430]

[0431] tert-Butyl 4-(aminomethyl)piperidine-1-carboxylate (1.7 g, 7.93 mmol) was dissolved in acetonitrile (15 mL), and then bromoethane (0.64 mL, 8.73 mmol) and K2CO3 (1.20 g, 8.73 mmol) were added. The mixture was stirred at 80°C for 15 h. After the reaction was completed, the mixture was diluted with dichloromethane and washed with water. The organic layer was filtered and concentrated, and then purified by MPLC to obtain the target compound (1.35 g, 70%, clear liquid). LC / MS (ESI) m / z: 243 [M+H] +

[0432] Step 2: Preparation of tert-butyl 4-((ethyl(6-((1-isopropyl-1H-indol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate

[0433]

[0434] The above-mentioned tert-butyl 4-((ethylamino)methyl)piperidine-1-carboxylate (262 mg, 0.54 mmol) and the intermediate N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine (150 mg, 0.45 mmol) prepared in step 3 of Example 35 were dissolved in NMP (1 mL), and K2CO3 (623 mg, 4.51 mmol) was added, followed by stirring at 130°C for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (240 mg, 99%). LC / MS (ESI) m / z: 539 [M+H] +

[0435] Step 3: N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 - Preparation of (piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0436]

[0437] The target compound was prepared by performing the same method as step 6 of Example 42 above. LC / MS (ESI) m / z: 439 [M+H] +

[0438] Step 4: N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0439]

[0440] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 439 [M+H] +

[0441]

[0442] <Example 54> N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0443]

[0444] Step 1: Preparation of tert-butyl 5-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0445]

[0446] 4,6-Dichloro-2-(methylthio)pyrimidine (3.0 g, 15.38 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (3.78 g, 16.15 mmol) were dissolved in DMF (20 mL), DIPEA (5.37 mL, 30.80 mmol) was added, and the mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to obtain the target compound (4.0 g, 66%, white solid). LC / MS (ESI) m / z: 393 [M+H] +

[0447] Step 2: Preparation of tert-butyl 5-((6-(((1-tert -butoxycarbonyl)piperidin-4-yl)methyl(ethyl)amino-2(methylthio)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0448]

[0449] The above-mentioned tert-butyl 5-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)indolin-1-carboxylate (1.0 g, 2.55 mmol) and the intermediate tert-butyl 4-((ethylamino)methyl)piperidine-1-carboxylate (925 mg, 3.82 mmol) prepared in step 1 of Example 35 were dissolved in NMP (20 mL), and K2CO3 (3.52 g, 25.5 mmol) was added, followed by stirring at 130°C for 15 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water. The residue of the organic layer was filtered and concentrated, and then purified by MPLC to prepare the target compound (370 mg, 24%). LC / MS (ESI) m / z: 599 [M+H] +

[0450] Step 3: N 4 -Ethyl-N 6 -(1-Indolin-5-yl)-2-(methylthio)-N 4 - Preparation of (piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0451]

[0452] The target compound was prepared by performing the same method as step 6 of Example 42 above. LC / MS (ESI) m / z: 499 [M+H] +

[0453] Step 4: N 4 -Ethyl-N 6 -(Indolin-5-yl)-2-(methylthio)-N 4 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0454]

[0455] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 477 [M+H] +

[0456] Step 5: N 4 -Ethyl-2-(methylthio)-N4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0457]

[0458] The target compound was prepared by performing the same method as step 2 of Example 29. LC / MS (ESI) m / z: 609 [M+H] +

[0459]

[0460] <Example 55> 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0461]

[0462] Step 1: Preparation of tert-butyl 5-((6-(((1-tert -butoxycarbonyl)piperidin-4-yl)methyl)amino)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0463]

[0464] The target compound was prepared by performing the same method as step 2 of Example 54 above. LC / MS (ESI) m / z: 571 [M+H] +

[0465] Step 2: N 4 -(1-Indolin-5-yl)-2-(methylthio)-N 6 - Preparation of (piperidin-4-ylmethyl)pyrimidine-4,6-diamine

[0466]

[0467] The target compound was prepared by performing the same method as step 6 of Example 42 above. LC / MS (ESI) m / z: 371 [M+H] +

[0468] Step 3: N 4 -(Indolin-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0469]

[0470] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 449 [M+H] +

[0471] Step 4: 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0472]

[0473] The target compound was prepared by performing the same method as step 2 of Example 29. LC / MS (ESI) m / z: 581 [M+H] +

[0474]

[0475] <Example 56> Preparation of N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide

[0476]

[0477] Step 1: Preparation of tert-butyl 5-((6-(((1-tert -butoxycarbonyl)piperidin-4-yl)methyl)amino)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0478]

[0479] In step 1 of Example 54, tert-butyl 5-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)indolin-1-carboxylate (100 mg, 0.255 mmol), tert-butyl 4-carbamonyl)piperidine-1-carboxylate (76.0 mg, 0.331 mmol), K2CO3 (1.76 g, 12.7 mmol), X-phos (12.13 mg, 0.025 mmol), and Pd2(dba)3 (23.31 mg, 0.025 mmol) synthesized in sec-butanol (2 mL) were dissolved, the mixture was degassed using a nitrogen balloon, and stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was filtered and concentrated, and then purified by MPLC to prepare the target compound (40 mg, 27%). LC / MS(ESI) m / z: 585 [M+H] +

[0480] Step 2: Preparation of N-(6-indolin-5-yl)amino-2-(methylthio)-pyrimidin-4-yl)piperidine-4-carboxamide

[0481]

[0482] The target compound was prepared by performing the same method as step 6 of Example 42 above. LC / MS (ESI) m / z: 385 [M+H] +

[0483] Step 3: Preparation of N-(6-indolin-5-ylamino-2-(methylthio)-pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide

[0484]

[0485] The target compound was prepared by performing the same method as step 3 of Example 11 above. LC / MS (ESI) m / z: 463 [M+H] +

[0486] Step 4: Preparation of N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide

[0487]

[0488] The target compound was prepared by performing the same method as step 2 of Example 29 above. LC / MS (ESI) m / z: 595 [M+H] +

[0489]

[0490] <Example 57> N 4 -Ethyl-N 6 Preparation of -(1H-indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0491] The target compound (55%, white solid) was prepared as in Example 53 above.

[0492]

[0493] <Examples 58 to 64> N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine, N-(2-(methylthio)-6-(4-(5-nitro pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine, N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine, N-(2-(methylthio)-6-morpholinopyrimidin-4-yl)-1H-indazol-5-amine, Preparation of N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine, N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine and N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0494] As in Example 1, Example 58, N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; Example 59, N-(2-(methylthio)-6-(4-(5-nitro pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; Example 60, N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; Example 61, N-(2-(methylthio)-6-morpholinopyrimidin-4-yl)-1H-indazol-5-amine; Example 62 N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; Example 63 N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; Example 64 N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; were prepared.

[0495]

[0496] <Example 65> N 1 Preparation of -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine

[0497]

[0498] Step 1: Preparation of 6-chloro-2-(methylthio)-N-(4-nitrophenyl)pyrimidin-4-amine hydrochloride

[0499]

[0500] 4,6-Dichloro-2-(methylthio)pyrimidine (0.25 g, 1.28 mmol) was dissolved in 2-propanol (2.5 mL), 4-nitroaniline (0.177 g, 1.28 mmol) and 12N hydrochloric acid (0.25 mL, 8.23 ​​mmol) were added, and the mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting precipitate was filtered to prepare the target compound (0.294 g, 69%, green solid). LC / MS(ESI) m / z: 297 [M+H] +

[0501] Step 2: Preparation of 2-(methylthio)-N-(4-nitrophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine

[0502]

[0503] The target compound was prepared by performing similarly to step 2 of the above example. LC / MS (ESI) m / z: 424 [M+H] +

[0504] Step 3: Preparation of N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine

[0505]

[0506] 2-(Methylthio)-N-(4-nitrophenyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine (67 mg, 0.158 mmol) was dissolved in ethanol (1 mL), and iron (35 mg, 0.632 mmol) and acetic acid (14 μL, 14.91 mmol) were added, and the mixture was stirred at 80 °C for 15 h. After the reaction was completed, the reaction mixture was filtered through a celite filter and washed with ethyl acetate. The filtrate was concentrated and purified by prep-HPLC to produce the target compound (5 mg, 8%, brown solid). LC / MS (ESI) m / z: 394 [M+H] +

[0507]

[0508] <Examples 66 to 68> Preparation of 2-(methylthio)-6-(4(pyridin-2-yl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine, 2-(methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine and N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine

[0509] As in Example 1, Example 66, 2-(methylthio)-6-(4(pyridin-2-yl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine; Example 67, 2-(methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; and Example 68, N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine were prepared.

[0510]

[0511] <Example 69> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)isoquinolin-6-amine

[0512]

[0513] Step 1: Preparation of N-(6-chloro-2(methylthio)pyrimidin-4-yl)isoquinolin-6-amine

[0514]

[0515] 4,6-Dichloro-2-(methylthio)pyrimidine (100 mg, 0.513 mmol) and isoquinolin-6-amine (111 mg, 0.769 mmol) were dissolved in n-BuOH (1 mL), 12N HCl (1 mL) was added, and the mixture was stirred at 100 °C for 17 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to produce the target compound (20 mg, 13%). LC / MS (ESI) m / z: 303 [M+H] +

[0516] Step 2: Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)isoquinolin-6-amine

[0517]

[0518] The target compound was prepared by performing the same method as step 2 of Example 1. LC / MS (ESI) m / z: 430 [M+H] +

[0519]

[0520] <Examples 70 and 71> Preparation of 2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine and N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine

[0521] As in Example 1, Example 70, 2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine; and Example 71, N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; were prepared.

[0522]

[0523] <Example 72> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-amine

[0524] The target compound (16%, white solid) was prepared as in Example 69 above.

[0525]

[0526] <Examples 73 to 75> Preparation of N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazol[3,4-c]pyridin-5-amine, N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine and N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0527] As in Example 1, Example 73 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazol[3,4-c]pyridin-5-amine; Example 74 N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; and Example 75 N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine were prepared.

[0528]

[0529] <Example 76> N 4 -Ethyl-N 6 -(Indolin-5-yl)-2-(methylthio)-N 4 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0530] The target compound (26%, white solid) was prepared as in Example 54 above.

[0531]

[0532] <Example 77> N 4-(Indolin-5-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0533] The target compound (24%, white solid) was prepared as in Example 55 above.

[0534]

[0535] <Examples 78 to 79> Preparation of N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine and N-(6-(4-(6-methoxynaphthalen-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0536] As in Example 1, Example 78, N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; and Example 79, N-(6-(4-(6-methoxynaphthalen-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; were prepared.

[0537]

[0538] <Example 80> Preparation of 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0539]

[0540] Step 1: Preparation of 5-(piperazin-1-yl)isoquinoline

[0541]

[0542] To a solution of 5-bromoisoquinoline (1 g, 4.81 mmol) in toluene (5 mL) were added piperazine (1.035 g, 12.02 mmol), NaOtBu (0.647 g, 6.73 mmol), Pd2(dba)3 (0.220 g, 0.240 mmol), and BINAP (0.449 g, 0.721 mmol). The solution was degassed using a nitrogen balloon and stirred at 90 °C for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and filtered through a Celite filter. The mixture was concentrated under reduced pressure and purified by MPLC to give the target compound (0.449 mg, 44%, yellow solid). LC / MS (ESI) m / z: 214 [M+H] +

[0543] Step 2: Preparation of tert-butyl 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0544]

[0545] To the intermediate tert-butyl 5-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)indolin-1-carboxylate (440 mg, 1.120 mmol) prepared in Example 54 above, 5-(piperazin-1-yl)isoquinoline (287 mg, 1.344 mmol), DMF (5 mL), and DIPEA (0.587 mL, 3.36 mmol) were added, and the mixture was stirred at 90 °C for 24 hours and at 100 °C for 7 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water and brine. The residue of the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by MPLC to prepare the target compound (316 mg, 50%, yellow solid). LC / MS (ESI) m / z: 570 [M+H] +

[0546] Step 3: Preparation of N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)indolin-5-amine

[0547]

[0548] The target compound (158 mg, 64%, brown solid) was prepared by performing the same method as step 6 of Example 42 above. LC / MS (ESI) m / z: 470 [M+H] +

[0549] Step 4: Preparation of 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0550]

[0551] Sulfuric diamine (15.35 g, 0.16 mmol) and dioxane (1.5 mL) were added to N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)indolin-5-amine (50 mg, 0.107 mmol) prepared in the above step 3, and the mixture was stirred at 110 °C for 4 h. After the reaction was completed, the solution was purified by prep-HPLC to prepare the target compound (35 mg, 59%, yellow solid). LC / MS (ESI) m / z: 549 [M+H] +

[0552]

[0553] <Example 81> 2-(methylthio)-N 4 -(1-(1-(pyrimidin-2-yl)piperidin-4-yl)ethyl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0554] The target compound (72%, white solid) was prepared in the same manner as in Example 55 above.

[0555]

[0556] <Example 82> Preparation of 1-isopropyl-N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indole-5-amine

[0557]

[0558] Step 1: Preparation of 1-isopropyl-N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine

[0559]

[0560] The target compound (4 mg, 8%, yellow solid) was prepared by performing the same method as step 2 of Example 80 above. LC / MS (ESI) m / z: 510 [M+H] +

[0561]

[0562] <Example 83> Preparation of N-(6-(4-(isoquinolin-8-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0563]

[0564] Step 1: Preparation of 8-(piperazin-1-yl)isoquinoline

[0565]

[0566] Piperazine (104 mg, 1.202 mmol) and Cs2CO3 (313 mg, 0.961 mmol) were added to a solution of 8-bromoisoquinoline (100 mg, 0.481 mmol) in t-BuOH (1 mL). While heating at 80 °C, Xphos Pd G2 (37.8 mg, 0.048 mmol) was added, and the mixture was stirred at 80 °C for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and filtered through a Celite filter. The mixture was concentrated under reduced pressure and purified by MPLC to give the target compound (51 mg, 50%, yellow solid). LC / MS (ESI) m / z: 214 [M+H] +

[0567] Step 2: Preparation of N-(6-(4-(isoquinolin-8-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine

[0568]

[0569] The target compound (18 mg, 36%, yellow solid) was prepared by performing the same method as step 2 of Example 80 above. LC / MS (ESI) m / z: 469 [M+H] +

[0570]

[0571] <Example 84> Preparation of N-(2-(methylthio)-6-(4-(quinazolin-8-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

[0572] The target compound (54%, yellow solid) was prepared in the same manner as in Example 83 above.

[0573]

[0574] <Example 85> Preparation of N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide

[0575] The target compound (4%, yellow solid) was prepared in the same manner as in Example 29 above.

[0576]

[0577] <Example 86> Preparation of N4-(1H-indazol-5-yl)-2-(methylthio)-N6-(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)pyrimidine-4,6-diamine

[0578] The target compound (15%, brown solid) was prepared in the same manner as in Example 1 above.

[0579]

[0580] <Example 87> Preparation of N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine

[0581] The target compound (7%, brown solid) was prepared in the same manner as in Example 1 above.

[0582]

[0583] <Example 88> Preparation of N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine

[0584] The target compound (17%, brown solid) was prepared by performing the same method as step 2 of Example 69 above.

[0585]

[0586] <Example 89> Preparation of N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine

[0587] The target compound (15%, yellow solid) was prepared in the same manner as in Example 29 above.

[0588]

[0589] <Example 90> Preparation of N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine

[0590] The target compound (5%, yellow solid) was prepared in the same manner as in Example 80 above.

[0591]

[0592] <Example 91> Preparation of N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)isoquinolin-6-amine

[0593] The target compound (8%, yellow solid) was prepared in the same manner as in Example 80 above.

[0594]

[0595] <Example 92> Preparation of 6-(4-(isoquinolin-5-yl)piperazin-1-yl)-N-(6-methoxynaphthalen-2-yl)-2-(methylthio)pyrimidin-4-amine

[0596] The target compound (13%, yellow solid) was prepared in the same manner as in Example 80 above.

[0597]

[0598] <Example 93> 2-(methylthio)-N 4 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)-N 6 Preparation of -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine

[0599] The target compound (19%, white solid) was prepared in the same manner as in Example 29 above.

[0600]

[0601] <Example 94> N 4 -(6-methoxynaphthalen-2-yl)-2-(methylthio)-N 6 Preparation of -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine

[0602] The target compound (27%, white solid) was prepared in the same manner as in Example 11 above.

[0603]

[0604] <Example 95> Preparation of 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0605]

[0606] Step 1: Preparation of 8-nitro-5-(piperazin-1-yl)isoquinoline

[0607]

[0608] The target compound (309 mg, 61%, brown solid) was prepared by performing the same method as step 1 of Example 83 above. LC / MS (ESI) m / z: 259 [M+H] +

[0609] Step 2: Preparation of tert-butyl 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-carboxylate

[0610]

[0611] The target compound (285 mg, 46%, red solid) was prepared by performing the same method as step 2 of Example 80 above. LC / MS (ESI) m / z: 615 [M+H] +

[0612] Step 3: Preparation of N-(2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)indolin-5-amine

[0613]

[0614] The target compound (234 mg, 100%, yellow solid) was prepared by performing the same method as step 3 of Example 80 above. LC / MS (ESI) m / z: 515 [M+H] +

[0615] Step 4: Preparation of 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0616]

[0617] The target compound (37%, yellow solid) was prepared by performing the same method as step 4 of Example 80 above. LC / MS (ESI) m / z: 594 [M+H] +

[0618]

[0619] <Example 96> Preparation of 5-((6-(4-(8-aminoisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0620]

[0621] Step 1: Preparation of 5-((6-(4-(8-aminoisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0622]

[0623] The target compound (35%, brown solid) was prepared by performing the same method as step 2 of Example 31 above. LC / MS (ESI) m / z: 564 [M+H] +

[0624]

[0625] <Examples 97 to 98> Preparation of 5-((6-(4-(3-methylisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide and 5-((6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0626] 5-((6-(4-(3-methylisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide (Example 97, 24 mg, 40%, light brown solid) and 5-((6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide (Example 98, 25 mg, 32%, white solid) were prepared in the same manner as in Example 95.

[0627]

[0628] <Example 99> Preparation of 5-((6-(4-(8-chloroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0629] The target compound (27%, brown solid) was prepared in the same manner as in Example 95 above.

[0630]

[0631] <Example 100> Preparation of 5-((6-(4-(8-methoxyisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide

[0632] The target compound (14%, brown solid) was prepared in the same manner as in Example 95 above.

[0633]

[0634] <Example 101> Preparation of N-(6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine

[0635] The target compound (14%, brown solid) was prepared in the same manner as in Example 29.

[0636]

[0637] [Experimental Example] Confirmation of the structure of a pyrimidine derivative compound

[0638] The compound structures and compound names of Examples 1 to 79 are as shown in Table 1 below.

[0639] Example structure name 1 H NMR, MS, HPLC1 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 9.12 - 8.96 (m, 1H), 8.20 - 8.06 (m, 2H), 7.98 - 7.80 (m, 1H), 7.60 - 7.39 (m, 2H), 7.27 - 7.09 (m, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.68 - 6.59 (m, 1H), 5.70 (s, 1H), 3.65 - 3.50 (m, 8H), 2.47 (s, 3H) ; MS(m / z): 419 [M+H] + (B), 3.984, 96%2 Methyl 2-((4-((1H-indazol-5-yl)amino)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-2-yl)thio)acetate 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.08 (s, 1H), 8.13 (dd,J= 4.9, 1.3 Hz, 1H), 7.99 (s, 1H), 7.92 - 7.85 (m, 1H), 7.56 (ddd,J= 8.8, 7.2, 2.0 Hz, 1H), 7.47 (d,J= 8.9 Hz, 1H), 7.34 (dd,J= 8.9, 1.8 Hz, 1H), 6.86 (d,J= 8.6 Hz, 1H), 6.70 - 6.61 (m, 1H), 5.65 (s, 1H), 3.92 (s, 2H), 3.68 - 3.48 (m, 11H) ;MS(m / z): 477 [M+H] + (B), 4.441, 99%3 5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)oxy)-1H-indazole 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.13 (dd,J= 4.9, 1.4 Hz, 1H), 8.06 (s, 1H), 7.60 - 7.52 (m, 2H), 7.50 (d,J= 2.0 Hz, 1H), 7.14 (dd,J= 8.9, 2.2 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.70 - 6.63 (m, 1H), 5.96 (s, 1H), 3.83 - 3.49 (m, 8H), 2.30 (s, 3H); MS(m / z): 420 [M+H] + (B), 4.927, 96%4 N-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.01 (s, 1H), 8.20 (s, 1H), 8.15 - 8.09 (m, 1H), 8.03 - 7.98 (m, 2H), 7.59 - 7.51 (m, 1H), 7.47 (d,J= 8.9 Hz, 1H), 7.38 (dd,J= 8.9, 1.9 Hz, 1H), 6.85 (d,J= 8.6 Hz, 1H), 6.69 - 6.62 (m, 1H), 5.96 (s, 1H), 3.60 (s, 8H) ; MS(m / z): 373 [M+H] + (B), 3.818, 96%5 4-((1H-indazol-5-yl)amino)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidine-5-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.39 (s, 1H), 8.17 - 8.10 (m, 1H), 8.04 (s, 1H), 7.78 (d,J= 1.2 Hz, 1H), 7.62 - 7.52 (m, 1H), 7.49 (d,J= 8.9 H z, 1H), 7.42 (dd,J= 8.9, 1.8 Hz, 1H), 6.85 (d,J= 8.7 Hz, 1H), 6.71 - 6.65 (m, 1H), 4.07 - 3.80 (m, 4H), 3.78 - 3.55 (m, 4H), 2.35 (s, 3H) ; MS(m / z) : 444 [M+H] + (B), 4.93 6, 98%6 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.03 (s, 1H), 8.13 (dd,J= 4.9, 1.4 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.61 - 7.51 (m, 1H), 7.48 (d,J= 8.9 Hz, 1H), 7.38 (dd,J= 8.9, 1.8 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.66 (dd,J= 6.9, 5.0 Hz, 1H), 5.66 (s, 1H), 3.67 - 3.50 (m, 8H), 2.45 (s, 3H) ; MS(m / z): 419 [M+H] + (B), 4.250, 99%7 N-(5-methyl-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.35 (s, 1H), 8.14 (dd,J= 4.9, 1.5 Hz, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.61 - 7.52 (m, 1H), 7.52 - 7.43 (m, 2H), 6.87 (d,J= 8.6 Hz, 1H), 6.71 - 6.64 (m, 1H), 3.69 - 3.55 (m, 4H), 3.32 - 3.25 (m, 4H), 2.36 (s, 3H), 2.11 (s, 3H) ; MS(m / z): 433 [M+H] + (B), 4.477, 98%8 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.18 (s, 1H), 8.13 (dd,J= 5.0, 1.5 Hz, 1H), 8.03 (s, 1H), 7.60 - 7.51 (m, 1H), 7.43 (s, 2H), 6.85 (d,J= 8.6 Hz, 1H), 6.70 - 6.63 (m, 1H), 5.69 (s, 1H), 3.68 - 3.52 (m, 8H), 2.46 (s, 3H) ; MS(m / z): 437 [M+H] + (B), 4.504, 99%9 N,1-Dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd,J= 4.9, 1.4 Hz, 1H), 7.99 (d,J= 0.7 Hz, 1H), 7.67 (d,J= 8.8 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.24 (dd,J= 8.8, 1.9 Hz, 1H), 6.83 (d,J= 8.6 Hz, 1H), 6.69 - 6.62 (m, 1H), 5.75 (s, 1H), 3.80 - 3.73 (m, 1H), 3.67 - 3.49 (m, 8H), 3.14 - 3.06 (m, 1H), 2.22 (s, 3H), 1.19 - 1.07 (m, 4H), 0.93 - 0.82 (m, 2H), 0.54 - 0.43 (m, 2H) ; MS(m / z): 499 [M+H] + (B), 5.026, 100%10 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.13 (dd,J= 4.9, 1.5 Hz, 1H), 7.93 (s, 2H), 7.63 (d,J= 9.0 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.47 (dd,J= 9.0, 1.9 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.66 (dd,J= 7.0, 5.0 Hz, 1H), 5.67 (s, 1H), 3.76 - 3.67 (m, 1H), 2.45 (s, 3H), 1.15 - 1.02 (m, 4H) ; MS(m / z): 459 [M+H] + (B), 4.674, 99%11 N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1H NMR (400 MHz, DMSO-d6) δ 12.93 (br s, 1H), 8.78 (br s, 1H), 8.07 (dd,J= 4.8, 1.5 Hz, 1H), 7.97 (s, 1H), 7.88 - 7.77 (m, 1H), 7.52 - 7.43 (m, 2H), 7.33 (d,J= 8.3 Hz, 1H), 6.98 - 6.90 (m, 1H), 6.80 (d,J= 8.7 Hz, 1H), 6.60 - 6.54 (m, 1H), 5.46 (s, 1H), 4.34 - 4.24 (m, 2H), 3.15 - 3.06 (m, 1H), 2.74 (t,J= 11.8 Hz, 2H), 2.41 (s, 3H), 1.72 (d,J= 11.8 Hz, 2H), 1.19 - 1.06 (m, 2H) ; MS(m / z): 447 [M+H] + (B), 4.319, 98%12 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.18 (dd,J= 4.9, 1.2 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.46 (m, 1H), 7.40 (d,J= 8.5 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.0 9 (d,J= 8.5, 2.0 Hz, 1H), 6.66 - 6.58 (m, 2H), 6.58 - 6.53 (m, 1H), 6.49 (s, 1H), 5.47 (s, 1H), 3.71 - 3.51 (m, 8H), 2.53 (s, 3H) ; MS(m / z): 418 [M+H] + (B), 4.420, 100%13 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-6-amine 1H NMR (400 MHz, DMSO-D6) δ 12.83 (s, 1H), 9.28 (s, 1H), 8.18 - 8.12 (m, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.65 - 7.51 (m, 2H), 7.07 (dd,J= 8.7, 1.6 Hz, 1H), 6.86 (d,J= 8.7 Hz, 1H), 6.69 - 6.64 (m, 1H), 5.79 (s, 1H), 3.65 - 3.60 (m, 8H) ; MS(m / z): 419 [M+H] + (B), 4.414, 97.4%14 1-Isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.17 (d,J= 3.8 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.37 (d,J= 8.7 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.09 (dd,J= 8.7, 2.1 Hz, 1H), 6.64 - 6.60 (m, 1H), 6.52 - 6.48 (m, 2H), 5.49 (s, 3H), 4.71 - 4.65 (m, 1H), 3.71 - 3.52 (m, 8H), 2.53 (s, 3H) ; MS(m / z): 460 [M+H] + (B), 4.962, 100%15 N-(2-(Methylsulfonyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.99 (s, 1H), 8.13 (dd,J= 4.8, 1.5 Hz, 1H), 7.99 (s, 2H), 7.58 -7.53 (m, 1H), 7.46 (d,J= 8.8 Hz, 1H), 7.39 (d,J= 8.8 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.68 - 6.62 (m, 1H), 5.62 (s, 1H), 4.26 (q,J= 7.0 Hz, 2H), 3.60 -3.50 (m, 8H), 1.30 (t,J= 7.0 Hz, 3H) ; MS(m / z): 451 [M+H] + (B), 5.532, 99.3%16 N-(2-ethoxy-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.99 (s, 1H), 8.13 (dd,J= 4.8, 1.5 Hz, 1H), 7.99 (s, 2H), 7.58 -7.53 (m, 1H), 7.46 (d,J= 8.8 Hz, 1H), 7.39 (d,J= 8.8 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.68 - 6.62 (m, 1H), 5.62 (s, 1H), 4.26 (q,J= 7.0 Hz, 2H), 3.60 - 3.50 (m, 8H), 1.30 (t,J= 7.0 Hz, 3H) ; MS(m / z): 417 [M+H] + (B), 4.150, 98.1%17 N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.86 (s, 1H), 8.14 - 8.11 (m, 1H), 7.99 - 7.96 (m, 2H), 7.58 - 7.54 (m, 1H), 7.46 (d,J= 8.9 Hz, 1H), 7.39 (d,J= 8.9 Hz, 1H), 6.84 (d,J= 8.6 Hz, 1H), 6.68 - 6.63 (m, 1H), 5.74 (s, 1H), 3.59 - 3.50 (m, 8H), 1.91 - 1.85 (m, 1H), 0.99 - 0.90 (m, 2H), 0.89 - 0.87 (m, 2H) ; MS(m / z): 413 [M+H] + (B), 4.195, 97.9%18 N-(6-(4-(5-aminopyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.02 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.62 (d,J= 2.8 Hz, 1H), 7.47 (d,J= 8.9 Hz, 1H), 7.38 (d,J= 8.9 Hz, 1H), 6.94 (dd,J= 8.9, 2.8 Hz, 1H), 6.67 (d,J= 8.9 Hz, 1H), 5.66 (s, 1H), 4 .60 (s, 2H), 3.58 - 3.50 (m, 4H), 3.37 - 3.33 (m, 4H), 2.44 (s, 3H) ; MS(m / z): 433 [M+H] + (B), 4.180, 98.5%19 Methyl 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylate 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.06 (s, 1H), 8.82 (s, 2H), 7.99 (s, 1H), 7.94 (s, 1H), 7.47 (d,J= 8.8 Hz, 1H), 7.39 (d,J= 8.8 Hz, 1H), 5.66 (s, 1H), 4.07 - 3.90 (m, 4H), 3.81 (s, 3H), 3.69 - 3.54 (m, 4H), 2.45 (s, 3H) ; MS(m / z): 478 [M+H] + (A), 3.88, 97.6%20 N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.77 (s, 1H), 8.32 (d,J= 4.7 Hz, 2H), 7.97 (s, 1H), 7.82 (s, 1H), 7.46 (d,J= 8.9 Hz, 1H), 7.33 (d,J= 7.8 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.56 (dd,J= 4.7, 4.7 Hz, 1H), 5.46 (s, 1H), 4.67 - 4.63 (m, 2H), 3.10 (s, 2H), 2.85 - 2.80 (m, 2H), 2.41 (s, 3H), 1.81 (s, 1H), 1.75 - 1.70 (m, 2H), 1.13 - 1.00 (m, 2H) ; MS(m / z): 44 8 [M+H] + (B), 4.619, 98.5%21 Methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.76 (s, 3H), 7.97 (s, 1H), 7.82 (s, 1H), 7.46 (d,J= 8.9 Hz, 1H), 7.33 (d,J= 8.9 Hz, 1H), 6.94 - 6.90 (m, 1H), 5.46 (s, 1H), 4.77 - 4.74 (m, 2 H), 3.79 (s, 3H), 3.00 - 2.95 (m, 2H), 2.41 (s, 3H), 1.80 - 1.75 (m, 2H), 1.15 - 1.10 (m, 2H) ; MS(m / z): 506 [M+H] + (A), 3.86, 94.3%22 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid 1 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.73 (s, 3H), 7.97 (s, 1H), 7.82 (s, 1H), 7.46 (d,J= 8.9 Hz, 1H), 7.33 (d,J= 8.9 Hz, 1H), 6.94 (s, 1H), 5.46 (s, 1H), 4.78 - 4.74 (m, 2H), 2.98 - 2. 90 (m, 2H), 2.41 (s, 3H), 1.89 - 1.86 (m, 1H), 1.79 - 1.75 (m, 2H), 1.15 - 1.10 (m, 2H) ; MS(m / z): 492 [M+H] + (A), 3.29, 98.6%23 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.06 (s, 1H), 8.70 (s, 2H), 7.99 (s, 1H), 7.93 (s, 1H), 7. 48 (d,J= 8.9 Hz, 1H), 7.38 (d,J= 8.9 Hz, 1H), 5.66 (s, 1H), 4.01 - 3.83 (m, 4H), 3.63 - 3.58 (m, 4H), 2.46 (s, 3H) ; MS(m / z): 593 [M+H] + (A), 3.02, 93.8%24 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide 1 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 11.48 (s, 1H), 8.76 (s, 1H), 8.66 (s, 2H), 7.97 (s, 1H), 7.82 (s, 1H), 7.46 (d,J=8.9 Hz, 1H), 7.33 (d,J= 8.9 H z, 1H), 6.94 (s, 1H), 5.46 (s, 1H), 4.94 (s, 1H), 4.75 - 4.70 (m, 2H), 4.05 - 4.00 (m, 1H), 3.55 - 3 .50 (m, 1H), 3.17 - 3.12 (m, 3H), 2.97 - 2.92 (m, 2H), 1.82 - 1.63 (m, 5H), 1.54 (s, 3H), 1.10 - 1.00 (m, 2H) ; MS(m / z): 591 [M+H] + (A), 3.12, 99.3%25 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5 -carboxamide 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.97 (s, 1H), 8.64 (s, 2H), 8.00 (s, 1H), 7.80 (s, 1H), 7.50 (d,J= 8.8 Hz, 1H), 7.32 (d,J= 8.8 Hz, 1H), 7.21 (s, 1H), 5.47 (s, 1H), 4.75 - 4.70 (m, 2H), 3.96 (s, 1H), 3.13 (s, 2H), 2.95 - 2.90 (m, 2H), 2.4 5 (s, 3H), 1.85 (s, 1H), 1.77 - 1.74 (m, 2H), 1.16 - 1.01 (m, 2H) ; MS(m / z): 621 [M+H] + (A), 3.12, 99.3%26 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)nicotinic acid 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d,J= 2.2 Hz, 1H), 8.05 (s, 1H), 7.95 (dd,J= 9.2, 2.3 Hz, 1H), 7.78 (brs, 1H), 7.55 (d,J= 8.8 Hz, 1H), 7.32 (d,J= 8.5 Hz, 1H), 6.96 (d,J= 9.0 Hz, 1H), 5.51 (s, 1H), 4.43 (d,J= 12.8 Hz, 2H), 3.21 - 3.13 (m, 2H), 2.97 (t,J= 12.1 Hz, 2H), 1.90 - 1.71 (m, 3H), 1.22 - 1.10 (m, 2H) ; MS(m / z): 491 [M+H] + (A), 2.919, 96%27 6-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxynicotinamide 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.99 (br s, 1H), 9.04 (s, 1H), 8.96 - 8.79 (m, 1H), 8.52 (d,J= 2.3 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.88 (dd,J= 9.0, 2.4 Hz, 1H), 7.48 (d,J= 8.9 Hz, 1H), 7.38 (dd,J= 8.9, 1.8 Hz, 1H), 6.85 (d,J= 9.0 Hz, 1H), 5.65 (s, 1H), 3.80 - 3.65 (m, 4H), 3.65 - 3.55 (m, 4H), 2.45 (s, 3H) ; MS(m / z): 478 [M+H] + (B), 4.189, 93%28 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxynicotinamide 1 H NMR (400 MHz, DMS O-d6) δ 12.92 (s, 1H), 10.93 (brs, 1H), 8.91 - 8.70 (m, 2H), 8.47 (d,J= 2.4 Hz, 1H), 7.97 (s, 1H), 7.81 (dd,J= 9.0, 2.4 Hz, 2H), 7.46 (d,J= 8.9 Hz, 1H), 7.33 (d,J= 9.0 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.83 (d,J= 9.1 Hz, 1H), 5.46 (s, 1H), 4.39 (d,J=12.9 Hz, 2H), 3.18 - 3.06 (m, 2H), 2.85 (t,J= 11.7 Hz, 2H), 2.41 (s, 3H), 1. 86 - 1.68 (m, 3H), 1.17 - 1.05 (m, 2H) ; MS(m / z): 506 [M+H] + (B), 4.173, 98%29 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine1 H NMR (400 MHz, CDCl3) δ 8.32 (d,J= 4.7 Hz, 2H), 7.87 (d,J= 8.8 Hz, 1H), 7.63 (d,J= 2.0 Hz, 1H), 7.39 (d,J= 3.76 Hz, 1H), 7.30 (dd,J= 8.8, 2.0 Hz, 1H), 6.80 (d,J= 3.7 Hz, 1H), 6.80 (d,J= 3.7 Hz, 1H), 6.56 - 6.51 (m, 2H), 5.48 (s, 1H), 3.90 - 3.88 (m, 4H), 3.66 - 3.63 (m, 4H), 2.53 (s, 3H) ; MS(m / z): 551 [M+H] + (A), 4.56, 98.9%30 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.19 (dd,J= 4.9, 1.2 Hz, 1H), 7.87 (d,J= 8.8 Hz, 1H), 7.62 (d,J= 2.0 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.40 (d,J= 3.8 Hz, 1H), 7.31 (dd,J= 8.8, 2.0 Hz, 1H), 6.81 (d,J= 3.8 Hz, 1H), 6.69 - 6.61 (m, 2H), 5.57 (s, 1H), 3.85 - 3.47 (m, 8H), 2.53 (s, 3H) ; MS(m / z): 550 [M+H] + (A), 4.01, 97.7%31 1-Isopropyl-N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine 1H NMR (400 MHz, CDCl-3) δ 7.48 (d,J= 1.9 Hz, 1H), 7.36 (d,J= 8.7 Hz, 1H), 7.07 (dd,J= 8.7, 1.9 Hz, 1H), 6.50 (d,J= 3.1 Hz, 1H), 6.44 (s, 1H), 5.48 (s, 1H), 4.69 - 4.64 (m, 1H), 4.29 - 4.25 (m, 2H), 2.75 - 2.70 (m, 2H), 2.58 - 2.37 (m, 11H), 2.27 (s, 3H), 1.83 - 1.79 (m, 2H), 1.55 (d,J= 6.7 Hz, 5H), 1.46 - 1.39 (m, 2H) ; MS(m / z): 480 [M+H] + (A), 3.22, 95.7%32 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.22 - 8.17 (m, 1H), 7.54 - 7.47 (m, 1H), 7.39 (d,J= 8.7 Hz, 1H), 7.12 (dd, = 8.7, 2.1 Hz, 1H), 6.69 - 6.61 (m, 2H), 6.37 (s, 1H), 5.51 (s, 1H), 4.24 (t,J= 8.4 Hz, 2H), 3.76 - 3.58 (m, 8H), 3.23 (t,J= 8.4 Hz, 2H), 2.51 (s, 3H) ; MS(m / z): 552 [M+H] + (B), 5.622, 98%33 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine 1H NMR (400 MHz, CDCl3) δ 8.33 (d,J= 4.7 Hz, 2H), 7.38 (d,J= 8.7 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.11 (dd,J= 8.7, 2.0 Hz, 1H), 6.53 (t,J= 4.7 Hz, 1H), 6.43 (s, 1H), 5.51 (s, 1H), 4.24 (t,J= 8.4 Hz, 2H), 3.94 - 3.86 (m, 4H), 3.71 - 3.59 (m, 4H), 3.22 (t,J= 8.4 Hz, 2H), 2.51 (s, 3H) ; MS(m / z): 553 [M+H] + (B), 7.063, 96%34 N-(6-(4-cyclohexylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indole-5-amine 1 H NMR (400 MHz, CDCl3) δ 7.48 (d,J= 1.9 Hz, 1H), 7.35 (d,J= 8.7 Hz, 1H), 7.08 (dd,J= 8.7, 1.9 Hz, 1H), 6.50 (d,J= 3.2 Hz, 1H), 6.45 (s, 1H), 5.45 (s, 1H), 4.70 - 4.64 (m, 1H), 3.50 - 3.45 (m, 4H), 2.69 - 2.37 (m, 4H), 2.50 (s, 3H), 2. 25 - 2.20 (m, 1H), 1.85 - 1.80 (m, 4 H), 1.54 (d,J= 6.4 Hz, 6H), 1.33 - 1.01 (m, 6H) ; MS(m / z): 465 [M+H] + (A), 3.95, 9 8.4%35 N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1H NMR (400 MHz, MeOD) δ 7.57 - 7.43 (m, 3H), 7.11 - 7.04 (m, 1H), 6.50 (d,J= 3.1 Hz, 1H), 5.41 (s, 1H), 4.82 - 4.72 (m, 1H), 4.06 (dd,J= 11.5, 4.0 Hz, 2H), 3.65 - 3.5 6 (m,2H), 3.47 - 3.35 (m, 4H), 2.99 (t,J= 12.2 Hz, 2H), 2.65 (s, 3H), 2.05 - 1.86 (m, 5H), 1.81 - 1.70 (m, 2H), 1.53 (d,J=6.7 Hz, 6H) ; MS(m / z): 495 [M+H] + (B), 4.900, 95%36 N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, MeOD) δ 8.03 - 7.96 (m, 1H), 7.93 - 7.88 (m, 1H), 7.57 - 7.49 (m, 2H), 7.45 (d,J= 3.2 Hz, 1H), 7.38 (d,J= 9.4 Hz, 1H), 7.11 - 7.05 (m, 1H), 6.95 (t,J= 6.6 Hz, 1H), 6.50 (d,J= 3.2 Hz, 1H), 5.42 (s, 1H), 4.81 - 4.73 (m, 1H), 4.24 - 4.14 (m, 2H), 3.28 - 3.21 (m, 2H), 2.64 (s, 3H), 2.06 - 1.85 (m, 4H), 1.53 (d,J= 6.7 Hz, 6H), 1.42 - 1.33 (m, 2H) ; MS(m / z): 488 [M+H] + (B), 5.026, 93%37 N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine1 H NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 7.77 (s, 1H), 7.61 (d,J= 8.8 Hz, 1H), 7.36 (d,J= 8.7 Hz, 1H), 5.46 (s, 1H), 4.06 (dd,J= 11.7, 4.1 Hz, 2H), 3.61 ( d,J= 13.7 Hz, 2H), 3.50 - 3.33 (m, 5H), 3.00 (t,J= 11.1 Hz, 2H), 2.61 (s, 3H), 2.1 2- 1.86 (m, 5H), 1.82 - 1.70 (m, 2H), 1.58 - 1.42 (m, 2H) ; MS(m / z): 454 [M+H] + (B), 4.136, 95%38 N 4 -(5-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.48 (s, 1H), 9.22 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.54 - 7.35 (m, 4H), 6.76 (s, 1H), 2.27 - 2.16 (m, 2H), 1.14 (d,J= 6.2 Hz, 6H) ; MS(m / z): 463 [M+H] + (A), 3.96, 96.5%39 N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(5-(piperazin-1-yl)pyridin-2-yl)pyrimidine-4,6-diamine 1H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.83 - 7.78 (m, 2H), 7.47 - 7.24 (m, 4H), 6.4 7 (s, 1H), 2.99 - 2.90 (m, 4H), 2.92 - 2.85 (m, 4H), 2.42 (s, 3H) ; MS(m / z): 434 [M+H] + (A), 2.90, 96.9%40 N 4 -(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 9.72 (s, 1H), 9.33 (s, 1H), 8.09 (d,J= 1.9 Hz, 1H), 8.01 (s, 2H), 7.62 - 7.57 (m, 1H), 7.55 - 7.39 (m, 3H), 7.05 (s, 1H), 2.28 (q,J= 7.2 Hz, 2H), 0.96 (t,J= 7.2 Hz, 3H) ; MS(m / z): 476 [M+H] + (A), 2.89, 99.2%41 N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1H NMR (400 MHz, MeOD) δ 8.28 (d,J= 4.8 Hz, 2H), 7.52 - 7.47 (m, 1H), 7.40 (d,J= 8 .8 Hz, 1H), 7.34 (d,J= 3.2 Hz, 1H), 7.09 (dd,J= 8.7, 1.9 Hz, 1H), 6.53 (t,J= 4.8 Hz, 1H), 6.41 (d,J= 3.2 Hz, 1H), 5.36 (s, 1H), 4.77 - 4.66 (m, 3H), 3.17 - 3.05 (m, 2 H), 2.86 (t,J= 11.8 Hz, 2H), 2.47 (s, 3H), 1.80 - 1.73 (m, 2H), 1.52 (d,J= 6.7 Hz, 6H), 1.18 - 1.10 (m, 2H) ; MS(m / z): 489 [M+H] + (B), 5.592, 97%42 1-Isopropyl-N 5 -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine 1 H NMR (400 MHz, CD Cl3) δ 8.18 (dd,J= 4.9, 1.3 Hz, 1H), 7.56 (d,J= 9.1 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.33 - 7.30 (m, 1H), 7.09 (dd,J= 9.1, 1.9 Hz, 1H), 6.66 - 6.59 (m, 2H), 6.49 (s, 1H), 5.40 (s, 1H), 4.77 - 4.66 (m, 1H), 3.82 (s, 2H), 3.72 - 3.52 (m, 8H), 2.52 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H) ; MS(m / z): 476 [M+H] + (B), 4.146, 98%43 1-Isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine 1H NMR (400 MHz, CDCl3) δ 8.13 (d,J= 5.7 Hz, 1H), 8.09 (d,J= 8.3 Hz, 1H), 7.76 (d,J= 8.1 Hz, 1H), 7.62 (t,J= 7.1 Hz, 1H), 7.54 - 7.48 ( m, 2H), 7.38 (d,J= 8.7 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.11 (dd,J= 8.7, 1.9 Hz, 1H), 6.54 (s, 1H), 6.51 (d,J= 3.2 Hz, 1H), 5.55 (s, 1H), 4.72 - 4.64 (m, 1H), 3.81 - 3.68 (m, 4H), 3.47 - 3.35 (m, 4H), 2.53 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H); MS(m / z): 510 [M+H] + (B), 5.356, 100%44 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.18 (dd,J= 4.9, 1.3 Hz, 1H), 7.56 (d,J= 8.6 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.18 (d,J= 3.2 Hz, 1H), 7.11 (dd,J= 8.6, 1.9 Hz, 1H), 6.67 - 6.57 (m, 2H), 6.50 (s, 1H), 6.42 (d,J= 3.1 Hz, 1H), 5.47 (s, 1H), 3.72 - 3.50 (m, 8H), 3.40 - 3.32 (m, 1H), 2.53 (s, 3H), 1.14 - 0.99 (m, 4H) ; MS(m / z): 458 [M+H] + (B), 4.940, 99%45 1-Cyclopropyl-3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, CDCl3) δ 8.22 - 8.16 (m, 1H), 7.58 - 7.45 (m, 3H), 7.34 (dd,J= 9.0, 1.9 Hz, 1H), 6.68 - 6.59 (m, 2H), 6.52 (s, 1H), 5.44 (s, 1H), 3.80 - 3.54 (m, 8H), 3.52 - 3.41 (m, 1H), 2.52 (s, 3H), 1.23 - 1.09 (m, 4H) ; MS(m / z): 477 [M+H] + (B), 5.118, 92%46 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine 1 H NMR (400 MHz, CDCl3) δ 8.32 (d,J= 4.7 Hz, 2H), 7.15 (d,J= 8.7 Hz, 1H), 6.97 (dd,J= 8.7, 2.4 Hz, 1H), 6.86 (d,J= 2.4 Hz, 1H), 6.52 (dd,J= 4.7, 4.7 Hz, 1H), 6.27 (s, 1H), 5.46 (s, 1H), 3.93 - 3.78 (m, 4H), 3.69 - 3.54 (m, 4H), 3.30 - 3.18 (m, 2H), 2.75 - 2.70 (m, 2H), 2.32 - 2.22 (m, 1H), 1.98 - 1.90 (m, 2H), 0.85 - 0.77 (m, 2H), 0.67 - 0.55 (m, 2H) ; MS(m / z): 475 [M+H] + (A), 4.56, 99.3%47 2-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine 1H NMR (400 MHz, CDCl3) δ 8.33 (d,J= 4.7 Hz, 2H), 7.05 - 6.96 (m, 3H), 6.53 (dd,J= 4.7, 4.7 Hz, 1H), 6.38 (s, 1H), 5.55 (s, 1H), 3.95 - 3.82 (m, 4H), 3.78 (s, 2H), 3.68 - 3.54 (m, 4 H), 2.98 - 2.82 (m, 4H), 2.51 (s, 3H), 1.84 - 1.78 (m, 1H) ; MS(m / z): 475 [M+H] + (A), 3.21, 97.7%48 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyrimidin-2-yl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.80 (d,J= 8.8 Hz, 1H), 8.72 (d,J= 4.8 Hz, 2H), 8.32 (d,J= 3.6 Hz, 1H), 8.18 (d,J= 3.6 Hz, 1H), 7.57 - 7.42 ( m, 2H), 7.25 - 7.22 (m, 1H), 7.09 (dd,J= 4.8, 4.8 Hz, 1H), 6.69 (d,J= 3.6 Hz, 1H), 6.67 - 6.59 (m, 2H), 6.55 (s, 1H), 5.57 (s, 1H), 3.79 - 3.52 (m, 8H), 2.53 (s, 3H) ; MS(m / z): 496 [M+H] + (A), 3.66, 100%49 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indol-5-amine 1H NMR (400 MHz, CDCl3) δ 8.55 (d,J= 6.0 Hz, 2H), 8.18 (d,J= 3.6 Hz, 1H), 7.55 (s, 1H), 7.54 - 7.47 (m, 1H), 7.19 - 7.15 (m, 2H), 7.09 - 7.06 (m, 1H), 6. 98 (d,J= 6.0 Hz, 2H), 6.67 - 6.57 (m, 2H), 6.51 (s, 1H), 5.49 (s, 1H), 5.35 (s, 2H), 3.64 - 3.58 (m, 8H), 2.52 (s, 3H) ; MS(m / z): 509 [M+H] + (A), 2.83, 98.9%50 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H- indazol-5-amine 1 H NMR (400 MHz, CDCl3) δ 8.57 (d,J= 5.9 Hz, 2H), 8.19 (d,J= 3.7 Hz, 1H), 7.65 (s, 1H), 7.55 - 7.44 (m, 1H), 7.36 - 7.48 (m, 1H), 7.26 - 7.20 (m, 1H), 7.08 (d,J= 5.9 Hz, 2H), 6.67 - 6.62 (m, 2H), 6.53 (s, 1H), 5.47 (s, 1H), 5.43 (s, 2H), 3.80 - 3.42 (m, 8H), 2.52 (s, 3H) ; MS(m / z): 528 [M+H] + (B), 4.314, 99.7%51 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-N-(pyrimidin-2-yl)-1H- indazol-5-amine 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 8.84 - 8.80 (m, 3H), 8.27 (d,J= 4.7 Hz, 1H), 7.83 (dd,J= 7.3, 7.3 Hz, 1H), 7.66 (s, 1H), 7.53 (d,J= 8.9 Hz, 1H), 7.21 (s, 1H), 6.90 (dd,J= 6.5, 6.5 Hz, 1H), 6.84 (d,J= 8.9 Hz, 1H), 5.44 (s, 1H), 3.87 (s, 8H), 2.60 (s, 3H) ; MS(m / z): 515 [M+H] + (A), 3.52, 99.7%52 3-Fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.13 (dd,J= 4.8, 1.5 Hz, 1H), 7.79 (s, 1H), 7.59 - 7.52 (m, 1H), 7.50 - 7.43 (m, 2H), 7.20 (dd,J= 9.0, 1.9 Hz, 1 H), 6.84 (d,J= 8.6 Hz, 1H), 6.69 - 6.63 (m, 1H), 5.65 (s, 1H), 4.75 - 4.65 (m, 1H), 3.68 - 3.50 (m, 8H), 2.45 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H) ; MS(m / z): 478 [M+H] + (B), 5.17 1, 98%53 N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1H NMR (400 MHz, CDCl3) δ 8.29 (d,J= 4.7 Hz, 2H), 7.47 (d,J= 1.9 Hz, 1H), 7.33 (d,J= 8.7 Hz, 1H), 7.24 (d,J= 3.2 Hz, 1H), 7.07 (dd,J= 8.7, 2.0 Hz, 1H), 6.57 - 6.40 (m, 3H), 5.41 (s, 1H), 4.80 - 4.71 (m, 2H), 4.69 - 4.60 (m, 1H), 3.47 - 3.17 (m, 4H), 2.87 - 2.74 (m, 2H), 2.49 (s, 3H), 2.05 - 1.92 (m, 1H), 1.72 - 1.66 (m, 2H), 1.54 (s, 3H), 1.53 (s, 3H), 1.23 - 1.13 (m, 2H), 1.07 (t,J= 7.0 Hz, 3H) ; MS(m / z): 517 [M+H] + (B), 6.014, 93%54 N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.29 (d,J= 4.7 Hz, 2H), 7.36 (d,J= 8.7 Hz, 1H), 7.08 (m, 1H), 6.45 (t,J= 4.7 Hz, 1H), 6.32 (s, 1H), 5.41 (s, 1H), 4.78 (d,J= 13.3 Hz, 2H), 4.22 (t, = 8.4 Hz, 2H), 3.38 (d,J= 41.8 Hz, 4H), 3.19 (t,J= 8.4 Hz, 2H), 2.89 - 2.74 (m, 2H), 2.47 (s, 3H), 1.73 (d,J= 11.0 Hz, 2H), 1.31 - 1.1 7 (m, 3H), 1.12 (t,J= 7.0 Hz, 3H) ; MS(m / z): 609 [M+H] + (A), 4.389, 97.2%55 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.29 (d,J= 4.7 Hz, 2H), 7.37 (d,J= 8.7 Hz, 1H), 7.08 (m, 1H), 6.45 (t,J= 4.7 Hz, 1H), 6.40 (s, 1H), 5.33 (s, 1H), 4.79 (d,J= 13.2 Hz, 3H), 4.23 (t,J= 8.4 Hz, 2H), 3.21 (t,J= 8.4 Hz, 2H), 3.14 (s, 2H), 2.86 (dd,J= 18.5, 7.5 Hz, 2H), 2.48 (s, 3H), 1.83 (t,J= 12.7 Hz, 3H), 1.61 (s, 3H) ; MS(m / z): 581 [M+H] + (A), 4.099, 96.3%56 N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide 1 H NMR (400 MHz, CDCl3) δ 8.30 (d,J= 4.7 Hz, 2H), 7.74 (s, 1H), 7.39 (d,J= 8.8 Hz, 2H), 7.23 (s, 1H), 7.18 (dd,J= 8.7, 2.1 Hz, 1H), 6.69 (s, 1H), 6.49 (t,J= 4.7 Hz, 1H), 4.82 (d,J= 13.5 Hz, 2H), 4.23 (t,J= 8.4 Hz, 2H), 3.22 (t,J= 8.4 Hz, 2H), 3.01 - 2.90 (m, 2H), 2.50 (s, 3H), 1.97 (d,J= 11.0 Hz, 2 H), 1.83 - 1.65 (m, 3H) ; MS(m / z): 595 [M+H] + (A), 4.622, 98.1%57 N4 -Ethyl-N 6 -(1H-indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2 -yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.30 (d,J= 4.7 Hz, 2H), 8.04 (s, 1H), 7.64 (s, 1H), 7.52 - 7.44 (m, 1H), 7.31 (dd,J= 8.8, 1.9 Hz, 1H), 6.45 (dd,J= 4.7, 4.7 Hz, 1H), 5.34 (s, 2H), 4.79 - 4.73 (m, 2H), 3.45 - 3.20 (m, 4H), 2.91 - 2.73 (m, 2H), 2.50 (s, 3H), 2.05 - 1.90 (m, 1H), 1.72 - 1.68 (m, 2H), 1.24 - 1.20 (m, 2H), 1.08 (t,J= 7.0 Hz, 3H) ; MS(m / z): 476 [M+H] + (A), 3.49, 91.6%58 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.05 (s, 1H), 8.39 (d,J= 4.7 Hz, 2H), 7.99 (s, 1H), 7.94 (d,J= 7.1 Hz, 1H), 7.48 (d,J= 8.8 Hz, 1H), 7.39 (dd,J= 8.8, 1.8 Hz, 1H), 6.66 (t,J= 4.7 Hz, 1H), 5.66 (s, 1H), 3.82 (t,J= 5.2 Hz, 4H), 3.57 (t,J= 5.1 Hz, 4H), 2.45 (s, 3H)59 N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.07 (s, 1H), 8.99 (d,J= 2.8 Hz, 1H), 8.27 (dd,J= 9.5, 2.8 Hz, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.48 (d,J= 8.8 Hz, 1H), 7.38 (dd,J= 8.9, 1.8 Hz, 1H), 6.93 (d,J= 6.9 Hz, 1H), 5.64 (s, 1H), 3.88 (m, 4H), 3.65 (m, 4H), 2.45 (s, 3H)60 N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.03 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.48 (d,J= 8.9 Hz, 1H), 7.38 (dd,J= 8.8, 1.9 Hz, 1H), 6.93 (d,J= 9.1 Hz, 2H), 6.84 (d,J= 9.0 Hz, 2H), 5.67 (s, 1H), 3.69 (s, 3H), 3.60 (t,J= 4.9 Hz, 4H), 3.06 (t,J= 4.9 Hz, 4H), 2.44 (s, 3H)61 N-(2-(methylthio)-6-morpholino pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.05 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7. 47 (d,J= 8.9 Hz, 1H), 7.37 (dd,J= 8.9, 1.7 Hz, 1H), 5.60 (s, 1H), 3.67 - 3.61 (m, 4H), 3.39 - 3.41 (m, 4H), 2.42 (s, 3H).62 N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine 1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.80 (s, 1H), 7.62 (s, 1H), 7.32 (m, 2H), 7.10 (d,J= 10.3 Hz, 1H), 6.92 (d,J= 9.1 Hz, 2H), 6.83 (d,J= 9.1 Hz, 2H), 6.37 (s, 1H), 5.60 (s, 1H), 3.68 (s, 3H), 3.56 (t,J= 5.0 Hz, 4H), 3.04 (t,J= 5.0 Hz, 4H), 2.43 (s, 3H)63 N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (500 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.04 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.38 (dd,J= 8.9, 1.9 H z, 1H), 6.10 (d,J= 5.6 Hz, 1H), 5.66 (s, 1H), 3.85 (s, 3H), 3.84 - 3.79 (m, 4H), 3.60 - 3.5 4 (m, 4H), 2.45 (s, 3H)64 N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.02 (s, 1H), 7.99 (s, 1H), 7.96 - 7.92 (m, 2H), 7.48 (d,J= 8.9 Hz, 1H), 7.39 (dd,J= 8.9, 1.8 Hz, 1H), 6.32 - 6.30 (m, 2H), 5.65 (s, 1H), 3.78 (s, 3H), 3.58 (s, 8H), 2.45 (s, 3H)65 N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine 1 H NMR (400 MHz, CDCl3) δ 8.21 (dd,J= 4.8, 1.2 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.31 - 7.28 (m, 1H), 7.05 (dd,J= 8.5, 2.9 Hz, 2H), 6.74 - 6.64 (m, 4H), 5.38 (s, 1H), 3.69 - 3.67 (m, 4H), 3.65 - 3.63 (m, 4H), 2.54 (s, 3H) ; MS(m / z): 394 [M+H] + (B), 4.02, 96.8%66 2-(Methylthio)-6-(4(pyridin-2-yl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.19 (m, 1H), 7.52 - 7.49 (m, 1H), 6.6 7 - 6.63 (m, 2H), 6.55 (s, 2H), 6.43 (s, 1H), 5.60 (s, 1H), 3.85 (s, 9H), 3.70 - 3.68 (m, 4H), 3.64 - 3.63 (m, 4H), 2.51 (s, 3H) ; MS(m / z): 469 M+H] + (A), 3.18, 99.9%67 2-(Methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.21 - 8.18 (m, 1H), 7.87 - 7.80 (m, 2H), 7.7 9 - 7.73 (m, 2H), 7.53 - 7.37 (m, 4H), 6.67 - 6.62 (m, 3H), 5.73 (s, 1H), 3.73 - 3.63 (m, 8H), 2.55 (s, 3H) ; MS(m / z): 429 [M+H] + (A), 3.73, 98.3%68 N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)pirerazin-1-yl)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.22 - 8.17 (m, 1H), 7.73 (d,J= 8.8 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.53 - 7.46 (m, 1H), 7.36 (dd,J= 8.7, 2.2 Hz, 1H), 7.19 - 7.1 0 (m, 2H), 6.74 (s, 1H), 6.67 - 6.59 (m, 2H), 5.62 (s, 1H), 3.93 (s, 3H), 3.72 - 3.65 (m, 4H), 3.65 - 3.58 (m, 4H), 2.54 (s, 3H), 1.29 - 1.22 (m, 1H) ; MS(m / z): 459 [M+H] + , (A), 3.672, 96%69 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.10 (s, 1H), 8.36 (d,J= 6.0 Hz, 2H), 8.18 - 8.09 (m, 1H), 8.00 (d,J= 8.9 Hz, 1H), 7.71 (dd,J= 8.9, 1.9 Hz, 1H), 7.64 - 7.53 (m, 2H), 6.86 (d,J= 8.6 Hz, 1H), 6.67 (dd,J= 6.9, 5.1 Hz, 1H), 5.88 (s, 1H), 3.64 (d,J= 5.6 Hz, 8H), 2.54 (s, 3H) ; MS(m / z): 430 [M+H] + (A), 3.110, 100%70 2-(Methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine 1H NMR (400 MHz, CDCl3) δ 8.24 - 8.22 (m, 1H), 7.60 (d,J= 8.5 H z, 2H), 7.53 (ddd,J= 7.3, 7.2, 2.0 Hz, 1H), 7.47 (d,J= 8.5 Hz, 2H), 6.70 - 6.66 (m, 2H), 6.61 (s, 1H), 5.71 (s, 1H), 3.76 - 3.75 (m, 4H), 3.70 - 3.67 (m, 4H), 2.55 (s, 3H) ; MS(m / z): 447 [M+H] + (B), 5.85, 97.6%71 N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.19 (m, 1H), 7.53 - 7.48 (m, 2H), 7.1 7 - 7.09 (m, 2H), 6.67 - 6.64 (m, 2H), 6.35 (s, 1H), 5.48 (s, 1H), 3.72 - 3.69 (m, 4H), 3.65 - 3.63 (m, 4H), 2.51 (s, 3H) ; MS(m / z): 430 [M+H] + (A), 3.72, 99.6%72 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.38 (s, 1H), 8.14 (dd,J= 4.9, 1.4 Hz, 1H), 7.85 (d,J= 8.8 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.31 (d,J= 8.8 Hz, 1H), 6.86 (d,J= 8.6 Hz, 1H), 6.68 - 6.65 (m, 1H), 5.80 (s, 1H), 3.65 - 3.60 (m, 8H) ; MS(m / z): 420 [M+H] +(A), 2.78, 99.1%73 N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 8.34 - 7.84 (m, 3H), 7.56 (m, 1H), 6.86 (d,J= 8.6 Hz, 1H), 6.67 (dd,J= 6.9, 5.1 Hz, 1H), 6.41 (s, 1H), 3.62 (d,J= 2.9 Hz, 8H), 2.54 (s, 3H) ; MS(m / z): 420 [M+H] + (A), 2.882, 100%74 N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.45 (d,J= 5.9 Hz, 1H), 8.01 (s, 1H), 7.85 (d,J= 5.9 Hz, 1H), 7.63 - 7.61 (m, 2H), 7.48 - 7.44 (m, 2H), 7.25 (dd,J= 8.8, 1.9 1H), 7.17 (dd,J= 4.6, 7.6 Hz, 1H), 6.77 (s, 1H), 5.44 (s, 1H), 3.74 - 3.71 (m, 4H), 2.49 - 2.47 (m, 4H), 1.65 (s, 3H) ; MS(m / z): 469 [M+H] + (B), 4.62, 100%75 N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.00 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.46 (d,J= 8.8 Hz, 1H), 7.38 (d,J= 1.7 Hz, 1H), 5.60 (s, 1H), 3.42 (s, 4H), 2 .67 (s, 1H), 2.49 - 2.46 (m, 4H), 2.42 (s, 3H), 0.97 (t,J= 7.3 Hz, 6H) ; MS(m / z): 384 [M+H] + (A), 2.592, 100%76 N 4 -Ethyl-N 6 -(Indolin-5-yl)-2-(methylthio0)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.29 (d,J= 4.6 Hz, 2H), 6.99 (s, 1H), 6.87 (d,J= 7.7 Hz, 1H), 6.60 (d,J= 8.1 Hz, 1H), 6.44 (t,J= 4.6 Hz, 1H), 6.22 (s, 1H), 5.28 (d,J= 12.2 Hz, 1H), 4.76 (d,J= 12.9 Hz, 2H), 3.57 (t,J= 8.3 Hz, 2H), 3.33 (d,J= 47.2 Hz, 4H), 3.01 (t,J= 8.3 Hz, 2H), 2.81 (t,J= 12.1 Hz, 2H), 2.47 (s, 3H), 1.71 (d,J= 12.1 Hz, 2H), 1.20 (dd,J= 24.7, 15.9 Hz, 2H), 1.07 (t,J= 6.8 Hz, 3H) ; MS(m / z): 477 [M+H] + (A), 3.115, 97.3%77 N 4 -(Indolin-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1H NMR (400 MHz, CDCl3) δ 8.28 (d,J= 4.7 Hz, 2H), 6.99 (s, 1H), 6.88 (d,J= 8.1 Hz, 1H), 6.61 (d,J= 8.1 Hz, 1H), 6.44 (t,J= 4.7 Hz, 1H), 6.26 (s, 1H), 5.18 (s, 1H), 4.76 (d,J= 13.4 Hz, 2H), 4.68 (s, 1H), 3.59 (t,J= 8.4 Hz, 2H), 3.04 (dd,J= 1 9.2, 10.8 Hz, 4H), 2.84 (t,J=12.0 Hz, 2H), 2.48 (s, 3H), 1.78 (d,J= 11.0 Hz, 3H), 1.61 (s, 3H) ; MS(m / z): 449 [M+H] + (A), 2.695, 95.3%78 N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 8.24 - 8.15 (m, 2H), 7.99 - 7.90 (m, 1H), 7.55 - 7.47 (m, 1H), 6.92 (dd, J = 8.7, 3.3 Hz, 1H), 6.85 (s, 1H), 6.71 - 6.61 (m, 2H), 5.45 (s, 1H), 3.73 - 3.66 (m, 4H), 3.66 - 3.58 (m, 4H), 2.48 (s, 3H) ; MS(m / z): 398 [M+H] + (A), 3.085, 99.6%79 N-(6-(4-(6-methoxynaphthalen-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, CDCl3) δ 10.29 (brs, 1H), 8.11 - 8.07 (m, 2H), 7.68 (s, 1H), 7.52 (d,J= 8.7 Hz, 1H), 7.46 (d,J= 8.2 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.14 - 7.11 (m, 2H), 6.92 (d,J= 7.3 Hz, 1H), 3.92 (s, 3H), 3.83 - 3.59 (m, 4H), 3.17 - 3.03 (m, 4H) ; MS(m / z): 498 [M+H] + (A), 4.72, 95.2%80 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.02 (s, 1H), 8.53 (d,J= 5.9 Hz, 1H), 7.99 (d,J= 5.9 Hz, 1H), 7.81 (d,J= 8.2 Hz, 1H), 7.61 (t,J= 7.8 Hz, 1H), 7.44 (s, 1H), 7.38 (d,J= 7.4 Hz, 1H), 7.29 (dd,J= 8.7, 1.8 Hz, 1H), 7.21 - 7.17 (m, 3H), 5.71 (s, 1H), 3.81 - 3.75 (m, 6H), 3.13 - 3.06 (m, 4H), 3.03 (t,J= 8.3 Hz, 2H), 2.45 (s, 3H) ; MS(m / z): 449 [M+H] + (A), 3.379, 99%81 2-(methylthio)-N 4 -(1-(1-(pyrimidin-2-yl)piperidin-4-yl)ethyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine 1H NMR (400 MHz, CDCl3) δ 8.28 (d,J= 4.7 Hz, 2H), 7.36 (d,J= 8.6 Hz, 1H), 7.09 (d,J= 8.6 Hz, 1H), 6.45 (dd,J= 4.7 Hz, 1H), 6.34 (s, 1H), 4.82 (m, 2H), 4.53 (br s, 1H), 4.22 (t,J= 8.3 Hz, 2H), 3.20 (t,J= 8.3 Hz, 2H), 2.83 - 2.75 (m, 2H), 2.47 (s, 3H), 1.84 - 1.75 (m, 1H), 1.74 - 1.67 (m, 2H), 1.32 - 1.125 (m, 3H), 1.16 (d,J= 6.8 Hz, 3H) ; MS(m / z): 595 [M+H] + (B), 5.849, 98.7%82 1-Isopropyl-N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.52 (d,J= 5.4 Hz, 1H), 7.91 (d,J= 5.8 Hz, 1H), 7.68 (d,J= 8.1 Hz, 1H), 7.55-7.50 (m, 2H), 7.38 (d,J= 8.7 Hz, 1H), 7.27 (d,J= 3.2 Hz, 1H), 7.23 (d,J= 7.5 Hz, 1H), 7.10 (dd,J= 8.7, 1.8 Hz, 1H), 6.51 (d,J= 3.1 Hz, 1H), 5.51 (s, 1H), 4.87 (s, 1H), 4.71 - 4.63 (m, 1H), 3.86 - 3.71 (m, 4H), 3.24 - 3.06 (m, 4H), 2.57 (s, 3H), 1.54 (d,J= 6.7 Hz, 6H) ; MS(m / z): 510 [M+H] + (A), 3.992, 96%83 N-(6-(4-(isoquinolin-8-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.54 (s, 1H), 9.05 (s, 1H), 8.51 (d,J= 5.7 Hz, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.79 (d,J= 5.6 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 7.63 (d,J= 8.2 Hz, 1H), 7.48 (d,J= 8.8 Hz, 1H), 7.40 (dd,J= 8.9, 1.6 Hz, 1H), 7.25 (d,J= 7.2 Hz, 1H), 5.71 (s, 1H), 3.84 - 3.72 (m, 4H), 3.19 - 3.14 (m, 4H), 2.46 (s, 3H) ; MS(m / z): 469 [M+H] + (A), 3.305, 98%84 N-(2-(methylthio)-6-(4-(quinazolin-8-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.54 (s, 1H), 9.28 (s, 1H), 9.05 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.65 (t,J= 7.7 Hz, 1H), 7.46 (d,J= 8.8 Hz, 1H), 7.42 - 7.37 (m, 2H), 5.71 (s, 1H), 3.78 - 3.71 (m, 4H), 3.49 - 3.93 (m, 4H), 2.46 (s, 3H) ; MS(m / z): 470 [M+H] + (A), 3.335, 99%85 N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide 1H NMR (400 MHz, CDCl3) δ 8.34 (d,J= 4.7 Hz, 2H), 7.39 (d,J= 8.4 Hz, 2H), 7.20 (d,J= 8.8 Hz, 1H), 7.12 (d,J= 6.0 Hz, 2H), 6.66 (s, 1H), 6.56 (t,J= 4.7 Hz, 1H), 4.23 (t,J= 8.4 Hz, 2H), 3.96 - 3.84 (m, 4H), 3.64 - 3.54 (m, 4H), 3.23 (t,J= 8.4 Hz, 3H), 2.51 (s, 3H) ; MS(m / z): 596 [M+H] + (A), 4.525, 92.07%86 N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.74 (d,J= 0.8 Hz, 1H), 8.60 (d,J= 8.7 Hz, 1H), 8.29 (m, 4H), 7.97 (d, J = 0.5 Hz, 1H), 7.54 (d,J= 9.2 Hz, 1H), 6.94 (d,J= 9.0 Hz, 1H), 6.86 (d,J= 4.6 Hz, 1H), 6.74 (d,J= 1.4 Hz, 1H), 6.68 (s, 1H), 6.44 (m, 1H), 4.87 (d,J= 12.9 Hz, 4H), 2.79 (m, 4H), 2.62 (s, 3H) ; MS(m / z) : 476 [M+H] + (A), 3.565, 97.77%87 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.76 (s, 1H), 8.34 (d,J= 4.7 Hz, 2H), 8.09 (s, 1H), 8.02 (s, 1H), 6.54 (t,J= 4.7 Hz, 1H), 6.14 (s, 1H), 3.94 (m, 4H), 3.75 - 3.71 (m, 4H), 2.58 (s, 3H) ; MS(m / z): 421 [M+H] + (A), 3.435, 98.42%88 N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine 1 H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.47 (d,J= 5.8 Hz, 1H), 8.34 (d,J= 4.7 Hz, 2H), 7.91 (t,J= 5.7 Hz, 2H), 7.56 - 7.50 (m, 2H), 6.77 (s, 1H), 6.54 (m, 1H), 5.78 (s, 1H), 3.93 (d,J= 4.7 Hz, 4H), 3.73 - 3.69 (m, 4H), 2.57 (s, 3H) ; MS(m / z): 431 [M+H] + (A), 3.499, 98.58%89 N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.54 (d,J= 5.9 Hz, 1H), 7.95 (d,J= 5.9 Hz, 1H), 7.70 (d,J= 8.2 Hz, 1H), 7.54 (m, 1H), 7.39 (d,J= 8.7 Hz, 1H), 7.14 (d,J= 8.7 Hz, 1H), 6.61 (s, 1H), 5.58 (s, 1H), 4.24 (m, 2H), 3.83 (s, 4H), 3.23 (m, 2H), 3.16 (s, 4H), 2.52 (s, 3H) ; MS(m / z): 602 [M+H] + (A), 4.139, 100%90 N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine 1 H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.52 (s, 1H), 9.25 (s, 1H), 8.76 (s, 1H), 8.49 (d,J= 5.9 Hz, 1H), 8.09 (d,J= 9.1 Hz, 2H), 7.96 (d,J= 5.9 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.57 (m, 1H), 7.35 (d,J= 7.4 Hz, 1H), 6.44 (s, 1H), 3.77 (s, 4H), 3.10 (s, 4H), 2.45 - 2.45 (m, 3H) ; MS(m / z): 470 [M+H] + (A), 3.332, 100%91 N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)isoquinolin-6-amine 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 9.13 (s, 1H), 8.55 (d,J= 5.9 Hz, 1H), 8.45 (d,J= 5.8 Hz, 1H), 7.96 - 7.92 (m, 2H), 7.90 (s, 1H), 7.70 (d,J= 8.2 Hz, 1H), 7.56 - 7.52 (m, 3H), 7.25 (s, 1H), 6.99 (s, 1H), 5.84 (s, 1H), 3.87 (s, 4H), 3.17 (s, 4H), 2.58 (s, 3H) ; MS(m / z): 480 [M+H] + (A), 3.502, 97.83%92 6-(4-(isoquinolin-5-yl)piperazin-1-yl)-N-(6-methoxynaphthalen-2-yl)-2-(methylthio)pyrimidin-4-amine 1 H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 8.53 (d,J= 5.9 Hz, 1H), 7.93 (d,J= 5.9 Hz, 1H), 7.74 (d,J= 8.7 Hz, 1H), 7.68 (d,J= 8.4 Hz, 3H), 7.52 (t,J= 7.8 Hz, 1H), 7.38 (m, 1H), 7.24 (d,J= 7.3 Hz, 1H), 7.16 (d,J= 8.9 Hz, 1H), 7.13 (d,J= 2.2 Hz, 1H), 6.60 (s, 1H), 5.68 (s, 1H), 3.92 (s, 3H), 3.81 (s, 4H), 3.14 (d,J= 4.4 Hz, 4H), 2.55 (s, 3H) ; MS(m / z): 509 [M+H] + (A), 3.962, 99.65%93 2-(methylthio)-N 4 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine 1H NMR (400 MHz, CDCl3) δ 8.31 (d,J= 9.8 Hz, 2H), 8.28 (s, 1H), 7.11 (s, 1H), 7.04 (m, 1H), 6.44 (t,J= 4.7 Hz, 1H), 5.30 (s, 1H), 4.85 (d,J= 13.2 Hz, 2H), 3.95 (t,J= 8.7 Hz, 2H), 3.20 (t,J= 8.6 Hz, 2H), 2.76 (t,J= 11.8 Hz, 2H), 2.54 (s, 3H), 2.46 (t,J= 12.1 Hz, 1H), 1.77 (d,J= 12.5 Hz, 3H), 1.35 - 1.21 (m, 6H), 0.90 - 0.83 (m, 1H) ; MS(m / z): 609 [M+H] + (A), 4.319, 100%94 N 4 -(6-methoxynaphthalen-2-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine 1 H NMR (400 MHz, CDCl3) δ 8.29 (d,J= 4.7 Hz, 2H), 7.72 (d,J= 8.7 Hz, 1H), 7.65 (d,J= 8.9 Hz, 2H), 7.34 (m, 1H), 7.17 - 7.11 (m, 2H), 6.73 (s, 1H), 6.45 (t,J= 4.7 Hz, 1H), 5.45 (s, 1H), 4.91 (s, 1H), 4.78 (d,J= 13.4 Hz, 2H), 3.92 (s, 3H), 3.11 (s, 2H), 2.85 (m, 2H), 2.52 (s, 3H), 1.31 - 1.15 (m, 5H) ; MS(m / z): 488 [M+H] + (A), 3.915, 100%95 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.06 (s, 1H), 9.70 (d,J= 5.8 Hz, 1H), 8.47 (d,J= 8.6 Hz, 1H), 8.09 (d,J= 5.8 Hz, 1H), 7.44 (s, 1H), 7.39 (d,J= 8.6 Hz, 1H), 7.29 (dd,J= 8.6, 1.6 Hz, 1H), 7.20 - 7.17 (m, 3H), 5.71 (s, 1H), 3.81 - 3.76 (m, 6H), 3.33 (t,J= 4.3 Hz, 4H), 3.03 (t,J= 8.3 Hz, 2H), 2.44 (s, 3H) ; MS(m / z): 594 [M+H] + (A), 3.779, 93%96 5-((6-(4-(8-aminoisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1 H NMR (400 MHz, CD3OD) δ 9.36 (s, 1H), 8.37 (d,J= 6.0 Hz, 1H), 8.11 (d,J= 6.0 Hz, 1H), 7.40 (s, 1H), 7.32 (d,J= 4.8 Hz, 1H), 7.30 (d,J= 4.5 Hz, 1H), 7.22 (d,J= 8.6 Hz, 1H), 6.85 (d,J= 8.1 Hz, 1H), 5.65 (s, 1H), 3.89 (t,J= 8.3 Hz, 2H), 3.39 - 3.32 (m, 4H), 3.10 (t,J=8.3 Hz, 2H), 3.07 - 2.95 (m, 4H), 2.48 (s, 3H) ; MS(m / z): 564 [M+H] + (B), 4.521, 97%97 5-((6-(4-(3-methylisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.04 (s, 1H), 7.79 (s, 1H), 7.75 (d,J= 8.1 Hz, 1H), 7.51 (t,J= 7.8 Hz, 1H), 7.44 (s, 1H), 7.33 (d,J= 7.4 Hz, 1H), 7.29 (d,J= 8.6 Hz, 1H), 7.25 - 7.14 (m, 3H), 5.70 (s, 1H), 3.83 - 3.68 (m, 6H), 3.14 - 3.07 (m, 4H), 3.03 (t,J=8.3 Hz, 2H), 2.65 (s, 3H), 2.44 (s, 3H) ; MS(m / z): 563 [M+H] + (A), 3.475, 98%98 5-((6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.03 (s, 1H), 8.66 (d,J= 5.9 Hz, 1H), 8.06 (d,J= 5.9 Hz, 1H), 7.45 - 7.42 (m, 2H), 7.39 (d,J= 6.6 Hz, 1H), 7.29 (d,J= 8.7 Hz, 1H), 7.20 - 7.17 (m, 3H), 5.71 (s, 1H), 3.84 - 3.67 (m, 6H), 3.12 - 3.01 (m, 6H), 2.45 (s, 3H) ; MS(m / z): 567 [M+H] + (A), 3.502, 100%99 5-((6-(4-(8-chloroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1H NMR (400 MHz, CDCl3) δ 10.86 (s, 1H), 9.67 (s, 1H), 8.64 (d,J= 5.7 Hz, 1H), 7.96 (d,J= 5.6 Hz, 1H), 7.58 (d,J= 8.0 Hz, 1H), 7.40 (d,J= 8.4 Hz, 1H), 7.18 (d,J= 8.1 Hz, 1H), 7.15 - 7.06 (m, 2H), 5.52 (s, 1H), 4.92 (s, 2H), 3.97 (t,J= 8.3 Hz, 2H), 3.13 (t,J= 7.5 Hz, 4H), 2.57 (s, 3H), 0.95 - 0.73 (m, 4H) ; MS(m / z): 584 [M+H] + (A), 3.699, 94.65%100 5-((6-(4-(8-methoxyisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.67 (s, 1H), 8.64 (d,J= 5.7 Hz, 1H), 7.96 (d,J= 5.6 Hz, 1H), 7.58 (d,J= 8.0 Hz, 1H), 7.40 (d,J= 8.4 Hz, 1H), 7.18 (d,J= 8.1 Hz, 1H), 7.15 - 7.06 (m, 2H), 5.52 (s, 1H), 4.92 (s, 2H), 3.97 (t,J= 8.3 Hz, 2H), 3.13 (t,J= 7.5 Hz, 4H), 2.57 (s, 3H), 0.95 - 0.73 (m, 4H) ; MS(m / z): 579 [M+H] + (A), 3.495, 98.89%101 N-(6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.23 (s, 1H), 8.67 (d,J= 6.0 Hz, 1H), 8.10 - 8.03 (m, 1H), 7.67 (d,J= 2.2 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.22 (d,J= 8.8 Hz, 1H), 5.75 (s, 1H), 4.22 (t,J= 8.2 Hz, 2H), 3.77 (br s, 4H), 3.22 (t,J= 8.2 Hz, 2H), 3.12 - 3.04 (m, 4H), 2.45 (s, 3H) ; MS(m / z): 620 [M+H] + (A), 4.369, 95.6%

[0640]

[0641] <Experimental Example 1> Evaluation of HEI-OC1 cell recovery from mouse inner ear

[0642] HEI-OC1 cells, which are mouse inner ear-derived cells, were seeded at 7,000 cells per 96-well plate and stabilized in a 33°C, CO2 10% incubator, and then treated with 20 μM cisplatin, which induces ototoxicity. After 1 hour, the pyrimidine derivatives prepared in the above example were treated at various concentrations. To measure cell viability 30 hours after cisplatin treatment, the cells were treated with 0.5 mg / ml of 2,5-diphenyl-2H-tetrazolium bromide (MTT) solution and cultured for 2 hours in a dark-blocked environment. After 2 hours, all media were discarded, and the insoluble purple formazan product, crystal, was dissolved using dimethyl sulfoxide (DMSO). The absorbance was measured at a wavelength of 550 nm using an ELISA reader. The drug efficacy was evaluated by quantifying cell viability by analyzing the absorbance values ​​of the experimental group compared to the control group, and the results are shown in Table 2.

[0643] Example HEI-OC1 recovery%@5uMHEI-OC1 recovery%@10uMExample HEI-OC1 recovery%@1uMHEI-OC1 recovery%@5uMHEI-OC1 recovery%@10uM1D52A2D53A3D54A4D55A5B56A6A57A7B58A8A59A9A60D10A61D11A62D12C63A 13B64A14A65A15DD66D16B67A17A68A18D69D19D70A20B71A21B72D22D73A23D74A24B75A25B76 C26D77B27B78A28D79B29A80A30A81B31D82C32A83B33A84B34B85D35B86C36B87C37D88D38B89 A39C90B40B91B41A92B42A92D43A94C44A95A45B96A46A97A47A98B48B99B49A100A50A101B51D

[0644] (A: 20% or more, B: 11-20%, C: 5-10%, D: less than 5%)

[0645]

[0646] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that modifications to other specific embodiments can be made without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0647] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. A compound selected from a pyrimidine derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 is one of hydrogen, cyano and (C1-C5)alkyl, R 2 is hydrogen, (C1-C5)alkoxy, -SR 21 , -SO2-(C1-C5)alkyl and (C3-C6)cycloalkyl, and the R 21 is (C1-C5)alkyl or -CH2COOCH3, M is -NR 4 - or -O-, and the above R 4 is hydrogen, (C3-C6)cycloalkyl and is one of them, Ar 1 is an unsubstituted or substituted (C5-C10)aryl or an unsubstituted or substituted heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or substituted heteroaryl of 5 to 10 atoms is selected from the group consisting of halogen, (C1-C5)alkyl, (C3-C6)cycloalkyl, (C1-C5)alkoxy, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and At least one selected from the group consisting of is substituted, n and m can be equal or different and are 0 or 1, K is -NR 5 - and the above R 5 is hydrogen or (C1-C5)alkyl, L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” may be the same or different, and are hydrogen or (C1-C5)alkyl, Ar 2 Is , , , and One of the above R 3 is an unsubstituted or substituted heteroaryl having 5 to 10 atoms, which comprises at least one heteroatom selected from the group consisting of (C1-C5)alkyl, (C3-C6)cycloalkyl, unsubstituted or substituted (C5-C10)aryl, N, O and S; and is one of them, The above substituted (C5-C10)aryl or substituted heteroaryl of 5 to 10 atoms is selected from the group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, amine, nitro, -COOCH3, COOH, -CONHOH and At least one selected from the group consisting of is substituted, The above p is 0 or 1, and the above A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 may be the same or different, and are hydrogen or (C1-C5)alkyl, and the above R 33 Silver hydrogen, (C1-C5)alkyl, (C1-C5)alkoxy, amine, nitro, -COOCH3, COOH, -CONHOH and It is one of them.

2. In claim 1, in the chemical formula 1, R 1 is one of hydrogen, cyano and methyl, R 2 is hydrogen, (C1-C3)alkoxy, -SR 21 , -SO2CH3 and cyclopropyl, and the R 21 is methyl or -CH2COOCH3, M is -NR 4 - or -O-, and the above R 4 is hydrogen, cyclopropyl and is one of them, Ar 1 is an unsubstituted or substituted (C6-C10)aryl or an unsubstituted or substituted 6 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O, wherein the substituted (C6-C10)aryl or substituted 6 to 10-membered heteroaryl is selected from the group consisting of fluorine, chlorine, (C1-C3)alkyl, cyclopropyl, methoxy, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and One to three selected from the group consisting of are substituted, K is -NR 5 - and the above R 5 is hydrogen or (C1-C3)alkyl, L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” may be the same or different, and are hydrogen or methyl, Ar 2 Is , , , and One of the above R 3 is an unsubstituted or substituted heteroaryl having 6 to 10 atoms, which comprises at least one heteroatom selected from the group consisting of (C1-C3)alkyl, cyclohexyl, unsubstituted or substituted (C6-C10)aryl, N or O; and is one of them, The above substituted (C6-C10)aryl or substituted heteroaryl of 6 to 10 atoms is (C1-C3)alkyl, fluorine, chlorine, methoxy, amine, nitro, -COOCH3, COOH, -CONHOH and One or two selected from the group consisting of are substituted, The above p is 0 or 1, and the above A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 may be the same or different, and are hydrogen or methyl, and the R 33 A compound selected from a pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof, characterized in that it is hydrogen or (C1-C5)alkyl.

3. In claim 1, in the chemical formula 1, R 2 is hydrogen, ethoxy, -SR 21 , -SO2CH3 and cyclopropyl, and the R 21 is methyl or -CH2COOCH3, Ar 1 is a substituted phenyl, an unsubstituted or methoxy substituted naphthyl and an unsubstituted or substituted 6, 9 or 10 membered heteroaryl containing nitrogen, wherein the substituted phenyl is substituted with one to three selected from the group consisting of amine, methoxy, trifluoromethyl, fluorine and chlorine, and the substituted 6, 9 or 10 membered heteroaryl is fluorine, isopropyl, cyclopropyl, trifluoromethyl, amine, -SO2CF3, -SO2NH2, and One or two selected from the group consisting of are substituted, K is -NR 5 - and the above R 5 is hydrogen or ethyl, L is -CR 5’ R 5” - or -CO-, and the above R 5’ and R 5” is hydrogen or methyl, Ar 2 Is , , , and One of the above R 3 isopropyl, cyclohexyl, methoxy substituted phenyl, methoxy substituted naphthyl, unsubstituted or substituted 6 or 10-membered heteroaryl containing nitrogen, and is one of them, The above substituted 6 or 10-membered heteroaryl is selected from the group consisting of methyl, methoxy, fluorine, chlorine, amine, nitro, -COOCH3, COOH, -CONHOH and One or two selected from the group consisting of are substituted, The above p is 0 or 1, and the above A 1 is N or CH, and the above A 2 is O or NR 33 and the above R 31 and R 32 is hydrogen or methyl, and the above R 33 A compound selected from a pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof, characterized in that one of hydrogen, methyl and ethyl is present.

4. In claim 1, the compound represented by the chemical formula 1 is a pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, characterized in that it is selected from the group of compounds below: (1) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine; (2) Methyl 2-((4-((1H-indazol-5-yl)amino)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-2-yl)thio)acetate; (3) 5-((2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)oxy)-1H-indazole; (4) N-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (5) 4-((1H-indazol-5-yl)amino)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidine-5-carbonitrile; (6) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (7) N-(5-methyl-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (8) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (9) N,1-Dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (10) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (11) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (12) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; (13) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-6-amine; (14) 1-Isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; (15) N-(2-(methylsulfonyl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (16) N-(2-ethoxy-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (17) N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (18) N-(6-(4-(5-aminopyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (19) Methyl 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxylate; (20) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (21) Methyl 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylate; (22) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxylic acid; (23) 2-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide; (24) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)pyrimidine-5-carboxamide; (25) 2-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5 -carboxamide; (26) 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)nicotinic acid; (27) 6-(4-(6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)piperazin-1-yl)-N-hydroxynicotinamide; (28) 6-(4-(((6-((1H-indazol-5-yl)amino)-2-(methylthio)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-N-hydroxynicotinamide; (29) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; (30) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; (31) 1-Isopropyl-N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; (32) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; (33) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; (34) N-(6-(4-cyclohexylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-isopropyl-1H-indol-5-amine; (35) N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (36) N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (37) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (38) N 4 -(5-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine; (39) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(5-(piperazin-1-yl)pyridin-2-yl)pyrimidine-4,6-diamine; (40) N 4 -(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-N 6 -(1H-indazol-5-yl)-2-(methylthio)pyrimidine-4,6-diamine; (41) N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (42) 1-Isopropyl-N 5 -(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine; (43) 1-Isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; (44) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; (45) 1-Cyclopropyl-3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (46) 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine; (47) 2-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine; (48) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyrimidin-2-yl)-1H-indol-5-amine; (49) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indol-5-amine; (50) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indazol-5-amine; (51) 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-N-(pyrimidin-2-yl)-1H-indazol-5-amine; (52) 3-Fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; (53) N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (54) N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; (55) 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; (56) N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide; (57) N 4 -Ethyl-N 6 -(1H-indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (58) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (59) N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (60) N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (61) N-(2-(methylthio)-6-morpholinopyrimidin-4-yl)-1H-indazol-5-amine; (62) N-(6-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; (63) N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (64) N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (65) N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine; (66) 2-(methylthio)-6-(4(pyridin-2-yl)piperazin-1-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine; (67) 2-(Methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; (68) N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)pirerazin-1-yl)pyrimidin-4-amine; (69) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine; (70) 2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine; (71) N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; (72) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-benzo[d][1,2,3]triazol-5-amine; (73) N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine; (74) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (75) N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (76) N 4 -Ethyl-N 6 -(Indolin-5-yl)-2-(methylthio0)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (77) N 4 -(Indolin-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (78) N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; (79) N-(6-(4-(6-methoxynaphthalen-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (80) 5-((6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (81) 2-(methylthio)-N 4 -(1-(1-(pyrimidin-2-yl)piperidin-4-yl)ethyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; (82) 1-Isopropyl-N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; (83) N-(6-(4-(isoquinolin-8-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; (84) N-(2-(methylthio)-6-(4-(quinazolin-8-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; (85) N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide; (86) N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)pyrimidine-4,6-diamine; (87) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine; (88) N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)isoquinolin-6-amine; (89) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; (90) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine; (91) N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)isoquinolin-6-amine; (92) 6-(4-(isoquinolin-5-yl)piperazin-1-yl)-N-(6-methoxynaphthalen-2-yl)-2-(methylthio)pyrimidin-4-amine; (93) 2-(methylthio)-N 4 -(2-(1-(pyrimidin-2-yl)piperidin-4-yl)propan-2-yl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; (94) N 4 -(6-methoxynaphthalen-2-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; (95) 5-((2-(methylthio)-6-(4-(8-nitroisoquinolin-5-yl)piperazin-1-yl)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (96) 5-((6-(4-(8-aminoisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (97) 5-((6-(4-(3-methylisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (98) 5-((6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (99) 5-((6-(4-(8-chloroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; (100) 5-((6-(4-(8-methoxyisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)indoline-1-sulfonamide; and (101) N-(6-(4-(8-fluoroisoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine.

5. A pharmaceutical composition for preventing or treating hearing loss, comprising as an active ingredient a compound selected from the pyrimidine derivative compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

6. A pharmaceutical composition according to claim 5, characterized in that the hearing loss disease is at least one selected from the group consisting of noise-induced hearing loss, ototoxic hearing loss, presbycusis, traumatic hearing loss, infectious hearing loss, Meniere's disease, autoimmune hearing loss, sudden hearing loss, and hereditary hearing loss.

7. A pharmaceutical composition according to claim 6, characterized in that the ototoxic hearing loss is ototoxic hearing loss caused by a drug that causes an abnormality in auditory function.

8. A pharmaceutical composition according to claim 7, characterized in that the drug causing an abnormality in the auditory function is at least one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, amikacin, gentamicin, kanamycin, tobramycin, capreomycin, biomycin, chloramphenicol, vancomycin, erythromycin, chloroquinone, furosemide, bumetanide, and acetaminophen.

9. In claim 5, the pyrimidine derivative compound is N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; 3-fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N,1-dicyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N 4 -(1H-indazol-5-yl)-2-(methylthio)-N 6 -((1-(pyridin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; 1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; N-(2-cyclopropyl-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)-1H-indol-5-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-((trifluoromethyl)sulfonyl)indolin-5-amine; N 4 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 6 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; 1-isopropyl-N 5 -(2-(Methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazole-3,5-diamine; 1-Isopropyl-N-(6-(4-(isoquinolin-1-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; 1-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolin-6-amine; 2-Cyclopropyl-N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indol-5-amine; 3-Fluoro-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1-(pyridin-4-ylmethyl)-1H-indazol-5-amine; 3-Fluoro-1-isopropyl-N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indol-5-amine; N 4 -Ethyl-N 6 -(1-Isopropyl-1H-indol-5-yl)-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; N 4 -Ethyl-2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; 2-(methylthio)-N 4 -((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)-N 6 -(1-((trifluoromethyl)sulfonyl)indolin-5-yl)pyrimidine-4,6-diamine; N-(2-(methylthio)-6-((1-((trifluoromethyl)sulfonyl)indolin-5-yl)amino)pyrimidin-4-yl)-1-(pyrimidin-2-yl)piperidine-4-carboxamide; N 4 -Ethyl-N 6 -(1H-Indazol-5-yl)-2-(methylthio)-N4-((1-(pyrimidin-2-yl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine; N-(2-(methylthio)-6-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(2-(methylthio)-6-(4-(5-nitropyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine; N-(6-(4-(4-methoxypyrimidin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; N-(6-(4-(4-methoxypyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; N1-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)benzene-1,4-diamine; 2-(methylthio)-N-(naphthalen-2-yl)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; N-(6-methoxynaphthalen-2-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; 2-(Methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-4-amine; N-(3-chloro-4-fluorophenyl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine; N-(2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-amine; N-(6-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; A pharmaceutical composition characterized in that it is one selected from the group consisting of N-(6-(4-isopropylpiperazin-1-yl)-2-(methylthio)pyrimidin-4-yl)-1H-indazol-5-amine; and N-(6-fluoropyridin-3-yl)-2-(methylthio)-6-(4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-4-amine.

10. A health functional food composition for preventing or improving hearing loss, comprising as an active ingredient a compound selected from the pyrimidine derivative compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

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