Composition for preventing or treating tyro3-related disease containing pyrimidine derivative compound as effective ingredient

Abstract

The present application relates to a cancer-preventing or -treating composition containing a pyrimidine derivative compound as an effective ingredient. Specifically, the present application relates to a pyrimidine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a cancer-preventing or -treating composition containing the same as an effective ingredient. The pyrimidine derivative compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present application is excellent in a TAM receptor inhibitory effect, particularly a selective inhibitory effect on Tyro3, and can be used as an excellent cancer-preventing or -treating composition without side effects due to inhibition of Axl and Mer.

Description

Technical Field

[0001] This invention relates to pyrimidine derivative compounds, their optical isomers or pharmaceutically acceptable salts thereof, and compositions for the prevention or treatment of Tyro3-related diseases containing them as active ingredients. Background Technology

[0002] The TAM receptor, also known as the TAM family, is a collective term for three tyrosine kinase receptors: Tyro3, ​​Axl, and Mer (Mertk). TAM receptors are proteins located in the cell membrane that bind to signaling molecules outside the cell and transmit signals inward, activating intracellular kinases and thus transmitting the signal into the cell (Lemke, G., 2013).

[0003] The typical ligands for the TAM receptor are growth arrest-specific gene 6 (Gas6) and protein S (Pros1). These two ligands are soluble circulating proteins and, despite having 42% protein identity, still exhibit unique specificity for the TAM receptor (Lew, ED, et al., 2014).

[0004] The TAM ligand possesses a γ-carboxyglutamic acid-rich (Gla) domain. The TAM receptor communicates with Ca... 2+ Phosphatidylserine (PtdSer), which binds to apoptotic cells, activated platelets, enveloped viruses, and as phospholipids exposed to the cell membrane of activated T cells, requires vitamin K-dependent carboxylation of a glutamate residue in the Gla domain. Importantly, only carboxylated ligands that bind to PtdSer can significantly activate TAM signaling (Lew, ED, et al., 2014; Tsou, WI, et al., 2014).

[0005] TAM receptor signal transduction is involved in platelet aggregation and thrombus formation, erythropoiesis, and the homeostasis regulation of endothelial cells and vascular smooth muscle. Furthermore, the TAM-dependent pathway is also known to be involved in spermatogenesis, the maintenance of retinal and lactating mammary gland function, bone physiology, atherosclerosis, neurobiology, and blood-brain barrier permeability (Linger, RMA, et al., 2008; Paolino M., et al., 2016).

[0006] Phenotypic observations of animal models with Tyro3, ​​Axl, and Mer gene knockouts (TAM receptors) revealed that knockout of Tyro3, ​​Axl, and Mer alone collectively exhibited overactivity in antigen-presenting cells (APCs) and autoantibody production, and protected against thrombosis. However, knockout of Mer induced impaired apoptotic cell excretion, retinitis pigmentosa, and increased inflammation. Furthermore, knockout of Axl is known to cause severe side effects such as autoimmune encephalomyelitis, enhanced demyelination, and impaired apoptotic cell excretion. Conversely, knockout of Tyro3 did not exhibit any specific problems. Therefore, the development of selective inhibitors of TAM receptors, especially Tyro3, ​​has attracted considerable attention as a strategy to overcome the side effects of TAM receptor inhibition.

[0007] To date, most research on TAM receptors has focused on their roles in cancer development and immune regulation. Regarding the cancer development of TAM receptors, Tyro3 inhibitors have recently been proposed as drug targets for breast cancer treatments. Studies have shown that Tyro3 expression is more than twice as high as in normal tissues of liver cancer patients and plays a crucial role in cancer growth and liver damage. Therefore, regulating the inhibition or overexpression of Tyro3 may be an important target for developing liver cancer therapeutics (Duan, Y., et al., 2016).

[0008] When diagnosed with stage III ovarian cancer, the survival rate is less than 5 years. It has been reported that in SKOV3 / TR, an ovarian cancer cell line resistant to the anticancer agent paclitaxel, Tyro3 RNA expression is increased, while Axl and Mer RNA expression is decreased. This increased Tyro3 expression can increase the survival of cancer cells in SKOV3 / TR and induce paclitaxel resistance (Lee, C., 2015). Furthermore, Tyro3 expression is known to be increased in skin cancers, and knocking down Tyro3 in melanoma cells can inhibit cell proliferation and colony formation.

[0009] Therefore, it is hoped that by developing selective Tyro3 inhibitors, cancer therapies with minimal side effects, excellent cancer treatment efficacy, and the ability to overcome resistance to anticancer drugs can be developed.

[0010] In the process of researching TAM receptor inhibitory compounds, the inventors of this invention discovered novel TAM receptor inhibitory compounds, and in particular confirmed that the selective inhibition effect of Tyro3 in the TAM receptor was excellent, thus completing this invention. Summary of the Invention

[0011] The problem the invention aims to solve

[0012] The purpose of this invention is to provide a pyrimidine derivative compound, its optical isomer or a pharmaceutically acceptable salt thereof, and a composition for the prevention or treatment of Tyro3-related diseases containing such a compound as an active ingredient.

[0013] means for solving problems

[0014] This invention relates to pyrimidine derivative compounds represented by the following chemical formula 1, their optical isomers, or pharmaceutically acceptable salts thereof.

[0015] [Chemical Formula 1]

[0016]

[0017] In the chemical formula 1,

[0018] R 1 It is hydrogen, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C 4-10 aryl, or substituted or unsubstituted C 4-10 Mixed aromatics,

[0019] Wherein, the substituted alkyl, substituted alkoxy, substituted aryl, or substituted heteroaryl is selected from halogen, hydroxyl, cyano, amino, nitro, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 The alkoxy group or substituted or unsubstituted piperidinyl group is substituted with one or more substituents.

[0020] Furthermore, the substituted alkyl, substituted alkoxy, or substituted piperidinyl group is selected from halogens, C1-C... 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Aryl or C4-C 10 One or more substituents in the group consisting of heteroaryl groups are substituted;

[0021] R 2 Is it substituted or unsubstituted C4-C? 10 Cycloalkyl, substituted or unsubstituted C4-C8 heterocycloalkyl, substituted or unsubstituted C4-C 10 aryl, substituted or unsubstituted C4-C 10 heteroaryl, or C4-C 10 A substituted or unsubstituted fused ring fused with an aryl group and a C4-C8 heterocyclic alkyl group.

[0022] Wherein, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or fused ring is selected from halogen, C1-C 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, acetamido, trihaloacetamido, trihaloacetyl, C4-C 10 Cycloalkyl, C4-C8 heterocycloalkyl, C4-C 10 Aryl, C4-C 10 Heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy or substituted or unsubstituted C 4-10 Aryl C 1-10 One or more substituents in the group consisting of alkyl groups are used for substitution.

[0023] Furthermore, the substituted amino, substituted alkyl, substituted alkoxy, or substituted arylalkyl is selected from halogen, oxo (=O), or substituted or unsubstituted C1-C. 10One or more substituents in the group consisting of alkyl groups are used for substitution.

[0024] Furthermore, wherein the substituted alkyl group is substituted with one or more substituents selected from halogens or oxo (=O); and

[0025] R 3 and R 4 Each can be independently hydrogen, halogen, substituted or unsubstituted C4-C 10 Cycloalkyl, substituted or unsubstituted C4-C8 heterocycloalkyl, substituted or unsubstituted C4-C 10 aryl, substituted or unsubstituted C4-C 10 heteroaryl, substituted or unsubstituted C 4-10 Aryl C 1-10 Alkyl, substituted or unsubstituted C4-C 10 heteroaryl C 1-10 Alkyl, or C4-C 10 Aryl and C4-C 10 A fused or unsubstituted fused ring consisting of cycloalkyl or C4-C8 heterocyclic alkyl groups.

[0026] Wherein, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or substituted fused ring is selected from halogen, C1-C 10 Halogenated alkyl, hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, oxo (=O), C4-C 10 Cycloalkyl, C4-C8 heterocycloalkyl, C4-C 10 heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy or substituted or unsubstituted C4-C 10 One or more substituents in the group consisting of aryl groups are substituted.

[0027] Furthermore, the substituted alkyl, substituted alkoxy, or substituted aryl groups are selected from halogens, oxo (=O), or substituted or unsubstituted C1-C. 10 One or more substituents in the group consisting of alkyl groups are used for substitution.

[0028] Furthermore, the substituted alkyl group is substituted with one or more substituents selected from halogens or oxo (=O).

[0029] Or, when R 3 and R 4 When they together form substituted or unsubstituted C4-C8 heterocyclic alkyl groups with the nitrogen atoms they are attached to,

[0030] The substituted heterocyclic alkyl group is selected from halogen, hydroxyl, amino, cyano, nitro, substituted or unsubstituted C. 4-10 Aryl C 1-10 Alkyl or C4-C 10 heteroaryl C 1-10 One or more substituents in the group consisting of alkyl groups are used for substitution.

[0031] Wherein, the substituted aryl alkyl or heteroaryl alkyl is substituted by one or more substituents selected from halogen or oxo (=O).

[0032] The term "alkyl" refers to a single-chain straight or branched hydrocarbon group, such as methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, etc.

[0033] The term "alkoxy" refers to an oxygen group consisting of a straight-chain or branched saturated hydrocarbon group bonded with a single bond, such as methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, etc.

[0034] The term "cycloalkyl" refers to a cyclic, single-bonded saturated hydrocarbon group, which can be cyclobutyl, cyclopentyl, cyclohexyl, etc., depending on the number of carbon atoms.

[0035] The term "heterocyclic alkyl" refers to a saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S in a cyclic single bond. Depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, it includes aziridine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyran, etc.

[0036] The term "aryl" refers to an aromatic substituent having at least one ring with a conjugated π-electron system.

[0037] The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S. Depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, it can be pyridine, indole, isoindole, etc.

[0038] Examples of the aryl or heteroaryl groups include phenyl, furan, pyran, pyridyl, pyrimidinyl, triazine, etc., but are not limited thereto.

[0039] Further specific examples of compounds of chemical formula 1 of the present invention are provided, then the choice of...

[0040] 5-Bromo-N4-cyclohexyl-N2-(p-Tolyl)pyrimidine-2,4-diamine (Compound 1)

[0041] N4-Cyclohexyl-N2,5-Di-(p-Tolyl)pyrimidin-2,4-diamine (Compound 2)

[0042] 5-Bromo-N4-cyclohexyl-N2-(3,5-dichlorophenyl)pyrimidine-2,4-diamine (compound 3)

[0043] 2-Chloro-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (compound 4),

[0044] N4-Cyclohexyl-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 5)

[0045] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-phenylpyrimidine-2,4-diamine (compound 6)

[0046] N2-(3-Chlorophenyl)-N4-Cyclohexyl-5-(1-Methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (Compound 7)

[0047] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidin-2,4-diamine (compound 8)

[0048] N2-(3-chloro-4-methoxyphenyl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 9)

[0049] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(o-tolyl)pyrimidin-2,4-diamine (compound 10)

[0050] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(5-methylisoxazol-3-yl)pyrimidin-2,4-diamine (compound 11)

[0051] N2-(5-tert-butylisoxazol-3-yl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 12)

[0052] N4-Cyclohexyl-N2-(2-Isopropylphenyl)-5-(1-Methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (Compound 13)

[0053] N4-Cyclohexyl-5-(furan-3-yl)-N2-(p-tolyl)pyrimidin-2,4-diamine (compound 14)

[0054] N4-Cyclohexyl-N2-(3,5-dichlorophenyl)-5-(furan-3-yl)pyrimidin-2,4-diamine (compound 15)

[0055] N4-Cyclohexyl-N2-(2,2-difluoro-2-(4-methoxyphenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 16)

[0056] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-(pyridin-4-yl)ethyl)pyrimidin-2,4-diamine (compound 17)

[0057] (4-(4-(cyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)(thiophen-2-yl)methyl ketone (compound 18),

[0058] 4-(4-(cyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (compound 19),

[0059] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-methylisoxazol-5-yl)pyrimidin-2,4-diamine (compound 20)

[0060] N4-Cyclohexyl-N2-(5-ethyl-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 21)

[0061] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(thiazo-2-yl)pyrimidin-2,4-diamine (compound 22)

[0062] N4-Cyclohexyl-N2-adamantyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 23)

[0063] N4-Cyclohexyl-N2-(2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 24)

[0064] N4-Cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(m-tolyl)pyrimidin-2,4-diamine (compound 25)

[0065] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 26)

[0066] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 27),

[0067] N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 28)

[0068] N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 29)

[0069] N2-(3,5-dichlorophenyl)-N4-((1s,4s)-4-(dimethylamino)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 30)

[0070] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-acetamide (compound 31),

[0071] N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1-methylpiperidin-4-yl)pyrimidin-2,4-diamine (compound 32)

[0072] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)acetone (compound 33),

[0073] 1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(phenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 34),

[0074] 1-(4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 35),

[0075] N2-(3-Chlorophenyl)-5-(1-Methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 36)

[0076] 1-(4-(2-(4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 37),

[0077] N4-(1-benzylpiperidin-4-yl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 38)

[0078] 1-(4-(2-(3-fluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 39),

[0079] N2-(4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 40)

[0080] N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 41)

[0081] 5-(1-Methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 42),

[0082] 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 43),

[0083] 1-(4-(2-(4-methoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 44),

[0084] 1-(4-(2-(3-chloro-4-methoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 45),

[0085] N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 46)

[0086] N2-(4-methoxyphenyl)-5-(1-methyl-1H-pyrazole-4-yl)-N4-(piperidin-4-yl)

[0087] Pyrimidine-2,4-diamine (compound 47)

[0088] N2-(3-chloro-4-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 48)

[0089] 1-(4-(2-(p-toluidine)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 49),

[0090] 1-(4-(2-(m-toluidine)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroacetone (compound 50),

[0091] 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-(p-tolyl)pyrimidin-2,4-diamine (compound 51),

[0092] 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-(m-tolyl)pyrimidin-2,4-diamine (compound 52),

[0093] 1-(4-(2-(3-chlorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 53),

[0094] 1-(4-(2-(3-fluorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 54),

[0095] N2-(3-fluorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 55)

[0096] N2-(3-chlorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 56)

[0097] 1-(4-(2-(3,5-dichlorophenylamino)-5-phenylpyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 57),

[0098] N2-(3,5-dichlorophenyl)-5-phenyl-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 58)

[0099] 1-(4-(2-(3,5-dichlorophenylamino)-5-(3-methoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 59),

[0100] N2-(3,5-dichlorophenyl)-5-(3-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 60)

[0101] 1-(4-(2-(3,5-dichlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 61),

[0102] N2-(3,5-dichlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 62)

[0103] 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 63),

[0104] 1-(4-(5-(3,4-dimethoxyphenyl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 64),

[0105] 1-(4-(5-(3,4-dimethoxyphenyl)-2-(2-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 65),

[0106] N2-(3-methyl-4-chlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 66)

[0107] 5-(3,4-Dimethoxyphenyl)-N2-(4-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine (compound 67)

[0108] 5-(3,4-Dimethoxyphenyl)-N2-(2-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine (compound 68)

[0109] 1-(4-(2-(3-chlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 69),

[0110] 1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroacetone (compound 70)

[0111] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 71),

[0112] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)-N2-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 72)

[0113] N2-(3,5-dichlorophenyl)-N4-(piperidin-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 73)

[0114] N2-(3-chlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine (compound 74)

[0115] 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 75),

[0116] 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 76),

[0117] 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 77),

[0118] 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 78),

[0119] 2-(4-(4-(piperidin-4-ylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 79),

[0120] 2-(4-(2-(3-methyl-4-chlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 80),

[0121] 2-(4-(2-(4-methoxyphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 81),

[0122] 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 82),

[0123] 1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroacetone (compound 83), N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine (compound 84),

[0124] N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 85)

[0125] N-((1s,4s)-4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 86)

[0126] 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 87),

[0127] N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 88)

[0128] 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 89),

[0129] N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 90)

[0130] N-((1s,4s)-4-(2-(3-acetylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 91),

[0131] N-((1s,4s)-4-(2-(m-toluidine)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 92)

[0132] 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 93),

[0133] 1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 94),

[0134] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 95)

[0135] N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 96)

[0136] N4-((1s,4s)-4-aminocyclohexyl)-N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 97)

[0137] N4-((1s,4s)-4-aminocyclohexyl)-N2-(3-acetylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 98)

[0138] N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(m-tolyl)pyrimidin-2,4-diamine (compound 99)

[0139] N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 100)

[0140] 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 101),

[0141] 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 102),

[0142] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 103),

[0143] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 104),

[0144] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 105),

[0145] N-((1s,4s)-4-((2-((4-chloro-3-methylphenyl)amino)-5-(1-(2-hydroxyphenyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 106),

[0146] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-methyl-4-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 107),

[0147] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 108)

[0148] N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 109),

[0149] N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 110), N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 111),

[0150] N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 112)

[0151] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 113),

[0152] N-((1r,4r)-4-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 114),

[0153] N-((1r,4r)-4-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 115), N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 116)

[0154] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-difluorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 117),

[0155] N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 118)

[0156] N-((1r,4r)-4-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 119),

[0157] N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 120)

[0158] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-bis(trifluoromethyl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 121),

[0159] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 122),

[0160] 1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 123),

[0161] 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 124),

[0162] 1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 125),

[0163] 1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 126),

[0164] 2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 127),

[0165] 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 128),

[0166] 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 129),

[0167] 2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 130),

[0168] N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 131)

[0169] N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 132)

[0170] N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 133)

[0171] N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 134)

[0172] N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 135)

[0173] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 136)

[0174] N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 137)

[0175] 1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 138),

[0176] 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 139),

[0177] 1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 140),

[0178] N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 141)

[0179] N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 142)

[0180] N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 143)

[0181] N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 144)

[0182] N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 145)

[0183] N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 146)

[0184] 2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 147),

[0185] 2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 148),

[0186] N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 149)

[0187] N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine (compound 150)

[0188] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)phenyl)pyrimidin-2,4-diamine (compound 151)

[0189] N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 152)

[0190] 5-(1-Methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 153),

[0191] N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 154)

[0192] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine (compound 155)

[0193] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(o-tolyl)pyrimidine-2,4-diamine (compound 156)

[0194] N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 157)

[0195] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 158)

[0196] N2-(5-fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 159)

[0197] N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 160)

[0198] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 161)

[0199] N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 162)

[0200] N2-(3-chloro-5-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 163)

[0201] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 164)

[0202] N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 165)

[0203] N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 166)

[0204] N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 167)

[0205] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (Compound 168)

[0206] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 169)

[0207] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 170)

[0208] N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 171)

[0209] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 172)

[0210] N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 173)

[0211] N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 174)

[0212] N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 175)

[0213] N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 176)

[0214] N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 177)

[0215] N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 178)

[0216] N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 179)

[0217] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isobutyl-1H-pyrazole-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 180)

[0218] N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 181)

[0219] N2-(3-chloro-5-fluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 182)

[0220] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 183)

[0221] N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazole-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 184)

[0222] N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 185)

[0223] N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 186)

[0224] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 187)

[0225] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (Compound 188)

[0226] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 189)

[0227] N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 190);

[0228] N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 191)

[0229] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine (compound 192)

[0230] 2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 193),

[0231] 2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 194),

[0232] 2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 195),

[0233] 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 196),

[0234] 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 197),

[0235] N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine (compound 198)

[0236] N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine (compound 199)

[0237] N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine (compound 200)

[0238] 2-(4-(2-(3,5-dichlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 201),

[0239] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine (compound 202)

[0240] N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine (compound 203)

[0241] 2-(4-(2-(3-chlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 204) and

[0242] One or more of the group consisting of 2-(4-(2-(3,5-difluorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl-1-ol (compound 205).

[0243] In addition, the present invention relates to pyrimidine derivative compounds represented by the following chemical formula 2, their optical isomers or pharmaceutically acceptable salts thereof.

[0244] [Chemical Formula 2]

[0245]

[0246] In the chemical formula 2,

[0247] R 1′ It is a hydroxyl, substituted, or unsubstituted piperidinyl group.

[0248] The substituted piperidinyl group is selected from halogens, C1-C... 10 Halogenated alkyl, hydroxyl, cyano, amino, acetamido, trihaloacetamido, trihaloacetyl, nitro, oxo (=O), C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Aryl or C4-C 10 One or more substituents in the group consisting of heteroaryl groups are substituted;

[0249] R 2′ Is it substituted or unsubstituted C4-C? 10 Cycloalkyl, substituted or unsubstituted C4-C8 heterocycloalkyl, substituted or unsubstituted C4-C 10 Aryl or substituted or unsubstituted C4-C 10 Mixed aromatics,

[0250] Wherein, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is selected from halogens, C1-C... 10Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 Cycloalkyl, C4-C8 heterocycloalkyl, C4-C 10 Aryl or C4-C 10 One or more substituents in the group consisting of heteroaryl groups are substituted;

[0251] R 3′ Is it substituted or unsubstituted C4-C? 10 Cycloalkyl, substituted or unsubstituted C4-C8 heterocycloalkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted C4-C 10 heteroaryl or C4-C 10 A fused ring, substituted or unsubstituted, of aryl and C4-C8 heterocyclic alkyl groups.

[0252] Wherein, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is selected from halogen, C1-C 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 Cycloalkyl, C4-C8 heterocycloalkyl, C4-C 10 Aryl or C4-C 10 Substitution of one or more substituents in the group consisting of heteroaryl groups; and

[0253] n is an integer from 0 to 4.

[0254] Preferably, in the chemical formula 2,

[0255] R 1′ It is a hydroxyl, substituted, or unsubstituted piperidin-4-yl group.

[0256] The substituted piperidine-4-yl group is selected from halogen, C1-C 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl or C1-C 10 One or more substituents in the group consisting of alkoxy groups are substituted;

[0257] R 2′ Is it substituted or unsubstituted C4-C? 10 Cycloalkyl or substituted or unsubstituted C4-C8 heterocycloalkyl,

[0258] Wherein, the substituted cycloalkyl or substituted heterocycloalkyl is selected from halogen, C1-C 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl or C1-C 10 One or more substituents in the group consisting of alkoxy groups; and

[0259] R 3′ Is it substituted or unsubstituted C4-C? 10 Aryl, or C4-C 10 A substituted or unsubstituted fused ring fused with an aryl group and a C4-C8 heterocyclic alkyl group.

[0260] The substituted aryl group or the substituted fused ring is selected from halogens, C1-C... 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl or C1-C 10 One or more substituents in the group consisting of alkoxy groups are substituted.

[0261] Further specific examples of compounds of chemical formula 2 of the present invention are provided, then the choice is...

[0262] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 71),

[0263] N2-(3,5-dichlorophenyl)-N4-(piperidin-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 73)

[0264] 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 75),

[0265] 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 76),

[0266] 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 77),

[0267] 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 78),

[0268] 2-(4-(4-(piperidin-4-ylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 79),

[0269] 2-(4-(2-(3-methyl-4-chlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 80),

[0270] 2-(4-(2-(4-methoxyphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 81),

[0271] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 95)

[0272] N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 96)

[0273] N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 100)

[0274] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 103),

[0275] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 104),

[0276] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 105),

[0277] N-((1s,4s)-4-((2-((4-chloro-3-methylphenyl)amino)-5-(1-(2-hydroxyphenyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 106);

[0278] 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-methyl-4-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 107),

[0279] N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 108)

[0280] N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 110), N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 111),

[0281] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 113),

[0282] N-((1r,4r)-4-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 115),

[0283] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-difluorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 117),

[0284] N-((1r,4r)-4-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 119),

[0285] 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-bis(trifluoromethyl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 121),

[0286] 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 122),

[0287] 2-(4-(2-(3,5-dichlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 201),

[0288] 2-(4-(2-(3-chlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 204) and

[0289] One or more of the group consisting of 2-(4-(2-(3,5-difluorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl-1-ol (compound 205).

[0290] In addition, the present invention relates to pyrimidine derivative compounds represented by the following chemical formula 3, their optical isomers or pharmaceutically acceptable salts thereof.

[0291] [Chemical Formula 3]

[0292]

[0293] In the chemical formula 3,

[0294] R 1″ It is hydrogen, substituted or unsubstituted C1-C 10 Alkyl or substituted or unsubstituted piperidinyl,

[0295] The substituted alkyl or substituted piperidinyl group is selected from halogens, C1-C... 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Aryl or C4-C 10 One or more substituents in the group consisting of heteroaryl groups;

[0296] R 2″ It is an amino, acetamino, or trihaloacetamino group; and

[0297] R 3″ Is it substituted or unsubstituted C4-C? 10 Cycloalkyl, substituted or unsubstituted C4-C8 heterocycloalkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted C4-C 10 heteroaryl, or C4-C 10 A substituted or unsubstituted fused ring fused with an aryl group and a C4-C8 heterocyclic alkyl group.

[0298] Wherein, the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is selected from halogen, C1-C 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl, C1-C 10 Alkoxy, C4-C 10 Cycloalkyl, C4-C8 heterocycloalkyl, C4-C 10 Aryl or C4-C 10 One or more substituents in the group consisting of heteroaryl groups are substituted.

[0299] Preferably, in the chemical formula 3,

[0300] R 1″ It is hydrogen, substituted or unsubstituted C1-C 10 Alkyl or substituted or unsubstituted piperidin-4-yl,

[0301] The substituted alkyl or substituted piperidin-4-yl group is selected from halogen, C1-C. 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl or C1-C 10One or more substituents in the group consisting of alkoxy groups are substituted;

[0302] R 2″ It is an amino, acetamino, or trihaloacetamino group; and

[0303] R 3″ Is it substituted or unsubstituted C4-C? 10 Aryl,

[0304] The substituted aryl group is selected from halogens, C1-C... 10 Halogenated alkyl, oxo (=O), hydroxyl, cyano, nitro, amino, acetamido, trihaloacetamido, trihaloacetyl, C1-C 10 Alkyl or C1-C 10 One or more substituents in the group consisting of alkoxy groups are substituted.

[0305] Further specific examples of compounds of chemical formula 3 of the present invention are provided, then the choice is...

[0306] 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 82),

[0307] 1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 83),

[0308] N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 84)

[0309] N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 85)

[0310] 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 87),

[0311] 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 89),

[0312] 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 93),

[0313] 1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 94),

[0314] 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 101),

[0315] 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 102),

[0316] 1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 123),

[0317] 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 124),

[0318] 1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 125),

[0319] 1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 126),

[0320] 2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 127),

[0321] 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 128),

[0322] 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 129),

[0323] 2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 130),

[0324] N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 131)

[0325] N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 132)

[0326] N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 133)

[0327] N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 134)

[0328] N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 135)

[0329] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 136)

[0330] N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 137)

[0331] 1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 138),

[0332] 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 139),

[0333] 1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 140),

[0334] N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 141)

[0335] N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 142)

[0336] N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 143)

[0337] N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 144)

[0338] N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 145)

[0339] N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 146)

[0340] 2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 147),

[0341] 2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 148),

[0342] N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 149)

[0343] N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine (compound 150)

[0344] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)phenyl)pyrimidin-2,4-diamine (compound 151)

[0345] N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 152)

[0346] 5-(1-Methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 153),

[0347] N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 154)

[0348] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine (compound 155)

[0349] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(o-tolyl)pyrimidine-2,4-diamine (compound 156)

[0350] N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 157)

[0351] 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 158)

[0352] N2-(5-fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 159)

[0353] N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 160)

[0354] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 161)

[0355] N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 162)

[0356] N2-(3-chloro-5-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 163)

[0357] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 164)

[0358] N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 165)

[0359] N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 166)

[0360] N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 167)

[0361] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (Compound 168)

[0362] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 169)

[0363] 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 170)

[0364] N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 171)

[0365] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 172)

[0366] N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 173)

[0367] N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 174)

[0368] N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 175)

[0369] N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 176)

[0370] N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 177)

[0371] N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 178)

[0372] N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 179)

[0373] N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isobutyl-1H-pyrazole-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 180)

[0374] N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 181)

[0375] N2-(3-chloro-5-fluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 182)

[0376] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 183)

[0377] N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazole-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 184)

[0378] N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 185)

[0379] N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 186)

[0380] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 187)

[0381] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (Compound 188)

[0382] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 189)

[0383] N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 190)

[0384] N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 191)

[0385] 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine (compound 192)

[0386] 2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 193),

[0387] 2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 194),

[0388] 2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 195),

[0389] 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol (compound 196) and

[0390] One or more of the group consisting of 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl-1-ol (compound 197).

[0391] Furthermore, the compounds of the present invention represented by the chemical formulas 1 to 3 are prepared by the method disclosed in Korean Patent Application No. 10-2017-0056002, namely the method of reaction formula 1 below.

[0392] A method for preparing compounds represented by the chemical formulas 1 to 3 is provided, comprising:

[0393] By reacting the compound represented by compound B with NH2R 2 The reaction, the step of preparing the compound represented by compound C (step 1);

[0394] Step 2: the preparation of compound D from the compound C prepared in step 1; and

[0395] Step 3: The preparation of a compound represented by compound A from the compound represented by compound D prepared in step 2.

[0396] [Reaction Formula 1]

[0397]

[0398] In the reaction formula 1,

[0399] R 1 R 2 R 3 and R 4 As defined in chemical formulas 1 to 3;

[0400] X 1 X 2 and X 3 It is halogen.

[0401] The following describes in detail the preparation method of the compounds represented by chemical formulas 1 to 3 (or compound A) of the present invention, step by step.

[0402] In the method for preparing the compounds represented by chemical formulas 1 to 3 (or compound A) of the present invention, step 1 of reaction formula 1 is performed by reacting a compound represented by compound B with NH2R. 2 The reaction, the steps for preparing the compound represented by compound C.

[0403] At this point, step 1 can be understood as -NH-R 2 The step of introducing a substituent into the core structure of the compound of the present invention. This applies as long as it is possible to introduce a substituent into the core structure of the compound represented by compound B. 1 Location introduction -NH-R 2 The method of preparing the compound represented by compound C by substituents may be included without limitation in the present invention. As an example, it may preferably be carried out by reacting N,N-diisopropylethylamine (DIPEA) and the compound represented by compound B in 1,4-dioxane.

[0404] At this point, any solvent that can dissolve the compound represented by compound B and DIPEA can be used without restriction. For example, tetrahydrofuran (THF), dioxane, ether solvents including diethyl ether and 1,2-dimethoxyethane, lower alcohols including methanol, ethanol, propanol and butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetyl sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β-hydroxybutyrate, glycolic acid, malate, tartrate, methane sulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and mixtures thereof can be used. 1,4-Dioxane can also be used.

[0405] Furthermore, there are no particular limitations on the reaction temperature, but it is preferably carried out at 0°C to 100°C, for example, it can be carried out at room temperature. Moreover, there are no particular limitations on the reaction time, for example, it can be set to 2 hours to 10 hours; as another example, the reaction can be carried out for 20 minutes to 8 hours when heated.

[0406] In the method for preparing compounds represented by chemical formulas 1 to 3 (or compound A) of the present invention, step 2 of reaction formula 1 is the step of preparing a compound represented by compound D from the compound represented by compound C prepared in step 1.

[0407] At this point, step 2 can be understood as R 1The step of introducing a substituent into a compound represented by compound C, wherein R is selectively introduced depending on the target compound. 1 The steps for preparing the compound represented by compound D.

[0408] On the one hand, as an example not limited to this, as an example of introducing the aforementioned R 1 One step of the method can be achieved by reacting Na2CO3 with a compound represented by compound C, and... The reaction of the compound represented by it and Pd(dppf)2Cl2 in DMF can be carried out, as long as the steps for preparing the compound represented by compound D can be performed by the same methods used in the art, as described in step 2 of the present invention.

[0409] At this point, there are no particular limitations on the solvents that can be used for the reaction. As an example, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetazonium sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, methyl phenylpropionate, phenylbutyric acid, citrate, lactate, β-hydroxybutyrate, glycolic acid, malic acid, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran (THF), dioxane, ether solvents (including diethyl ether, 1,2-dimethoxyethane, etc.), lower alcohols (including methanol, ethanol, propanol, and butanol) and mixtures thereof can be used, with DMF being preferred.

[0410] Furthermore, there are no particular restrictions on the reaction temperature, but it is preferably carried out at 50°C to 150°C, for example, at 90°C. Moreover, there are no particular restrictions on the reaction time, for example, it can be set to 10 hours to 40 hours, or, as another example, the reaction can be carried out over 20 hours to 30 hours.

[0411] In the method for preparing compounds represented by chemical formulas 1 to 3 (or compound A) of the present invention, step 3 of reaction formula 1 is a step of preparing compounds represented by chemical formulas 1 to 3 (or compound A) from the compound represented by compound D prepared in step 2.

[0412] At this point, step 3 can be understood as transferring -NR 3 R 4 The step of introducing a substituent into a compound represented by compound D, wherein, depending on the target compound, -NR is selectively introduced. 3 R 4 The substituents are used to prepare the compounds of the present invention represented by chemical formulas 1 to 3 (or compound A).

[0413] On the one hand, but not limited to this, as an example, as the introduction of the -NR3 R 4 As part of the substituent method, it can be achieved by using a compound represented by compound D and NHR. 3 R 4 The compound represented is reacted in acid-treated ethoxyethanol, and any step that can be performed to prepare a compound represented by chemical formulas 1 to 3 (or compound A) as in step 3 of the present invention may be included in the present invention.

[0414] At this time, there are no particular limitations on the solvents that can be used for the reaction. As an example, ethoxyethanol, 1,4-dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetyl sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β-hydroxybutyrate, glycolic acid, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran (THF), dioxane, ether solvents including diethyl ether, 1,2-dimethoxyethane, lower alcohols including methanol, ethanol, propanol and butanol and mixtures thereof, are preferred.

[0415] Furthermore, there are no particular restrictions on the reaction temperature, but it is preferably carried out at 50°C to 150°C, for example, at 100°C. Moreover, there are no particular restrictions on the reaction time, for example, it can be set to 10 hours to 40 hours, or, as another example, the reaction can be carried out over 10 hours to 20 hours.

[0416] On the one hand, in the preparation method of the compound represented by chemical formulas 1 to 3 (or compound A) of the present invention, the reaction is carried out according to the above-described reaction formula 1. As a preferred example, the reaction is carried out according to the following reaction formula 2.

[0417] [Reaction 2]

[0418]

[0419] In reaction formula 2,

[0420] R 1 R 2 R 3 and R 4 As defined in chemical formulas 1 to 3.

[0421] Furthermore, as a more preferred specific example in the preparation methods of the compounds represented by chemical formulas 1 to 3 of the present invention, the preparation methods of the compounds of the embodiments of the present invention described below can be cited. The preparation methods of the compounds represented by chemical formulas 1 to 3 of the present invention shown in reaction formulas 1, 2, and the preparation methods of the compounds of the embodiments of the present invention described below should be understood as examples of methods for preparing the compounds of the present invention. Any method capable of preparing the compounds represented by chemical formulas 1 to 3 prepared according to the present invention is included without limitation in the present invention. In addition, it should be understood that the methods described in this specification and preparation methods that can be easily modified and altered by those skilled in the art are also included within the scope of the present invention, which is obvious to those skilled in the art.

[0422] The compounds of the present invention, represented by chemical formulas 1 to 3, can be used in the form of pharmaceutically acceptable salts, wherein acid addition salts formed by pharmaceutically acceptable free acids are useful. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; aliphatic mono- and dicarboxylic acid esters; phenyl-substituted alkanes; hydroxy alkanes and alkanedides; aromatic acids; non-toxic organic acids such as aliphatic and aromatic sulfonic acids; and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. The types of pharmaceutically non-toxic salts include: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propionates, oxalates, malonates, succinates, persulfates, sebacic acid esters, fumarates, malates, and 1,4-butanediol. Butyl ester, hexyl 1,6-hexanoate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalic acid, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β-hydroxybutyrate, glycolic acid, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0423] The acid addition salt of the present invention can be prepared by conventional methods. For example, the derivatives of chemical formulas 1 to 3 can be dissolved in organic solvents such as methanol, ethanol, acetone, dichloromethane, and acetonitrile, and the precipitate formed by adding organic or inorganic acids can be filtered and dried. Alternatively, the solvent and excess acid can be distilled under reduced pressure and dried, and crystallized in an organic solvent.

[0424] Alternatively, alkalis can be used to prepare pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the insoluble compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable for preparation as metal salts. Alternatively, the corresponding salts can also be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0425] Furthermore, the present invention includes not only compounds represented by the chemical formulas 1 to 3 and their pharmaceutically acceptable salts, but also solvates, stereoisomers, hydrates, etc., that can be prepared therefrom.

[0426] In addition, the present invention relates to compositions for the prevention or treatment of Tyro3 (Tyrosine-protein kinase receptor) related diseases, comprising compounds represented by the chemical formulas 1 to 3, their optical isomers or pharmaceutically acceptable salts thereof, and the active ingredients thereof.

[0427] The pharmaceutical composition exhibits preventive or therapeutic effects on Tyro3-related diseases by targeting Tyro3 to inhibit its activity. Examples of Tyro3-related diseases include all types of diseases caused by abnormal Tyro3 effects such as abnormal expression or activity of Tyro3. In addition, any disease that is identified as alleviating, improving, preventing, or treating by inhibiting Tyro3 activity in diseases such as cancer is understood to be a Tyro3-related disease that exhibits effective preventive, improving, or therapeutic effects using a pharmaceutical composition with compounds represented by chemical formulas 1 to 3 of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof as active ingredients, and is included within the scope of the present invention.

[0428] Additionally, for example, Tyro3-related diseases include all known Tyro3-related diseases, such as cancers identified as Tyro3-related as described in the background section of this invention, such as breast cancer, ovarian cancer, etc.

[0429] Cancer, also known as malignant tumor, is an abnormally growing mass caused by the excessive autonomous production of body tissue. It refers to a disease that infiltrates surrounding tissues and rapidly grows, spreads, and metastasizes to various parts of the body to threaten life, including carcinoma and sarcoma. More specifically, it may include pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B-cell lymphoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, non-sinusoidal carcinoma, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, and small Colorectal cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal carcinoma, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorioretinopathy of pregnancy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic cancer, etc.

[0430] The pharmaceutical compositions of the present invention can be formulated into suitable forms with commonly used pharmaceutically acceptable carriers. "Pharmaceutically acceptable" means a composition that is physiologically permissible and, when administered to humans, generally does not cause intestinal disorders, dizziness, or other allergic reactions or similar reactions. Furthermore, the compositions can be formulated into oral dosage forms, topical medications, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, according to conventional methods for pharmaceutical formulation.

[0431] The carrier, excipients, and diluents that may be included in the composition may include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. In the case of formulation, commonly used fillers, stabilizers, binders, disintegrants, surfactants, and other diluents or excipients may be used. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., which are prepared by mixing at least one or more excipients with the compounds of the present invention, such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations intended for oral administration include suspensions, internal solutions, emulsions, and syrups. Besides commonly used simple diluents like water and liquid paraffin, they can also contain various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives. Formulations intended for non-oral administration can include sterile aqueous solutions, non-water-soluble agents, suspensions, emulsions, freeze-dried formulations, and suppositories. Non-aqueous solvents and suspensions can use plant oils such as propylene glycol, polyethylene glycol, and olive oil, as well as injectable esters such as ethyl oleate. Suppository bases can use witepsol, polyethylene glycol, Tween 61, cocoa butter, glyceryl laurate, glycerin, and gelatin. For formulation of non-oral drug delivery, a compound represented by the chemical formulas 1 to 3 or a pharmaceutically acceptable salt thereof is mixed with sterile / sterilized preservatives, stabilizers, humectants or emulsifying agents, salts for adjusting osmotic pressure, and / or buffers, and other therapeutically useful substances in water to form a solution or suspension, which can be formulated into ampoules or vials for unit delivery.

[0432] The pharmaceutical composition provides a pharmaceutical composition comprising a compound represented by chemical formulas 1 to 3 and an excipient. The compound is preferably added at a concentration of 0.001% to 50% by weight relative to the total weight of the composition, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight.

[0433] The pharmaceutical compositions of the present invention, comprising compounds of chemical formulas 1 to 3 as active ingredients, can be administered to mammals such as rats, livestock, and humans via various routes. All possible routes of administration are foreseeable, including oral, rectal or intravenous, intramuscular, subcutaneous, intradural, or intracerebral injection. Dosage can vary depending on the age, sex, weight, specific disease or pathological condition requiring treatment, severity of the disease or pathological condition, timing of administration, route of administration, absorption, distribution, and excretion rate of the drug, types of other drugs used, and the prescriber's judgment. Dosage determination based on these factors is typically within the range of 0.01 mg / kg / day to approximately 2000 mg / kg / day, as understood by those skilled in the art. More preferably, dosages range from 1 mg / kg / day to 500 mg / kg / day. Administration can be once daily or in multiple doses. The stated dosages are not intended to limit the scope of the invention.

[0434] Invention Effects

[0435] This invention relates to pyrimidine derivative compounds, their optical isomers, or pharmaceutically acceptable salts thereof, and cancer prevention or treatment compositions comprising them as active ingredients. The pyrimidine derivative compounds, their optical isomers, or pharmaceutically acceptable salts thereof of this invention exhibit excellent selective inhibition of Tyro3, ​​particularly in TAM receptor inhibition, and can be used as excellent cancer prevention or treatment compositions without the side effects of inhibiting Axl and Mer. Detailed Implementation

[0436] The preferred embodiments of the present invention will now be described in detail. However, the present invention is not limited to the embodiments described herein and may be implemented in other forms. The purpose of this description is to make the content herein thorough and complete, and to fully convey the spirit of the invention to those skilled in the art.

[0437] <Example 1. Synthesis and physicochemical property confirmation of pyrimidine derivative compounds>

[0438] Compounds 1 to 205, which are pyrimidine derivative compounds of the present invention, were prepared by means of the method disclosed in Patent Application No. 10-2017-0056002, and their structures and physicochemical properties are described below.

[0439] Compound 1. 5-Bromo-N4-cyclohexyl-N2-(p-Tolyl)pyrimidine-2,4-diamine

[0440]

[0441] 1HNMR (300MHz, CDCl3) δ7.98 (s, 1H), 7.50 (d, J = 9.0Hz, 2H), 7.50 (d, J = 9.0Hz, 2H), 6.85 (brS, 1H), 5.16 (m, 1H), 3.98 (m, 1H), 2.34 (s, 3H), 2.13 (m 2H), 1.82(m, 2H), 1.71(m, 1H), 1.48(m, 2H), 1.28(m, 3H);

[0442] LC / MS m / z C 17 H 21 BrN4(MH + Calculated value: 361.3, measured value: 362.1.

[0443] Compound 2.N4-cyclohexyl-N2,5-di-(p-tolyl)pyrimidine-2,4-diamine

[0444]

[0445] 1 HNMR (300MHz, CDCl3) δ7.85 (m, 2H), 7.51 (m, 6H), 7.21 (d, J=8.1Hz, 2H), 4.91 (s, 1H), 4.10 (s, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (m 2H), 1.82(m, 2H), 1.71(m, 1H), 1.48(m, 2H), 1.28(m, 3H);

[0446] LC / MS m / z C 24 H 28 N4(MH + The calculated value is 372.5, and the measured value is 373.2.

[0447] Compound 3. 5-Bromo-N4-cyclohexyl-N2-(3,5-dichlorophenyl)pyrimidine-2,4-diamine

[0448]

[0449] 1 HNMR (300MHz, CDCl3) δ8.01 (s, 2H), 7.61 (s, 2H), 7.00 (s, 2H), 5.25 (s, 1H), 4.10 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (m 2H), 1.82(m, 2H), 1.71(m, 1H), 1.48(m, 2H), 1.28(m, 3H).

[0450] Compound 4. 2-Chloro-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0451]

[0452] 1 HNMR (300MHz, CDCl3) δ7.86 (s, 2H), 7.59 (s, 1H), 7.49 (s, 1H), 5.12 (s, 1H), 4 .10(s, 1H), 4.01(s, 3H), 2.02(s, 2H), 1.71(m, 3H), 1.48(m, 2H), 1.19(m, 3H);

[0453] LC / MS m / z C 14 H 18 ClN5(MH + Calculated value: 291.7, measured value: 292.2.

[0454] Compound 5.N4-cyclohexyl-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0455]

[0456] 1 HNMR (300MHz, CDCl3) δ7.76 (s, 1H), 7.68 (s, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 5. 12(brs, 1H), 4.10(s, 1H), 4.01(s, 3H), 2.02(m, 2H), 1.71(m, 3H), 1.48(m, 2H), 1.19(m, 3H);

[0457] LC / MS m / z C 20 H 22 Cl2N6(MH + Calculated value: 417.4, measured value: 418.2.

[0458] Compound 6. N4-cyclohexyl-5-(1-methyl-1H-pyrazole-4-yl)-N2-phenylpyrimidine-2,4-diamine

[0459]

[0460] 1HNMR (300MHz, CDCl3) δ7.81 (s, 1H), 7.70 (d, J=9.0Hz, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.32 (m, 2H), 7.01 (m, 1H), 4.95 (d, J=6.0Hz, 1H), 4.01 (m, 1H), 3.99 (s, 3H), 2.11 (m, 2H), 1.75 (m, 3H), 1.45 (m, 2H), 1.20 (m, 3H);

[0461] LC / MS m / z C 20 H 24 N6(MH + Calculated value: 348.20, measured value: 349.1.

[0462] Compound 7.N2-(3-chlorophenyl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0463]

[0464] 1 HNMR (300MHz, CDCl3) δ8.21 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 7.24 (m, 3H), 6.98 (m, 1H), 4.95 (d, J=6.0Hz, 1H), 4.01 (m, 1H), 3.99 (s, 3H), 2.11 (m, 2H), 1.75 (m, 3H), 1.45 (m, 2H), 1.20 (m, 3H);

[0465] LC / MS m / z C 20 H 23 ClN6(MH + Calculated value: 382.17, measured value: 382.2.

[0466] Compound 8. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine

[0467]

[0468] 1HNMR (300MHz, CDCl3) δ7.45 (m, 2H), 7.65-7.28 (m, 5H), 5.32 (s, 1H), 4.75 (d, J=9.0Hz, 1H), 4 .72(d, J=9.0Hz, 1H), 3.97(s, 3H), 3.85(m, 1H), 1.78(m, 3H), 1.70(m, 3H), 1.45-1.10(m, 5H);

[0469] LC / MS m / z C 22 H 25 F3N6(MH + Calculated value: 430.21, measured value: 431.1.

[0470] Compound 9. N2-(3-chloro-4-methoxyphenyl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0471]

[0472] 1 HNMR (300MHz, CDCl3) δ8.02 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (m, 2H), 7.28 (m, 2H), 6.90 (m, 1H), 4.96 (d, J =9.0Hz, 1H), 4.02(m, 1H), 4.00(s, 3H), 3.97(s, 3H), 2.06(m, 2H), 1.78(m, 2H), 1.52(m, 2H), 1.45-1.10(m, 3H);

[0473] LC / MS m / z C 21 H 25 ClN6O(MH + Calculated value: 412.18; Measured value: 413.0.

[0474] Compound 10. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(o-tolyl)pyrimidine-2,4-diamine

[0475]

[0476] 1HNMR (300MHz, CDCl3) δ8.21 (d, J=6.0Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (m, 2H), 7.28 (m, 2H), 6.98 (m, 1H), 4.93 (d, J=9.0Hz, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 2.38 (s, 3H), 2.06 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.45-1.10 (m, 3H);

[0477] LC / MS m / z C 21 H 26 N6(MH + Calculated value: 362.22, measured value: 363.10.

[0478] Compound 11. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(5-methylisoxazol-3-yl)pyrimidine-2,4-diamine

[0479]

[0480] 1 HNMR (300MHz, CDCl3) δ8.38 (brs, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 6.74 (s, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.00 (s, 3H), 3.97 (m, 1H), 2.39 (s, 3H), 2.06 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.45-1.10 (m, 3H);

[0481] LC / MS m / z C 18 H 23 N7O(MH + Calculated value: 353.20, measured value: 354.10.

[0482] Compound 12.N2-(5-tert-butylisoxazol-3-yl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0483]

[0484] 1HNMR (300MHz, CDCl3) δ8.65 (brs, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 6.83 (s, 1H), 4.97 (d, J= 9.0Hz, 1H), 4.00 (s, 3H), 4.00 (m, 1H), 2.08 (m, 2H), 1.82-1.60 (m, 3H), 1.47 (s, 3H), 1.49-1.21 (m, 4H);

[0485] LC / MS m / z C 21 H 29 N7O(MH + The calculated value is 395.2, and the measured value is 397.2.

[0486] Compound 13. N4-cyclohexyl-N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0487]

[0488] 1 HNMR (300MHz, CDCl3) δ8.06 (d, J=6.0Hz, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (s , 1H), 7.31 (d, J=9.0Hz, 1H), 7.22 (d, J=6.0Hz, 1H), 7.07 (d, J=6.0Hz, 1H), 6.73 ( brs, 1H), 4.97 (d, J = 9.0Hz, 1H), 4.00 (s, 3H), 4.00 (m, 1H), 3.22 (m, 1H), 2.08 (m , 2H), 1.82-1.60 (m, 3H), 1.47 (s, 3H), 1.29 (d, J=9.0Hz, 9H), 1.49-1.21 (m, 4H);

[0489] LC / MS m / z C 23 H 30 N6(MH + The calculated value is 390.3, and the measured value is 391.2.

[0490] Compound 14. N4-cyclohexyl-5-(furan-3-yl)-N2-(p-tolyl)pyrimidin-2,4-diamine

[0491]

[0492] 1HNMR (300MHz, CDCl3) δ7.85 (s, 1H), 7.56 (m, 4H), 7.15 (d, J=6.0Hz, 1H), 6.52 (s, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.03 (m, 1H), 2.34 (s, 3H), 2.08 (m, 2H), 1.82-1.63 (m, 3H), 1.47 (s, 3H), 1.49-1.21 (m, 3H);

[0493] LC / MS m / z C 21 H 24 N4O(MH + The calculated value is 348.4, and the measured value is 349.3.

[0494] Compound 15. N4-cyclohexyl-N2-(3,5-dichlorophenyl)-5-(furan-3-yl)pyrimidin-2,4-diamine

[0495]

[0496] 1 HNMR (300MHz, CDCl3) δ7.80 (s, 1H), 7.65 (m, 2H), 7.52 (m, 2H), 6.98 (m, 1H), 6.53 (m, 1H) , 5.04 (d, J=9.0Hz, 1H), 4.03 (m, 1H), 2.09 (m, 2H), 1.82-1.40 (m, 6H), 1.49-1.21 (m, 3H);

[0497] LC / MS m / z C 20 H 20 Cl2N4O(MH + Calculated value: 403.1, measured value: 403.9.

[0498] Compound 16. N4-cyclohexyl-N2-(2,2-difluoro-2-(4-methoxyphenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0499]

[0500] 1HNMR (300MHz, CDCl3) δ7.80 (s, 1H), 7.76 (s, 1H), 7.55-7.42 (m, 2H), 7.34-7.28 (m, 3H), 7.09-6.99 (m, 2H), 6.91- 6.81 (m, 2H), 4.48 (t, J=6.0Hz, 1H), 3.97 (s, 3H), 3.88-3.78 (m, 5H), 3.51 (s, 3H), 3.7 (s, 1H), 2.00-1.98 (m, 3H);

[0501] LC / MS m / z C 23 H 28 F2N6O(MH + Calculated value: 442.1, measured value: 443.2.

[0502] Compound 17. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-(pyridin-4-yl)ethyl)pyrimidin-2,4-diamine

[0503]

[0504] 1 HNMR (300MHz, CDCl3) δ8.57-8.52 (m, 2H), 7.65 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.18-7.15 (m, 2H), 4.89 (d, J=6.0Hz, 1H), 3. 98(s, 4H), 3.63-3.50(m, 2H), 2.97-2.86(m, 2H), 2.06-1.97(m, 2H), 1.76-1.71(m, 3H), 1.47-1.33(m, 2H), 1.30-1.11(m, 4H);

[0505] LC / MS m / z C 21 H 27 N7(MH + The calculated value is 377.2, and the measured value is 378.2.

[0506] Compound 18. (4-(4-(cyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)(thiophen-2-yl)methyl ketone

[0507]

[0508] 1HNMR (300MHz, CDCl3) δ7.89-7.70 (m, 1H), 7.59-7.45 (m, 2H), 7.45-7.32 (m, 2H), 7.19-6.91 (m, 1H), 4.84 (d, J=7.4Hz, 1H), 4. 03-3.93 (m, 4H), 3.90-3.79 (m, 4H), 2.17-1.86 (m, 3H), 1.83-1.66 (m, 2H), 1.40 (dd, J=24.1, 11.8Hz, 2H), 1.33-1.08 (m, 4H);

[0509] LC / MS m / z C 37 H 47 ClN 12 OS(MH + Calculated value: 451.6, measured value: 452.2.

[0510] Compound 19. 4-(4-(cyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one

[0511]

[0512] 1 HNMR (300MHz, CDCl3) δ9.51 (s, 1H), 8.21 (s, 1H), 7.96 (m, 2H), 7.59 (m, 3H), 7.35 (m, 3H), 3 .92(s, 3H), 3.11(s, 3H), 2.65(m, 1H), 2.15(s, 3H), 1.82(m, 2H), 1.45(m, 3H), 1.21(m, 5H);

[0513] LC / MS m / z C 25 H 30 N8O(MH + Calculated value: 458.2; Measured value: 459.2.

[0514] Compound 20.N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-methylisoxazol-5-yl)pyrimidin-2,4-diamine

[0515]

[0516] 1HNMR (300MHz, CDCl3) δ8.49 (s, 1H), 8.20 (s, 1H), 7.98 (m, 2H), 6.52 (s, 1H), 3 .98(s, 3H), 2.52(m, 1H), 2.42(s, 3H), 1.81(m, 2H), 1.47(m, 3H), 1.20(m, 5H);

[0517] LC / MS m / z C 18 H 23 N7O(MH + Calculated value: 352.2, measured value: 353.1.

[0518] Compound 21. N4-cyclohexyl-N2-(5-ethyl-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0519]

[0520] 1 HNMR (300MHz, CDCl3) δ12.10 (s, 1H), 8.24 (s, 1H), 7.92 (m, 2H), 3.93 (s, 3H) , 3.11(t, J=7.2Hz, 2H), 2.69(m, 1H), 1.83(m, 2H), 1.47(m, 3H), 1.22(m, 5H);

[0521] LC / MS m / z C 18 H 24 N8S(MH + The calculated value is 384.5, and the measured value is 385.1.

[0522] Compound 22. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(thiazo-2-yl)pyrimidine-2,4-diamine

[0523]

[0524] 1 HNMR (300MHz, CDCl3) δ8.21 (s, 1H), 7.95 (m, 2H), 7.21 (d, J=3.5Hz, 1H), 6.78 (d, J=3.5Hz, 1H), 3.98 (s, 3H), 1.83 (m, 2H), 1.47 (m, 3H), 1.22 (m, 5H);

[0525] LC / MS m / z C 17 H 21 N7S(MH +The calculated value is 355.5, and the measured value is 356.1.

[0526] Compound 23. N4-cyclohexyl-N2-adamantyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0527]

[0528] 1 HNMR (300MHz, CDCl3) δ8.20 (s, 1H), 7.94 (m, 2H), 3.98 (s, 3H), 2.67 (m, 1H), 2.28 (m, 2H), 1.98(m, 2H), 1.78(m, 2H), 1.75(m, 3H), 1.68(m, 3H), 1.42(m, 5H), 2.21(m, 9H);

[0529] LC / MS m / z C 24 H 34 N6(MH + Calculated value: 405, measured value: 406.2.

[0530] Compound 24. N4-cyclohexyl-N2-(2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0531]

[0532] 1 HNMR (300MHz, CDCl3) δ8.20 (s, 1H), 7.89 (m, 2H), 7.35 (m, 2H), 6.97 (m, 2H), 3 .97(s, 3H), 3.83(s, 3H), 2.62(m, 1H), 1.75(m, 3H), 1.45(m, 3H), 1.21(m, 4H);

[0533] LC / MS m / z C 21 H 26 N6O(MH + The calculated value is 378.4, and the measured value is 379.2.

[0534] Compound 25. N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine

[0535]

[0536] 1HNMR (300MHz, CDCl3) δ7.85 (s, 1H), 7.57 (m, 2H), 7.45 (m, 2H), 7.23 (m, 1H), 6.84 (d, J = 6.0Hz, 1H), 4.84 (d, J = 7.4Hz, 1H ), 4.03(m, 1H), 3.98(s, 3H), 2.38(s, 3H), 2.18-2.10(m, 4H), 1.83-1.65(m, 3H), 1.51-1.28(m, 2H), 1.28-1.08(m, 3H);

[0537] LC / MS m / z C 21 H 26 N6(MH + The calculated value is 362.4, and the measured value is 363.3.

[0538] Compound 26,N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0539]

[0540] 1 HNMR (300MHz, chloroform-d) δ7.79 (s, 1H), 7.42 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 6.95 (s, 1H), 6.76 (b rs, 1H), 5.10 (d, J=9.0Hz, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.98 (s, 3H), 2.19-1.62 (m, 4H), 1.61-1.23 (m, 4H);

[0541] LC / MS m / z C 22 H 22 Cl2F3N7O(MH + Calculated value: 527.01; Measured value: 528.1.

[0542] Compound 27. 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0543]

[0544] 1HNMR (300MHz, CDCl3) δ7.75 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 4.90 (d , J=9.00Hz, 1H), 4.51 (m, 1H), 4.31 (m, 1H), 4.10 (m, 1H), 4.09 (s, 3H), 3.26 (m, 1H), 2.98 (m, 1H), 2.28 (m, 1H), 1.45 (m, 1H).

[0545] Compound 28.N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0546]

[0547] 1 HNMR (300MHz, chloroform-d) δ8.12 (s, 1H), 5.49 (d, J=7.6Hz, 1H), 4.57 (s, 1H), 4.25-4.08 (m, 1H), 3.68 (d, J=8.9Hz, 1H), 1.85 (ddt, J=12.8, 8.5, 4.0Hz, 4H), 1.71-1.53 ​​(m, 4H), 1.46 (s, 9H);

[0548] LC / MS m / z C 20 H 23 Cl2N7(MH + Calculated value: 432.3, measured value: 433.2.

[0549] Compound 29. N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine

[0550]

[0551] 1 HNMR (300MHz, chloroform-d) δ7.82 (s, 1H), δ7.72 (m, 3H), 7.61 (s, 1H), 7.48 (s, 1H), 6.99 (s, 1H) ), 5.10(m, 1H), 4.24(m, 1H), 3.91(s, 3H), 3.48(m, 1H), 3.10(m, 1H), 2.40-1.75(m, 4H);

[0552] LC / MS m / z C 19 H 21Cl2N7(MH + Calculated value: 418.2; Measured value: 419.3.

[0553] Compound 30.N2-(3,5-dichlorophenyl)-N4-((1s,4s)-4-(dimethylamino)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0554]

[0555] 1 HNMR (300MHz, CDCl3) δ8.07 (s, 1H) 7.90-7.83 (m, 1H), 7.66 (d, J=3Hz, 2H), 7.58-7.53 (m, 2H), 6.946 (t, J=1.8Hz, 1H), 5.44 (d, J=6 Hz, 1H), 4.30-4.28 (m, 1H), 4.07 (s, 1H), 2.91-2.85 (m, 1H), 2.79 (s, 6H), 2.28-2.22 (m, 2H), 2.05-2.03 (m, 4H), 1.88-1.80 (m, 3H).

[0556] Compound 31.N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-acetamide

[0557]

[0558] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.81 (s, 1H), 7.64 (d, J = 1.8 Hz, 2H), 7.58 (s, 1H), 7.45 (s, 1H), 7.20 (d, J = 1.9 Hz, 1H), 6.97 (s, 0H), 5.45 (d, J = 7.8 Hz, 0H), 5.11 (d, J = 7.0 Hz, 1H), 4.22–4.10 (m, 1H), 4.00 (s, 3H), 2.04 (d, J = 6.4 Hz, 1H), 1.93–1.77 (m, 3H), 1.25 (s, 5H).

[0559] Compound 32.N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1-methylpiperidin-4-yl)pyrimidin-2,4-diamine

[0560]

[0561] 1¹H NMR (300 MHz, chloroform-d) δ 7.82–7.78 (m, 1H), 7.63 (d, J = 1.8 Hz, 2H), 7.52 (s, 1H), 7.44 (s, 1H), 7.21 (dd, J = 2.2, 1.2 Hz, 1H), 6.98 (t, J = 1.8 Hz, 1H), 5.12–5.02 (m, 1H), 4.21–4.07 (m, 2H), 4.00 (s, 3H), 3.27–3.15 (m, 2H), 2.57 (s, 3H), 2.22–2.14 (m, 3H), 2.03 (d, J = 5.7 Hz, 3H);

[0562] LC / MS m / z C 20 H 23 Cl2N7(MH + Calculated value: 432.1; Measured value: 433.0.

[0563] Compound 33. 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)acetone

[0564]

[0565] 1 HNMR (300MHz, chloroform-d) δ7.79 (s, 1H), 7.64 (d, J = 1.8Hz, 2H), 7.53 (s, 1H), 7.42 (s, 1H), 6.98 (t, J = 1.8Hz, 1H), 4.99 (d, J = 7.3Hz, 1H), 4.61 (d, J = 13.4Hz, 2H), 4.24 (dd, J=11.5, 4.0Hz, 2H), 3.98 (s, 3H), 3.84 (d, J=13.4Hz, 2H), 3.34 (d, J=11.5Hz, 2H), 2.87 (d, J=13.6Hz, 2H), 2.11 (s, 3H).

[0566] Compound 34. 1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(phenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0567]

[0568] 1HNMR (300MHz, CDCl3) δ7.83 (s, 1H), 7.62-7.58 (m, 2H), 7.52 (s, 1H), 7.40 (s, 1H), 7.35-7.28 (m, 2H), 7.05-7.02 (m, 1H), 6.9 6-6.93(m, 1H), 4.88-4.85(m, 1H), 4.55-4.47(m, 2H), 3.98(s, 3H), 3.35-3.24(m, 2H), 3.05-2.95(m, 2H), 2.27-2.19(m, 3H);

[0569] LC / MS m / z C 21 H 22 F3N7O(MH + Calculated value: 445.1, measured value: 446.0.

[0570] Compound 35. 1-(4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0571]

[0572] 1 HNMR (300MHz, CDCl3) δ8.16 (t, J=1.9Hz, 1H) 7.82 (s, 1H) 7.52 (S, 1H) 7.43 (S, 1H) 7.19 (d, J=9Hz, 1H) 4.92 (d, J=7.2Hz, 1H) 4.59-4. 57 (m, 1H) 4.54-4.53 (m, 1H) 4.08-4.02 (m, 1H) 3.98 (s, 3H) 3.42-3.33 (m, 1H) 3.10-3.01 (m, 1H) 2.33-2.20 (m, 2H) 1.47-1.42 (m, 2H);

[0573] LC / MS m / z C 21 H 21 ClF3N7O(MH + Calculated value: 479.1; Measured value: 480.0.

[0574] Compound 36.N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0575]

[0576] 1HNMR (300MHz, CDCl3) δ8.11 (s, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.19 (dd, J=4.9, 1.2Hz, 3H), 7.00-6.91 (m, 1H), 4.97 (d, J=7.5Hz, 1H), 4.22-4.05 (m, 1H), 3.98 (s, 3H), 3.12 (d, J=12.8Hz, 2H), 2.85 (dd, J=17.7 , 6.3Hz, 2H), 2.10 (d, J=10.2Hz, 2H), 1.35 (ddd, J=23.3, 11.4, 3.7Hz, 3H);

[0577] LC / MS m / z C 19 H 22 ClN7(MH + The calculated value is 383.8, and the measured value is 384.6.

[0578] Compound 37. 1-(4-(2-(4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0579]

[0580] 1 HNMR (300MHz, CDCl3) δ7.83 (s, 1H) 7.56 (d, J = 3Hz, 1H) 7.54 (d, J = 3Hz, 1H) 7.51 (d, J = 3Hz, 1H) 7.40 (s, 1H) 7.27 (s, 1H) 7.24 (d, J = 3Hz, 1H) 4.88 ( d, J=6Hz, 1H) 4.50 (d, J=15Hz, 1H) 4.29-4.20 (m, 1H) 4.05-4.01 (m, 1H) 3 .34-3.24(m,1H)3.05-2.95(m,1H)2.23-2.04(m,2H)1.47-1.39(m,2H);

[0581] LC / MS m / z C 21 H 21 ClF3N7O(MH + Calculated value: 479.1; Measured value: 480.0.

[0582] Compound 38. N4-(1-benzylpiperidin-4-yl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0583]

[0584] 1 HNMR (300MHz, CDCl3) δ7.83 (s, 1H), 7.56 (d, J=3.0Hz, 1H), 7.54 (d, J=3.0Hz, 1 H), 7.51 (d, J=3.0Hz, 1H), 7.40 (s, 1H) 7.27 (s, 1H) 7.24 (d, J=3.0Hz, 1H), 4.88 (d, J=6.0Hz, 1H), 4.50 (d, J=15.1Hz, 1H), 4.29-4.20 (m, 1H), 4.05-4.01 (m, 1H ), 3.34-3.24(m, 1H), 3.05-2.95(m, 1H), 2.23-2.04(m, 2H), 1.47-1.39(m, 2H);

[0585] LC / MS m / z C 26 H 27 Cl2N7(MH + Calculated value: 508.5; Measured value: 509.2.

[0586] Compound 39. 1-(4-(2-(3-fluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0587]

[0588] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.84 (d, J = 11.5 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.15–7.09 (m, 1H), 6.81 (t, J = 8.3 Hz, 1H), 5.37 (d, J = 7.5 Hz, 1H) , 4.62 (d, J = 14.2Hz, 1H), 4.33 (s, 1H), 4.10 (d, J = 14.5Hz, 1H), 4.02 (s, 3H), 3.34 (t, J =13.0Hz, 1H), 3.01 (t, J = 12.9Hz, 1H), 2.25 (d, J = 14.9Hz, 2H), 1.51 (d, J = 11.6Hz, 3H).

[0589] Compound 40.N2-(4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0590]

[0591] 1 HNMR (300MHz, chloroform-d) δ7.80 (s, 1H), 7.61 (d, J=2.0Hz, 1H), 7.58 (d, J=2.1Hz, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.27 (d, J=1.6Hz, 1H), 7.25-7.19 (m, 2H), 4. 94 (d, J=7.4Hz, 1H), 4.06 (dtd, J=11.0, 7.1, 4.0Hz, 1H), 3.98 (s, 3H), 3.20- 3.06 (m, 2H), 2.84-2.69 (m, 2H), 2.07 (d, J=12.5Hz, 2H), 1.48-1.27 (m, 3H).

[0592] Compound 41. N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine

[0593]

[0594] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.88 (dt, J = 12.1, 2.3 Hz, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.25–7.15 (m, 2H), 7.09–7.01 (m, 1H), 6.67 (td, J = 8.2, 1.8 Hz, 1H). H), 4.97 (d, J = 7.5Hz, 1H), 4.19-4.03 (m, 1H), 3.98 (s, 3H), 3.13 (d, J = 12.6Hz, 2H), 2.80 (td, J=12.0, 2.5Hz, 2H), 2.11 (d, J=12.4Hz, 2H), 1.46-1.30 (m, 3H).

[0595] Compound 42. 5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(piperidin-4-yl)pyrimidin-2,4-diamine

[0596]

[0597] 1¹H NMR (300 MHz, chloroform-d) δ 7.80 (s, 1H), 7.67–7.60 (m, 2H), 7.54 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.12 (s, 1H), 6.99 (t, J = 7.4 Hz, 1H), 4.92 (d, J = 7.4 Hz, 1H), 4.10 (ddd, J = 10.8, 9.0, 5.4 Hz, 1H), 3.98 (s, 3H), 3.12 (d, J = 12.6 Hz, 2H), 2.84–2.70 (m, 2H), 2.09 (d, J = 10.2 Hz, 2H), 1.45–1.28 (m, 3H).

[0598] Compound 43. 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0599]

[0600] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.83 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 3.7 Hz, 2H), 7.23 (s, 1H), 6.93 (s, 1H), 4.87 (d, J = 7.4 Hz, 1H), 4.50 (d, J = 13.3 Hz, 1H) , 4.27 (dd, J=10.8, 4.1Hz, 2H), 4.05 (s, 1H), 3.97 (s, 3H), 3.29 (t, J=11.6Hz, 1 H), 3.07-2.94 (m, 1H), 2.37 (s, 3H), 2.20 (d, J=9.5Hz, 2H), 1.52-1.40 (m, 3H).

[0601] Compound 44. 1-(4-(2-(4-methoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0602]

[0603] 1HNMR (300MHz, chloroform-d) δ7.80 (s, 1H), 7.54-7.43 (m, 3H), 7.39 (s, 1H), 7.00 (s, 1H), 6.90-6.83 (m, 2H), 4.83 (d, J=7.2Hz, 1H), 4.49 (d, J=13.3H z, 1H), 4.28-4.18 (m, 1H), 3.97 (s, 4H), 3.81 (s, 3H), 3.33-3.21 (m, 1H), 2.98 (t, J=11.7Hz, 1H), 2.19 (d, J=13.5Hz, 2H), 1.56-1.35 (m, 2H).

[0604] Compound 45. 1-(4-(2-(3-chloro-4-methoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0605]

[0606] 1 HNMR (300MHz, chloroform-d) δ8.08 (d, J=2.6Hz, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.40 (d, J=3.7Hz, 2H), 7.10 (dd, J=8.8, 2.6Hz, 1H), 6.88 (d, J=8.9Hz, 1H), 4.90 (d, J=7.4Hz, 1H), 4.53 (d, J= 13.5Hz, 1H), 4.29 (dt, J=7.4, 4.0Hz, 1H), 4.03 (d, J=14.2Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3 H), 3.42-3.29 (m, 1H), 3.03 (t, J=11.9Hz, 1H), 2.23 (t, J=11.0Hz, 3H), 1.54-1.35 (m, 2H).

[0607] Compound 46. N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0608]

[0609] 1HNMR (300MHz, chloroform-d) δ7.79 (s, 1H), 7.54 (dd, J=3.2, 1.6Hz, 2H), 7.45-7.39 (m, 2H), 7.24 (d, J=8.7Hz, 1H), 6.90 (s, 1H), 4.93 (d, J=7.5Hz, 1H), 4.08 (d, J=7.5Hz, 1H), 3.98 (s, 3H), 3.12 (d, J=12.8Hz, 2H), 2.76 (t, J=10.7Hz, 2H), 2.38 (s, 3H), 2.07 (d, J=12.8Hz, 2H), 1.36 (dd, J=18.0, 5.7Hz, 3H).

[0610] Compound 47.N2-(4-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0611]

[0612] 1 HNMR (300MHz, chloroform-d) δ7.77 (s, 1H), 7.56-7.51 (m, 2H), 7.50 (d, J=2.2Hz, 1H ), 7.40 (s, 1H), 6.88 (d, J = 2.2Hz, 1H), 6.87-6.81 (m, 2H), 4.88 (d, J = 7.5Hz , 1H), 4.12-4.01 (m, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 3.11 (d, J=12.7Hz, 2H) , 2.81-2.69 (m, 2H), 2.07 (d, J=12.5Hz, 2H), 1.34 (td, J=11.9, 3.9Hz, 3H).

[0613] Compound 48. N2-(3-chloro-4-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0614]

[0615] 1¹H NMR (300 MHz, chloroform-d) δ 8.03 (d, J = 2.6 Hz, 1H), 7.78 (s, 1H), 7.56–7.52 (m, 1H), 7.41 (s, 1H), 7.19 (dd, J = 8.8, 2.7 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 8.9 Hz, 1H), 4.93 (d, J=7.7Hz, 1H), 4.18-4.04 (m, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.11 (d, J=12.7 Hz, 2H), 2.88-2.75 (m, 2H), 2.08 (d, J=9.9Hz, 2H), 1.35 (td, J=11.6, 4.0Hz, 3H).

[0616] Compound 49. 1-(4-(2-(p-toluidine)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0617]

[0618] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.87 (s, 1H), 7.55 (t, J = 1.7 Hz, 1H), 7.50 (dd, J = 2.9, 1.6 Hz, 2H), 7.46 (s, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.06 (s, 1H), 6.47 (dd, J = 1.8, 0.8 Hz, 1H), 4.87 (d, J = 7.1 Hz) , 1H), 4.51 (d, J=11.7Hz, 1H), 4.28 (dt, J=7.5, 3.9Hz, 1H), 4.03 (d, J=13.9Hz, 1H), 3.37-3 .23 (m, 1H), 3.02 (t, J=11.6Hz, 1H), 2.33 (s, 3H), 2.22 (d, J=8.1Hz, 2H), 1.55-1.38 (m, 2H).

[0619] Compound 50. 1-(4-(2-(m-toluidine)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0620]

[0621] 1¹H NMR (300 MHz, chloroform-d) δ 7.89 (s, ¹H), 7.55 (t, J = 1.7 Hz, ¹H), 7.53–7.50 (m, ¹H), 7.45–7.40 (m, 2H), 7.23–7.16 (m, ¹H), 7.04 (s, ¹H), 6.85 (d, J = 7.4 Hz, ¹H), 6.48 (dd, J = 1.8, 0.9 Hz, ¹H), 4.88 (d, J=7.3Hz, 1H), 4.50 (d, J=11.4Hz, 1H), 4.37-4.22 (m, 1H), 4.02 (d, J=14.4Hz, 1H), 3.39-3 .24 (m, 1H), 3.02 (t, J=11.6Hz, 1H), 2.36 (s, 3H), 2.23 (d, J=10.3Hz, 2H), 1.57-1.39 (m, 2H).

[0622] Compound 51. 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-(p-tolyl)pyrimidin-2,4-diamine

[0623]

[0624] 1 HNMR (300MHz, CDCl3) δ7.85 (s, 1H), 7.60-7.45 (m, 4H), 7.11 (d, J = 8.2Hz, 2H), 6.96 (s, 1H), 6.50 (s, 1H), 4.91 (d, J = 7.2Hz, 1H), 4. 12 (dd, J=7.0, 3.7Hz, 1H), 3.13 (d, J=12.6Hz, 2H), 2.78 (t, J=10.9Hz, 2H), 2.32 (s, 3H), 2.08 (t, J=9.7Hz, 2H), 1.48-1.29 (m, 3H).

[0625] Compound 52. 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-(m-tolyl)pyrimidin-2,4-diamine

[0626]

[0627] 1HNMR (300MHz, MeOH-d4) δ7.70 (s, 1H), 7.59 (s, 1H), 7.57-7.53 (m, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.07 (t, J=7.7Hz, 1H), 6.72 (d, J=7.2Hz, 1H), 6.4 9(d, J=1.0Hz, 1H), 4.17(t, J=12.9Hz, 1H), 3.27(d, J=12.9Hz, 2H), 2.90( t, J=11.4Hz, 2H), 2.24 (s, 4H), 2.13 (d, J=9.8Hz, 3H), 1.71-1.41 (m, 3H).

[0628] Compound 53. 1-(4-(2-(3-chlorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0629]

[0630] 1 HNMR (300MHz, CDCl3) δ8.17 (t, J=2.0Hz, 1H), 7.89 (s, 1H), 7.57 (t, J=1.6Hz, 1H), 7.53 (s, 1H), 7 .30 (s, 1H), 7.22 (t, J=8.0Hz, 1H), 7.09 (d, J=9.2Hz, 1H), 6.98 (d, J=7.8Hz, 1H), 6.48 (d, J=0.9Hz , 1H), 4.95 (d, J=7.4Hz, 1H), 4.55 (d, J=13.9Hz, 1H), 4.42-4.27 (m, 1H), 4.06 (d, J=16.9Hz, 1H), 3.37 (dd, J=19.1, 7.3Hz, 1H), 3.07 (t, J=11.9Hz, 1H), 2.27 (t, J=12.5Hz, 2H), 1.56-1.40 (m, 2H).

[0631] Compound 54. 1-(4-(2-(3-fluorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0632]

[0633] 1¹H NMR (300 MHz, chloroform-d) δ 7.96–7.89 (m, 2H), 7.59 (t, J = 1.6 Hz, 1H), 7.57–7.53 (m, 1H), 7.34 (s, 1H), 7.24 (dd, J = 8.1, 6.8 Hz, 1H), 7.06–6.99 (m, 1H), 6.72 (td, J = 8.3, 1.9 Hz, 1H), 6.53–6.49 (m, 1H) , 4.96 (d, J = 7.1Hz, 1H), 4.58 (d, J = 15.2Hz, 1H), 4.33 (dt, J = 7.4, 4.1Hz, 1H), 4.08 (d, J = 15.5Hz, 1H), 3.44-3.30 (m, 1H), 3.05 (t, J=12.0Hz, 1H), 2.30 (t, J=13.6Hz, 2H), 1.50 (d, J=11.9Hz, 2H).

[0634] Compound 55. N2-(3-fluorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine

[0635]

[0636] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.91–7.84 (m, 2H), 7.59–7.48 (m, 3H), 7.26–7.17 (m, 1H), 7.08–7.03 (m, 1H), 6.68 (td, J = 8.2, 2.2 Hz, 1H), 6.50 (dd, J = 1.7, 0.8 Hz, 1H), 5.01 (d, J = 7.4 Hz, 1H), 3.20 (d, J = 12.7 Hz, 3H), 2.92–2.79 (m, 2H), 2.19–2.10 (m, 2H), 1.53–1.43 (m, 2H), 0.95–0.80 (m, 1H).

[0637] Compound 56. N2-(3-chlorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidin-2,4-diamine

[0638]

[0639] 1HNMR (300MHz, CDCl3) δ8.12 (d, J=1.9Hz, 1H), 7.86 (s, 1H), 7.56 (dd, J=6.2, 4.5Hz, 2H ), 7.29 (s, 1H), 7.25-7.12 (m, 2H), 6.96 (dt, J=7.0, 2.0Hz, 1H), 6.50 (dd, J=1.7, 0.8H z, 1H), 4.99 (d, J=7.6Hz, 1H), 4.15 (ddd, J=13.8, 7.2, 3.1Hz, 1H), 3.19 (d, J=12.8Hz, 2H), 3.00-2.80 (m, 2H), 2.15 (d, J=15.2Hz, 2H), 1.56-1.35 (m, 3H), 0.92-0.79 (m, 2H).

[0640] Compound 57. 1-(4-(2-(3,5-dichlorophenylamino)-5-phenylpyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0641]

[0642] 1 HNMR (300MHz, chloroform-d) δ7.92 (s, 1H), 7.81 (s, 1H), 7.67 (d, J=1.9Hz, 2H), 7.51 (d, J=1.6Hz, 1H), 7.49 (q, J=1.4Hz, 1H), 7.46-7.42 (m, 1H), 7.38 (d, J=1.7Hz, 1H), 7.35 (d, J=1.3Hz, 1H), 7.01 (t, J=1.8H z, 1H), 4.99 (d, J=7.5Hz, 1H), 4.57 (d, J=13.7Hz, 1H), 4.37 (td, J=7.6, 6.7, 3.1Hz, 1H), 4.11-4.01 (m, 1H), 3.48-3.34 (m, 1H), 3.07 (t, J=12.4Hz, 1H), 2.27 (t, J=12.3Hz, 2H), 1.46 (q, J=12.1Hz, 2H);

[0643] LC / MS m / z C 23 H 20 Cl2F3N5O(MH + Calculated value: 508.5; Measured value: 509.2.

[0644] Compound 58. N2-(3,5-dichlorophenyl)-5-phenyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0645]

[0646] 1 HNMR (300MHz, chloroform-d) δ7.86 (s, 1H), 7.69 (d, J=1.8Hz, 2H), 7.62 (d, J=11.3Hz, 1H), 7.49 (dd, J=7.5, 3.0Hz, 2H), 7.45-7.35 (m, 3H), 6.98 (s, 1H), 5. 03(d, J=7.6Hz, 1H), 4.23-4.02(m, 1H), 3.94-3.75(m, 1H), 2.96-2.72(m , 2H), 2.11 (d, J=12.8Hz, 2H), 1.91 (d, J=11.7Hz, 2H), 1.43-1.31 (m, 2H);

[0647] LC / MS m / z C 21 H 21 Cl2N5(MH + Calculated value: 413.9, measured value: 415.0.

[0648] Compound 59. 1-(4-(2-(3,5-dichlorophenylamino)-5-(3-methoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0649]

[0650] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.90 (s, 1H), 7.64 (d, J = 1.8 Hz, 2H), 7.58 (s, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.99 (t, J = 1.7 Hz, 1H), 6.97–6.89 (m, 2H), 6.88–6.83 (m, 1H), 5.04 (d, J = 7.5 Hz, 1H). H), 4.54 (d, J=13.5Hz, 1H), 4.40-4.24 (m, 1H), 4.09-3.98 (m, 1H), 3.85 (s, 3H), 3.38 (t, J=12.1Hz, 1H), 3.05 (t, J=12.0Hz, 1H), 2.24 (t, J=11.0Hz, 2H), 1.44 (q, J=12.2Hz, 2H).

[0651] Compound 60.N2-(3,5-dichlorophenyl)-5-(3-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0652]

[0653] 1¹H NMR (300 MHz, chloroform-d) δ 7.85 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.47 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.96 (q, J = 1.6 Hz, 2H), 6.94–6.91 (m, 1H), 6.89 (t, J = 2.0 Hz, 1H), 5.08 (d, J = 7.6 Hz, 2H). Hz, 1H), 4.23-4.07 (m, 1H), 3.85 (s, 3H), 3.11 (d, J=12.7Hz, 2H), 2.85 (td, J=12.6, 12. 1, 2.6Hz, 2H), 2.10 (d, J=13.3Hz, 2H), 2.05-1.95 (m, 1H), 1.37 (td, J=11.7, 4.0Hz, 2H).

[0654] Compound 61. 1-(4-(2-(3,5-dichlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0655]

[0656] 1 HNMR (300MHz, chloroform-d) δ8.31 (s, 1H), 7.91 (s, 1H), 7.68 (d, J=1.8Hz, 2H), 7.02-6.96 (m, 2H), 6. 91 (dd, J=8.2, 1.9Hz, 1H), 6.84 (d, J=1.9Hz, 1H), 5.04 (d, J=7.5Hz, 1H), 4.61-4.52 (m, 1H), 4 .43-4.27 (m, 1H), 4.06 (d, J=14.3Hz, 1H), 3.95 (s, 3H), 3.92 (s, 4H), 3.63-3.53 (m, 1H), 3.46 -3.33 (m, 1H), 3.07 (t, J=12.9Hz, 1H), 2.27 (t, J=11.1Hz, 2H), 1.45 (q, J=12.3, 11.8Hz, 2H).

[0657] Compound 62.N2-(3,5-dichlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0658]

[0659] 1¹H NMR (300 MHz, chloroform-d) δ 7.84 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.45 (s, 1H), 6.98–6.94 (m, 2H), 6.91 (dd, J = 8.2, 2.0 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 5.03 (d, J = 7.6 Hz, 1H), 4.19-4.04 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.10 (d, J=12.7Hz, 2H), 2.91- 2.79 (m, 2H), 2.09 (d, J=12.5Hz, 2H), 1.80 (s, 1H), 1.35 (td, J=11.7, 4.0Hz, 2H).

[0660] Compound 63. 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0661]

[0662] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.85 (s, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.44 (dd, J = 8.6, 2.7 Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.94 (s, 1H), 6.87 (dd, J = 8.2, 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.90 (d, J = 7.3 Hz, 1H), 4.4 7 (d, J=13.7Hz, 1H), 4.27 (ddt, J=15.1, 11.0, 5.6Hz, 1H), 4.02 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.29 (t, J =11.8Hz, 1H), 3.01 (t, J = 12.1Hz, 1H), 2.38 (s, 3H), 2.20 (d, J = 13.0Hz, 2H), 1.70 (s, 1H), 1.47-1.37 (m, 2H).

[0663] Compound 64. 1-(4-(5-(3,4-dimethoxyphenyl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0664]

[0665] 1¹H NMR (300 MHz, chloroform-d) δ 7.83 (s, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 6.93 (t, J = 7.8 Hz, 2H), 6.90–6.87 (m, 2H), 6.85 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.86 (d, J = 7.3 Hz, 1H), 4.46 (d, J = 7.3 Hz, 1H). =13.7Hz, 1H), 4.31-4.16 (m, 1H), 3.99 (d, J = 14.5Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.81 (s, 3H), 3.3 3-3.22 (m, 1H), 2.99 (t, J=12.4Hz, 1H), 2.19 (d, J=13.5Hz, 2H), 1.75 (s, 1H), 1.42 (q, J=11.8Hz, 2H).

[0666] Compound 65. 1-(4-(5-(3,4-dimethoxyphenyl)-2-(2-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0667]

[0668] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.52–8.45 (m, ¹H), 7.88 (s, ¹H), 7.57 (s, ¹H), 7.00–6.86 (m, 5H), 6.82 (d, J = 1.9 Hz, ¹H), 4.89 (d, J = 7.2 Hz, ¹H), 4.49 (d, J = 13.7 Hz, ¹H), 4.34 (dd, J = 10 .8, 4.0Hz, 1H), 4.02 (d, J=14.6Hz, 1H), 3.92 (d, J=2.0Hz, 6H), 3.90 (s, 3H), 3.32 (t, J =12.9Hz, 1H), 3.04 (t, J = 12.6Hz, 1H), 2.22 (d, J = 10.8Hz, 2H), 1.46 (t, J = 11.9Hz, 2H).

[0669] Compound 66.N2-(3-methyl-4-chlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0670]

[0671] 1¹H NMR (300 MHz, chloroform-d) δ 7.81 (s, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 8.6, 2.7 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.10 (s, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.90 (dd, J = 8.1, 2.0 Hz, 1H), 6.84 ( d, J=1.9Hz, 1H), 4.97 (d, J=7.5Hz, 1H), 4.19-4.01 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.16 -3.06 (m, 2H), 2.85-2.72 (m, 2H), 2.38 (s, 3H), 2.08 (d, J=12.0Hz, 2H), 1.42-1.31 (m, 2H).

[0672] Compound 67. 5-(3,4-dimethoxyphenyl)-N2-(4-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0673]

[0674] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.80 (s, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 1.7 Hz, 1H), 6.88 (d, J = 2.1 Hz, 2H), 6.86 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.3 Hz, 2H). =1.9Hz, 1H), 4.92 (d, J = 7.5Hz, 1H), 4.17-3.99 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.81 (s, 3H), 3.10 (d, J=12.6Hz, 2H), 2.82-2.69 (m, 2H), 2.06 (d, J=12.7Hz, 3H), 1.38-1.28 (m, 2H).

[0675] Compound 68. 5-(3,4-dimethoxyphenyl)-N2-(2-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0676]

[0677] 1¹H NMR (300 MHz, chloroform-d) δ 8.61–8.51 (m, 1H), 7.85 (s, 1H), 7.57 (s, 1H), 6.97 (dd, J = 2.5, 1.7 Hz, 1H), 6.96–6.93 (m, 2H), 6.93–6.91 (m, 1H), 6.89 (q, J = 2.7 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H) H), 4.94 (d, J=7.4Hz, 1H), 4.26-4.12 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3. 16 (d, J=12.5Hz, 2H), 2.82 (t, J=10.9Hz, 2H), 2.14 (d, J=13.0Hz, 2H), 1.46-1.31 (m, 2H).

[0678] Compound 69. 1-(4-(2-(3-chlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0679]

[0680] 1 HNMR (300MHz, chloroform-d) δ8.14 (s, 1H), 7.83 (s, 1H), 7.19 (d, J=5.8Hz, 2H), 7.15 ( s, 1H), 6.96 (d, J = 8.1Hz, 2H), 6.91-6.86 (m, 1H), 6.81 (d, J = 1.9Hz, 1H), 5.00 (d, J=7.6Hz, 1H), 4.23-4.09 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.15 (d, J=12 .4Hz, 2H), 2.87 (t, J=11.7Hz, 2H), 2.12 (d, J=12.9Hz, 2H), 1.46-1.34 (m, 2H).

[0681] Compound 70. 1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0682]

[0683] 1HNMR (300MHz, chloroform-d) δ7.77 (d, J=7.9Hz, 1H), 7.57 (s, 2H), 7.51 (s, 1H), 7.45 (d, J=8.7Hz, 1H) , 7.15 (dd, J=9.2, 4.9Hz, 1H), 6.02 (t, J=8.8Hz, 1H), 4.75 (d, J=8.6Hz, 2H), 4.63-4.51 (m, 1H ), 4.30 (s, 1H), 4.06 (d, J = 15.0Hz, 1H), 3.99 (s, 3H), 3.89 (q, J = 6.3Hz, 2H), 3.48 (q, J = 7.0Hz , 1H), 3.25 (q, J=11.8, 11.2Hz, 1H), 3.00-2.89 (m, 3H), 2.36 (s, 1H), 2.17 (d, J=12.7Hz, 2H).

[0684] Compound 71. 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0685]

[0686] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.82 (s, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.58 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 6.99 (t, J = 1.9 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H), 4.56 (d, J = 13). 7Hz, 1H), 4.37-4.28 (m, 3H), 4.11-4.03 (m, 3H), 3.75 (s, 1H), 3.38 (t, J=13.2H z, 1H), 3.05 (t, J=12.8Hz, 1H), 2.25 (t, J=12.3Hz, 3H), 1.46 (q, J=12.1Hz, 2H).

[0687] Compound 72. 5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)-N2-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0688]

[0689] 1HNMR (300MHz, MeOH-d4) δ7.79 (s, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.3Hz, 2H), 7.51 (s, 1H), 7.19 (d, J = 8.4Hz, 1H), 4.32 (s, 2H), 3 .97 (s, 3H), 3.47 (d, J = 5.9Hz, 3H), 3.12-3.03 (m, 3H), 2.25 (d, J = 14.0Hz, 2H), 1.94 (d, J = 0.7Hz, 3H), 1.75 (d, J = 13.2Hz, 2H).

[0690] Compound 73. N2-(3,5-dichlorophenyl)-N4-(piperidin-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0691]

[0692] 1 HNMR (300MHz, MeOH-d4) δ7.85 (s, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 6.97 (d, J=1.9Hz, 1H), 4.42-4.29 (m, 1H), 4.29 -4.09 (m, 1H), 3.19 (dd, J=21.9, 13.0Hz, 4H), 2.83 (dt, J=22.5, 11.6Hz, 4H), 2.15 (t, J=13.1Hz, 3H), 2.09-1.94 (m, 3H), 1.63-1.43 (m, 3H).

[0693] Compound 74. N2-(3-chlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

[0694]

[0695] 1HNMR (300MHz, chloroform-d) δ8.13 (s, 1H), 7.82 (s, 1H), 7.20 (d, J=5.8Hz, 2H), 7.16 ( s, 1H), 6.97 (d, J = 8.1Hz, 2H), 6.92-6.88 (m, 1H), 6.84 (d, J = 1.9Hz, 1H), 5.00 (d, J=7.6Hz, 1H), 4.23-4.09 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.15 (d, J=12 .4Hz, 2H), 2.87 (t, J=11.7Hz, 2H), 2.12 (d, J=12.9Hz, 2H), 1.46-1.34 (m, 2H).

[0696] Compound 75. 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0697]

[0698] 1 HNMR (300MHz, MeOH-d4) δ7.81 (t, J=2.2Hz, 4H), 7.64 (s, 1H), 6.97 (d, J=1.8Hz, 1H), 4.31 (t, J=5.2Hz, 2H), 4.19 (d, J=10.9H z, 1H), 3.96 (t, J=5.2Hz, 2H), 3.12 (d, J=12.9Hz, 2H), 2.84 (dd, J=13.6, 11.0Hz, 2H), 2.11-1.99 (m, 2H), 1.59-1.40 (m, 3H).

[0699] Compound 76. 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0700]

[0701] 1¹H NMR (300 MHz, chloroform-d) δ 7.79 (d, J = 2.6 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.50–7.38 (m, 3H), 7.10 (t, J = 7.3 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 4.76 (d, J = 12.4 Hz, 2H), 4.49 (d, J = 13.3 Hz, 1H), 4.31 (t, J=4.8Hz, 3H), 4.06 (t, J=4.7Hz, 3H), 3.88 (dt, J=11.5, 6.0Hz, 2H), 3.31 (t, J=12.8 Hz, 1H), 3.03 (d, J=12.5Hz, 1H), 2.92 (q, J=6.3Hz, 2H), 2.20 (s, 2H), 1.44 (d, J=21.2Hz, 3H).

[0702] Compound 77. 1-(4-(2-(3-methyl-4-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0703]

[0704] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.81 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.42 (dd, J = 8.5, 2.7 Hz, 1H), 6.97 (s, 1H), 4.88 (d, J = 7.3 Hz, 1H), 4.49 (d, J = 13.8 Hz, 1H) ), 4.38-4.27(m, 2H), 4.25(d, J=4.1Hz, 1H), 4.11-4.03(m, 2H), 4.00(s, 1H), 3.29(t, J=13.0Hz, 1H), 3.00(t, J=12.8Hz, 1H), 2.37(s, 3H), 2.19(s, 2H), 1.56-1.35(m, 2H).

[0705] Compound 78. 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone

[0706]

[0707] 1¹H NMR (300 MHz, chloroform-d) δ 7.73 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.06 (s, 1H), 6.90–6.83 (m, 2H), 4.87 (d, J = 7.2 Hz, 1H), 4.49 (dd, J = 11.2, 6.7 Hz, 1H). H), 4.34-4.27 (m, 2H), 4.21 (dq, J=11.0, 6.8, 5.5Hz, 1H), 4.09-4.00 (m, 3H), 3.80 (s, 3H), 3.26 (ddd, J=14.4, 11.9, 2.7Hz, 2H), 2.96 (t, J=12.5Hz, 1H), 2.27-2.11 (m, 2H), 1.52-1.33 (m, 3H).

[0708] Compound 79. 2-(4-(4-(piperidin-4-ylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0709]

[0710] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.32–7.27 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 4.90 (d, J = 7.7 Hz, 1H), 4.30 (t, J=4.7Hz, 3H), 4.10 (d, J=7.1Hz, 1H), 4.05 (t, J=4.8Hz, 3H), 4.01 (s, 2H), 3.19-3.05(m, 5H), 2.80-2.70(m, 4H), 2.06(d, J=12.5Hz, 3H), 1.41-1.28(m, 5H).

[0711] Compound 80. 2-(4-(2-(3-methyl-4-chlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0712]

[0713] 1HNMR (300MHz, chloroform-d) δ7.73 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.51 (d, J=2.6Hz, 1H), 7.41 (dd, J=8 .6, 2.6Hz, 1H), 7.23 (d, J=8.6Hz, 1H), 7.14 (s, 1H), 4.94 (d, J=7.6Hz, 1H), 4.30 (dd, J=5.6, 4.0Hz , 2H), 4.09 (q, J=3.3Hz, 1H), 4.04 (dd, J=5.6, 4.0Hz, 2H), 3.08 (dt, J=12.7, 3.7Hz, 2H), 2.99-2.7 9 (m, 1H), 2.73 (td, J=12.4, 11.9, 2.6Hz, 3H), 2.36 (s, 3H), 2.10-1.99 (m, 2H), 1.41-1.26 (m, 3H).

[0714] Compound 81. 2-(4-(2-(4-methoxyphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0715]

[0716] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.51 (d, J = 2.1 Hz, 2H), 7.49 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 3.3 Hz, 2H), 6.85 (d, J = 2.2 Hz, 1H), 4.89 (d, J = 7.5 Hz, 1H), 4 .37-4.25(m, 2H), 4.09(s, 1H), 4.05(dd, J=5.5, 4.0Hz, 2H), 3.80(s, 3H), 3.12(d, J=12.8Hz, 2H), 2.76 (t, J=11.4Hz, 2H), 2.07 (d, J=13.3Hz, 3H), 1.43-1.29 (m, 3H).

[0717] Compound 82. 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0718]

[0719] 1¹H NMR (300 MHz, chloroform-d) δ 7.99 (s, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 7.52–7.46 (m, 2H), 7.32 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 7.23–7.14 (m, 2H), 6.98–6.92 (m, 1H), 6.83 (s, 1H), 4.72 (d, J = 14.2 Hz, 2H), 4.02 (s, 3H), 3.87 (dt, J = 12.8, 6.0 Hz, 3H), 2.94 (t, J = 5.3 Hz, 3H).

[0720] Compound 83. 1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0721]

[0722] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.97 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.45–7.34 (m, 3H), 7.33 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.78 (s, 1H), 4.71 (d, J = 20.2 Hz, 2H), 4.01 (s, 3H), 3.88 (dt, J = 12.4, 6.0 Hz, 2H), 2.94 (q, J = 5.5 Hz, 2H), 2.31 (d, J = 2.2 Hz, 3H).

[0723] Compound 84.N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0724]

[0725] 1HNMR (300MHz, chloroform-d) δ7.96 (s, 1H), 7.64 (s, 1H), 7.51 (d, J = 2.1Hz, 3H), 7.31 (d, J = 2.5Hz, 1H), 7.28 (d, J = 5.9Hz, 1H), 7.11 (d, J = 8.2Hz, 1H), 7. 03 (d, J=2.2Hz, 1H), 6.94 (t, J=1.9Hz, 1H), 6.76 (s, 1H), 4.01 (s, 3H), 3.96 (s, 2H), 3.13 (t, J=5.9Hz, 2H), 2.76 (t, J=6.0Hz, 2H), 1.73 (s, 1H).

[0726] Compound 85.N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0727]

[0728] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.94 (s, 1H), 7.62 (d, J = 0.9 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37 (dd, J = 8.6, 2.7 Hz, 1H), 7.33–7.28 (m, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7. 10 (d, J=2.4Hz, 1H), 7.07 (s, 1H), 7.04 (d, J=4.0Hz, 1H), 6.73 (s, 1H), 4.01 (s, 3H), 3 .95(s, 2H), 3.15(t, J=5.9Hz, 2H), 2.78(t, J=5.9Hz, 2H), 2.30(s, 3H), 1.70(s, 1H).

[0729] Compound 86.N-((1s,4s)-4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0730]

[0731] 1¹H NMR (300 MHz, chloroform-d) δ 7.83 (d, J = 2.9 Hz, 1H), 7.57 (s, 1H), 7.56–7.54 (m, 1H), 7.47 (s, 1H), 7.37 (ddd, J = 16.1, 8.2, 2.2 Hz, 1H), 7.19 (d, J = 21.2 Hz, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 5.06 (t, J =7.1Hz, 1H), 4.75 (d, J = 22.2Hz, 2H), 4.24-4.14 (m, 1H), 4.02-4.00 (m, 1H), 3.99 (s, 4H), 3.89 (t, J = 6. 1Hz, 1H), 3.85 (t, J=5.9Hz, 1H), 2.91 (dt, J=9.8, 6.0Hz, 2H), 1.96-1.83 (m, 5H), 1.69 (t, J=9.7Hz, 4H).

[0732] Compound 87. 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0733]

[0734] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.96 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.52–7.43 (m, 3H), 7.34 (dd, J = 19.8, 8.2 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J = 9.6 Hz, 2H), 6.94 (s, 1H) H), 6.85 (s, 1H), 4.71 (d, J=10.5Hz, 2H), 4.35 (t, J=4.7Hz, 2H), 4.10 (t, J=4.7 Hz, 2H), 3.85 (q, J=7.1, 5.8Hz, 2H), 3.41-3.04 (m, 1H), 2.94 (d, J=6.6Hz, 2H).

[0735] Compound 88.N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0736]

[0737] 1¹H NMR (300 MHz, chloroform-d) δ 7.79 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.48–7.41 (m, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.2, 2.3 Hz, 1H), 7.03 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 5.3 Hz, 1H), 6.35 (d, J = 7. 6Hz, 1H), 5.01 (d, J=6.9Hz, 1H), 4.19 (s, 1H), 4.01 (s, 2H), 3.98 (d, J=2.2Hz, 3H), 3.14 (t, J=5.9Hz , 2H), 2.75 (t, J=5.8Hz, 2H), 1.87 (q, J=13.0, 9.3Hz, 3H), 1.78-1.59 (m, 6H), 1.38 (d, J=5.8Hz, 1H).

[0738] Compound 89. 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0739]

[0740] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.92 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 1.8 Hz, 2H), 7.48–7.39 (m, 1H), 7.25 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.93 (t, J = 1.8 Hz, 2H). Hz, 1H), 6.78 (s, 1H), 4.32 (t, J=4.7Hz, 2H), 4.07 (t, J=4.7Hz, 2H), 3.91 (s, 2H), 3.1 2(t, J=5.9Hz, 2H), 2.76 (t, J=6.0Hz, 2H), 1.35-1.28 (m, 1H), 0.87 (d, J=7.3Hz, 1H).

[0741] Compound 90.N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0742]

[0743] 1HNMR (300MHz, chloroform-d) δ8.10 (d, J=2.4Hz, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.4 6 (s, 1H), 7.23 (s, 1H), 7.20 (d, J=4.0Hz, 1H), 7.18 (s, 1H), 6.96 (dt, J=6.8 , 2.2Hz, 1H), 6.29 (s, 1H), 5.06 (d, J=7.0Hz, 1H), 4.29-4.15 (m, 1H), 4.04 ( s, 1H), 4.00 (s, 3H), 1.94 (tt, J=13.0, 3.9Hz, 5H), 1.70 (d, J=14.9Hz, 4H).

[0744] Compound 91.N-((1s,4s)-4-(2-(3-acetylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0745]

[0746] 1 HNMR (300MHz, chloroform-d) δ8.40 (t, J=1.9Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=7.8Hz, 1H), 7.59 (s, 1H), 7.57 (d, J=1.6Hz, 1H), 7.55 (d, J=1.4Hz, 1H), 7.50 (s, 1H), 7.38 (t, J=7.9Hz, 1H), 6.38 (s, 1H), 5.10 (d, J=7.1Hz, 1H), 4.32 (s, 1H), 4.03 (s, 1H), 3.99 (s, 4H), 2.61 (s, 3H), 1.93 (q, J=4.1Hz, 4H), 1.77-1.55 (m, 5H).

[0747] Compound 92.N-((1s,4s)-4-(2-(m-toluidine)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0748]

[0749] 1HNMR (300MHz, chloroform-d) δ7.82 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=4.6Hz, 2H), 7.41 (d, J=8.1Hz, 1H), 7.19 (t, J=7.8Hz, 1H), 7.01 (s, 1H), 6.83 (d, J=7. 5Hz, 1H), 6.30 (s, 1H), 5.02 (d, J=6.9Hz, 1H), 4.21 (s, 1H), 3.99 (s, 3H), 2.36 (s, 3H), 1.90 (td, J=18.2, 15.7, 6.8Hz, 5H), 1.70 (d, J=9.1Hz, 4H).

[0750] Compound 93. 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0751]

[0752] 1 HNMR (300MHz, chloroform-d) δ7.92 (d, J=0.9Hz, 1H), 7.76 (t, J=1.9Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.39 (d, J=4.7Hz, 1H), 7.33 (d, J=2.1Hz, 1H), 7.29 (d, J=3.3Hz, 1H), 7.25-7.21 (m, 1H), 7.20-7.16 (m, 1H ), 7.13 (d, J=8.8Hz, 1H), 6.98 (dq, J=7.5, 1.8Hz, 1H), 6.84 (s, 1H), 4.69 (d, J=10.5Hz, 2H), 4.37-4 .31 (m, 2H), 4.12-4.06 (m, 2H), 3.88 (t, J = 6.0Hz, 1H), 3.83 (t, J = 5.9Hz, 1H), 2.92 (t, J = 5.8Hz, 2H).

[0753] Compound 94. 1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0754]

[0755] 1¹H NMR (300 MHz, chloroform-d) δ 7.95 (s, 1H), 7.68 (s, 2H), 7.64 (d, J = 2.7 Hz, 2H), 7.39 (t, J = 3.3 Hz, 1H), 7.26–7.19 (m, 2H), 7.15 (t, J = 8.3 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H) , 6.82 (s, 1H), 6.74-6.64 (m, 1H), 4.72 (d, J = 12.3Hz, 2H), 4.39-4.31 (m, 2H), 4. 13-4.07 (m, 2H), 3.87 (dd, J=13.6, 7.0Hz, 2H), 3.31-3.12 (m, 1H), 2.97 (s, 2H).

[0756] Compound 95.N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0757]

[0758] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.82 (s, 1H), 7.66–7.59 (m, 4H), 6.97 (s, 1H), 6.52 (s, 1H), 5.16 (d, J = 7.2 Hz, 1H), 4.40–4.31 (m, 2H), 4.24 (s, 1H), 4.08 (t, J = 4.7 Hz, 2H), 4.00 (s, 1H), 1.90 (dd, J = 10.5, 5.3 Hz, 5H), 1.70 (ddd, J = 14.0, 6.8, 4.3 Hz, 5H).

[0759] Compound 96.N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0760]

[0761] 1¹H NMR (300 MHz, chloroform-d) δ 7.72 (d, J = 3.8 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 2H), 7.51 (s, 1H), 7.37 (t, J = 9.2 Hz, 1H), 7.09 (t, J = 7.3 Hz, 1H), 6.92 (s, 1H), 5.34–5.22 (m, 1H), 4.74 (d, J = 3.8 Hz, 1H). =11.8Hz, 2H), 4.41-4.29 (m, 2H), 4.24 (s, 1H), 4.05 (d, J = 5.5Hz, 2H), 3.94 (s, 1H), 3.8 6 (dt, J=11.3, 6.1Hz, 2H), 2.92 (t, J=5.9Hz, 2H), 1.80 (s, 6H), 1.61 (d, J=10.6Hz, 2H).

[0762] Compound 97.N4-((1s,4s)-4-aminocyclohexyl)-N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0763]

[0764] 1 HNMR (300MHz, chloroform-d) δ8.09 (d, J=2.5Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.19 (d, J=6.4Hz, 2H), 7.11 (s, 1H), 6.94 (dt , J=6.2, 2.1Hz, 1H), 5.14 (d, J=7.3Hz, 1H), 4.19 (s, 1H), 3.98 (s, 3H), 3.02 (s, 1H), 1.80 (t, J=4.3Hz, 6H), 1.40 (d, J=10.3Hz, 4H).

[0765] Compound 98.N4-((1s,4s)-4-aminocyclohexyl)-N2-(3-acetylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0766]

[0767] 1HNMR (300MHz, chloroform-d) δ8.33 (t, J=1.9Hz, 1H), 7.84 (d, J=3.1Hz, 1H), 7.82-7.78 (m, 1H), 7 .57 (d, J=3.0Hz, 1H), 7.54 (t, J=1.3Hz, 1H), 7.46 (s, 2H), 7.38 (t, J=7.9Hz, 1H), 5.18 (d , J=7.4Hz, 1H), 4.24 (d, J=14.1Hz, 1H), 3.99 (s, 3H), 2.98 (d, J=7.6Hz, 1H), 2.61 (s, 3H) , 1.80 (dt, J=8.1, 4.6Hz, 5H), 1.73 (d, J=5.3Hz, 2H), 1.54 (s, 3H), 1.35 (t, J=6.9Hz, 2H).

[0768] Compound 99.N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine

[0769]

[0770] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.79 (s, 1H), 7.58–7.54 (m, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.10 (d , J=7.2Hz, 1H), 4.18 (d, J=6.1Hz, 1H), 3.98 (s, 3H), 3.02-2.89 (m, 1H), 2.35 (s, 3H), 1.80 (dd, J=12.5, 7.7Hz, 5H), 1.71 (q, J=3.8Hz, 2H), 1.48 (s, 2H), 1.44-1.30 (m, 3H).

[0771] Compound 100.N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0772]

[0773] 1¹H NMR (300 MHz, chloroform-d) δ 8.06 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.39 (s, 1H), 7.20 (dd, J = 4.1, 1.9 Hz, 2H), 7.00–6.93 (m, 1H), 6.68 (d, J = 7.5 Hz, 1H) ), 5.19 (d, J = 7.2Hz, 1H), 4.40-4.31 (m, 2H), 4.25 (s, 1H), 4.07 (t, J = 4.7Hz, 2H ), 3.99 (s, 1H), 3.36-2.93 (m, 1H), 1.89 (s, 4H), 1.72 (dd, J=14.6, 7.9Hz, 4H).

[0774] Compound 101. 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0775]

[0776] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.92 (s, ¹H), 7.75 (d, J = 2.1 Hz, ¹H), 7.65 (s, ¹H), 7.56 (s, ¹H), 7.32–7.27 (m, ¹H), 7.23 (d, J = 2.3 Hz, ¹H), 7.16 (t, J = 8.0 Hz, ¹H), 7.10–7.04 (m, 2H), 6.95 (ddd, J=8.0, 2.1, 1.0Hz, 1H), 6.75 (s, 1H), 4.31 (dd, J=5.4, 4.0Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 3.92 (s, 2H), 3.12 (t, J=5.9Hz, 2H), 2.76 (t, J=5.9Hz, 2H), 2.49-2.08 (m, 2H).

[0777] Compound 102. 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0778]

[0779] 1HNMR (300MHz, chloroform-d) δ7.95 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.20 (d, J = 9.0Hz, 3H), 7.07 (t, J = 8.9Hz, 3H), 6.74 ( s, 1H), 6.67 (t, J=7.3Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.05 (m, 2H), 3.97 (s, 2H), 3.15 (t, J=6.0Hz, 2H), 2.79 (t, J=6.0Hz, 2H).

[0780] Compound 103. 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0781]

[0782] 1 HNMR (300MHz, chloroform-d) δ7.85 (s, 1H), 7.78 (s, 1H), 7.65 (d, J = 1.9Hz, 2H), 7.55 (d, J = 0.9Hz, 1H), 7.31 (s, 1H), 6.94 (t, J = 1.8Hz, 1H), 5.34-5 .28 (m, 1H), 4.37-4.32 (m, 2H), 4.31 (s, 1H), 4.00-3.92 (m, 2H), 2.95 (d, J=9.6Hz, 1H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 4H), 1.26 (s, 2H).

[0783] Compound 104. 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0784]

[0785] 1¹H NMR (300 MHz, chloroform-d) δ 7.82 (d, J = 1.0 Hz, 1H), 7.76 (s, 1H), 7.53 (s, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 5.23 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 4.6 Hz, 3H) H), 4.00 (s, 2H), 3.98-3.91 (m, 2H), 3.13 (t, J=5.9Hz, 2H), 2.99-2.88 (m, 1H), 2.74 (t, J=6.0Hz, 2H), 1.80 (d, J=11.4Hz, 3H), 1.63 (t, J=13.2Hz, 4H), 1.26 (t, J=11.6Hz, 3H).

[0786] Compound 105. 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0787]

[0788] 1 HNMR (300MHz, chloroform-d) δ8.05 (t, J=2.0Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.55 (d, J=0.9Hz, 1 H), 7.24-7.22 (m, 1H), 7.18 (t, J=7.9Hz, 1H), 6.94 (dt, J=7.6, 1.6Hz, 1H), 5.28 (d, J=8.2H z, 1H), 4.34 (dd, J=5.3, 3.9Hz, 2H), 3.96 (dd, J=5.3, 3.9Hz, 2H), 2.96 (dt, J=9.6, 5.4Hz, 1 H), 2.77-2.50 (m, 2H), 1.89-1.75 (m, 2H), 1.74-1.60 (m, 4H), 1.26 (dd, J=9.0, 4.6Hz, 3H).

[0789] Compound 106.N-((1s,4s)-4-((2-((4-chloro-3-methylphenyl)amino)-5-(1-(2-hydroxyphenyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

[0790]

[0791] 1¹H NMR (300 MHz, chloroform-d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.40 (dd, J = 8.7, 2.7 Hz, 1H), 7.25 (s, 1H), 7.06 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5 .10(d, J=7.2Hz, 1H), 4.38-4.30(m, 2H), 4.23(d, J=6.6Hz, 1H), 4.12-4.03(m, 2H) , 3.96 (s, 1H), 2.36 (s, 3H), 1.91-1.79 (m, 4H), 1.76 (d, J=6.8Hz, 2H), 1.62 (s, 2H).

[0792] Compound 107. 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-methyl-4-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0793]

[0794] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.84 (s, 1H), 7.77 (s, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.40 (dd, J = 8.6, 2.7 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 5.26 (d, J = 8.3 Hz, 1H), 4.34 (dd, J=5.3, 3.9Hz, 2H), 4.31 (s, 1H), 4.00-3.90 (m, 2H), 2.94 (dt, J=10.0, 5.7 Hz, 1H), 2.36 (s, 3H), 1.89-1.76 (m, 3H), 1.64 (t, J=13.4Hz, 5H), 1.24 (d, J=10.9Hz, 3H).

[0795] Compound 108.N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0796]

[0797] 1¹H NMR (300 MHz, chloroform-d) δ 7.84 (s, ¹H), 7.63 (d, J = 1.8 Hz, ¹H), 7.58 (s, ¹H), 7.29 (s, ¹H), 6.98 (t, J = 1.8 Hz, ¹H), 6.32 (s, ¹H), 5.10 (d, J = 7.0 Hz, ¹H), 4.67 (d, J = 13.4 Hz, ¹H), 4.59-4 .42(m, 2H), 4.22(s, 1H), 3.99(s, 1H), 3.37(t, J=13.1Hz, 1H), 3.07(t, J=12.5Hz, 1H), 2 .34(d, J=13.0Hz, 2H), 2.22-2.08(m, 2H), 2.03-1.86(m, 5H), 1.82(s, 2H), 1.67(s, 2H).

[0798] Compound 109.N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0799]

[0800] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.82 (s, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.54 (s, 1H), 7.42 (s, 1H), 7.22 (s, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 4.92 (d, J = 7.7 Hz, 1H) , 4.03 (d, J = 3.9Hz, 1H), 3.99 (s, 3H), 3.84 (d, J = 10.8Hz, 1H), 2.24 (d, J = 12.6Hz, 2H ), 2.13 (d, J = 12.6Hz, 2H), 1.58 (s, 1H), 1.58-1.45 (m, 2H), 1.31 (d, J = 12.3Hz, 2H).

[0801] Compound 110.N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0802]

[0803] 1¹H NMR (300 MHz, chloroform-d) δ 7.80 (s, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 6.98 (t, J = 1.8 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.35-4 .28 (m, 2H), 4.07 (d, J = 4.7Hz, 2H), 4.05-3.94 (m, 1H), 3.83 (s, 1H), 2.24 (d, J = 12.8Hz, 2H), 2.13 (d, J=12.6Hz, 2H), 1.78-1.61 (m, 1H), 1.52 (q, J=12.4Hz, 3H), 1.36 (d, J=12.4Hz, 2H).

[0804] Compound 111.N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0805]

[0806] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.82 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.59 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 6.94 (t, J = 1.8 Hz, 1H), 5.19 (d, J = 7.3 Hz, 1H), 4.28 (tt, J = 11.8, 4.1 Hz, 1H) , 4.17 (s, 1H), 3.27 (d, J = 12.5Hz, 2H), 3.03 (s, 1H), 2.86-2.74 (m, 2H), 2.22 (d, J = 12. 3Hz, 2H), 1.94 (qd, J=12.1, 4.2Hz, 3H), 1.80 (d, J=3.6Hz, 6H), 1.44 (d, J=16.6Hz, 5H).

[0807] Compound 112.N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0808]

[0809] 1HNMR (300MHz, chloroform-d) δ7.80 (s, 1H), 7.64 (d, J=1.8Hz, 2H), 7.54 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.96 (t, J=1.8Hz, 1H), 4.91 (d, J=7.7Hz, 1H), 3.98 (s, 3 H), 3.94 (dd, J=7.5, 3.8Hz, 1H), 2.67 (td, J=10.9, 5.4Hz, 1H), 2.15 (d, J=12. 2Hz, 2H), 1.93 (d, J=12.8Hz, 2H), 1.47 (d, J=12.0Hz, 3H), 1.42-1.29 (m, 3H).

[0810] Compound 113. 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

[0811]

[0812] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.78 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.60 (s, 1H), 7.55 (s, 1H), 7.36 (s, 1H), 6.98 (d, J = 1.8 Hz, 1H), 4.93 (d, J = 7.7 Hz, 1H), 4.38–4.30 (m, 2H) , 4.13-4.07(m, 2H), 4.06-3.91(m, 1H), 2.68(td, J=10.7, 5.3Hz, 1H), 2.16(d, J= 12.2Hz, 2H), 1.94 (d, J=13.0Hz, 2H), 1.39 (q, J=12.1Hz, 3H), 1.30-1.15 (m, 3H).

[0813] Compound 114.N-((1r,4r)-4-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0814]

[0815] 1HNMR (300MHz, chloroform-d) δ7.79 (s, 1H), 7.52 (d, J = 0.9Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 2.2Hz, 1H), 7.27-7.23 (m, 2H), 6.45-6.34 (m, 1H), 4.90 (d .

[0816] Compound 115.N-((1r,4r)-4-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0817]

[0818] 1 HNMR (300MHz, chloroform-d) δ7.81 (s, 1H), 7.52 (d, J = 0.9Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 2.2Hz, 1H), 7.30-7.23 (m, 2H), 6.45-6.35 (m, 1H), 4.91 (d .

[0819] Compound 116.N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0820]

[0821] 1HNMR (300MHz, chloroform-d) δ7.80 (s, 1H), 7.54 (d, J = 0.9Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 2.2Hz, 1H), 7.29-7.25 (m, 2H), 6.47-6.36 (m, 1H), 4.92 (d .

[0822] Compound 117. 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-difluorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[0823]

[0824] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.77 (d, J = 1.0 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 6.46–6.36 (m, 1H), 4.91 (d, J = 1.0 Hz, 1H) 7.4Hz, 1H), 4.32 (t, J=4.7Hz, 2H), 4.07 (dd, J=5.4, 4.0Hz, 2H), 4.00-3.87 (m, 1H), 2 .71-2.60 (m, 1H), 2.16 (d, J=12.2Hz, 2H), 1.94 (d, J=12.5Hz, 3H), 1.40-1.13 (m, 6H).

[0825] Compound 118.N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0826]

[0827] 1¹H NMR (300 MHz, chloroform-d) δ 8.18 (s 1H), 7.82 (s 1H), 7.71 (s 1H), 7.52 (s 1H), 7.42 (s 1H), 7.40 (s 1H), 7.52 (s 1H), 4.90 (d, J = 6.0 Hz), 4.07 (m, 1H), 4.00 (s, 3H), 2.46 (m, 1H), 2.15 (m, 2H), 1.96 (m, 2H), 1.40 (m, 3H).

[0828] Compound 119.N-((1r,4r)-4-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0829]

[0830] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.20 (s 2H), 7.81 (s 1H), 7.60 (s 1H), 7.54 (s 1H), 7.45 (s 1H), 7.41 (s 1H), 4.91 (d, J = 6.0 Hz), 4.06 (m, 1H), 4.32 (m, 2H), 4.06 (m, 2H), 4.01 (m, 1H), 2.61 (m, 1H), 2.14 (m, 2H), 1.96 (m, 2H), 1.43 (m, 3H).

[0831] Compound 120.N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0832]

[0833] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.21 (s 1H), 7.84 (s 1H), 7.75 (s 1H), 7.57 (s 1H), 7.45 (s 1H), 7.42 (s 1H), 7.57 (s 1H), 4.91 (d, J = 6.0 Hz), 4.09 (m, 1H), 4.02 (s, 3H), 2.48 (m, 1H), 2.19 (m, 2H), 1.98 (m, 2H), 1.42 (m, 3H).

[0834] Compound 121. 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-bis(trifluoromethyl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[0835]

[0836] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.24 (s 2H), 7.82 (s 1H), 7.61 (s 1H), 7.56 (s 1H), 7.47 (s 1H), 7.42 (s 1H), 4.91 (d, J = 6.0 Hz), 4.09 (m, 1H), 4.34 (m, 2H), 4.08 (m, 2H), 4.02 (m, 1H), 2.62 (m, 1H), 2.15 (m, 2H), 1.98 (m, 2H), 1.42 (m, 3H).

[0837] Compound 122. 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

[0838]

[0839] 1 HNMR (300MHz, CDCl3) δ7.84 (s, 1H), 7.62 (d, J=1.8Hz, 2H), 7.58 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 6.9 9 (t, J=1.8Hz, 1H), 4.92 (d, J=7.5Hz, 1H), 4.62 (dd, J=25.6, 13.5Hz, 2H), 4.46 (dq, J=10.6, 5.4, 4.2Hz , 1H), 4.32 (dd, J=7.5, 3.9Hz, 1H), 4.20 (d, J=14.3Hz, 1H), 4.07 (d, J=14.2Hz, 1H), 3.38 (t, J=12.9Hz, 2H), 3.06 (q, J=11.7Hz, 2H), 2.28 (q, J=12.3, 10.7Hz, 4H), 2.20-2.06 (m, 2H), 1.47 (t, J=12.4Hz, 3H).

[0840] Compound 123. 1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0841]

[0842] 1 HNMR (300MHz, chloroform-d) δ7.98 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.35 (d, J=2.5Hz, 1H), 7.26 (dd, J=8.1, 2.2Hz, 1H), 7.20-7.13 (m, 3H), 6.8 7 (s, 1H), 6.47-6.39 (m, 1H), 4.75 (d, J=11.2Hz, 2H), 4.38 (dd, J=5.5, 4.0H z, 2H), 4.14-4.09 (m, 2H), 3.90 (dt, J=12.3, 5.9Hz, 2H), 3.03-2.92 (m, 4H).

[0843] Compound 124. 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0844]

[0845] 1 HNMR (300MHz, chloroform-d) δ8.06 (d, J=3.0Hz, 2H), 8.03 (s, 1H), 7.81 (d, J=13.9Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 7 .18-7.12 (m, 1H), 6.88 (s, 1H), 4.70 (d, J=15.3Hz, 2H), 4.43-4.33 (m, 2H), 4.17-4.08 (m, 2H), 3.94-3.82 (m, 2H), 2.95 (t, J=6.0Hz, 2H).

[0846] Compound 125. 1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0847]

[0848] 1HNMR (300MHz, chloroform-d) δ8.38-8.30 (m, 1H), 8.01 (d, J=1.8Hz, 1H), 7.69 (s, 1H) , 7.63 (s, 1H), 7.50 (s, 1H), 7.39 (d, J = 18.1Hz, 1H), 7.32 (d, J = 7.0Hz, 0H), 7 .18-7.15(m, 1H), 7.14-7.08(m, 1H), 4.71(d, J=14.2Hz, 2H), 4.40-4.33(m, 2H), 4.14-4.04 (m, 2H), 3.87 (dd, J=13.0, 6.4Hz, 2H), 2.95 (t, J=5.5Hz, 2H).

[0849] Compound 126. 1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone

[0850]

[0851] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.91 (d, J = 1.9 Hz, 1H), 7.69–7.64 (m, 2H), 7.63 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 12.5, 2.2 Hz, 1H), 7.34–7.28 (m, 1H), 7.25–7.17 (m, 1H), 7.13 (dd, J = 10.9, 2.7 Hz, 1H), 7.04 (t, J=7.9Hz, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 4.59 (d, J=14.3Hz, 2H), 4.37 (dd, J= 5.6, 4.0Hz, 2H), 4.15-4.08 (m, 2H), 3.91-3.80 (m, 2H), 2.90 (q, J=5.5Hz, 2H), 2.37 (s, 3H).

[0852] Compound 127. 2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol-1-ol

[0853]

[0854] 1HNMR (300MHz, chloroform-d) δ7.97 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.24-7.08 (m, 5H), 6.79 (s, 1H), 6.47-6.36 (m, 1H), 4.39-4.33 (m, 2H), 4.14-4.08 (m, 2H), 3.98 (s, 2H), 3.17 (t, J=5.9Hz, 2H), 2.81 (t, J=5.9Hz, 2H).

[0855] Compound 128. 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol-1-ol

[0856]

[0857] 1 HNMR (300MHz, chloroform-d) δ8.05 (d, J=1.5Hz, 2H), 8.00 (s, 1H), 7.69 (d, J=0.8Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.30 (d, J=2.2Hz, 1H), 7 .05(d, J=8.3Hz, 1H), 6.97(s, 1H), 6.79(s, 1H), 4.39-4.30(m, 2H), 4.12 -4.05 (m, 2H), 3.92 (s, 2H), 3.13 (t, J=6.0Hz, 2H), 2.76 (t, J=6.0Hz, 2H).

[0858] Compound 129. 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol-1-ol

[0859]

[0860] 1 HNMR (300MHz, chloroform-d) δ8.43-8.35 (m, 1H), 7.96 (s, 1H), 7.67 (d, J=0.8Hz, 1H), 7.60 (d, J=0.8Hz, 1H), 7.52 (s, 1H), 7.24-7.16 (m, 2H) , 7.14-7.03 (m, 3H), 6.80 (s, 1H), 4.36-4.27 (m, 2H), 4.13-4.03 (m, 2H), 3.95 (s, 2H), 3.15 (t, J=5.9Hz, 2H), 2.80 (t, J=6.0Hz, 2H).

[0861] Compound 130. 2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol-1-yl

[0862]

[0863] 1 HNMR (300MHz, chloroform-d) δ7.88 (s, 1H), 7.71 (d, J=7.8Hz, 1H), 7.64 (d, J=0.8Hz, 1H), 7.57 (d, J=0.8Hz, 1H), 7.21-7.07 (m, 4H), 6.96 (d, J=8.3Hz, 1H), 6.80(s, 1H), 6.75(s, 1H), 4.39-4.26(m, 2H), 4.09-4.02(m, 2H), 3 .85(s, 2H), 3.11(t, J=6.0Hz, 2H), 2.74(t, J=5.9Hz, 2H), 2.35(s, 3H).

[0864] Compound 131.N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0865]

[0866] 1 HNMR (300MHz, chloroform-d) δ7.99 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.24-7.09 (m, 6H), 6.80 (s, 1H), 6.41 (d, J=8.9Hz, 1H), 4.36-4 .27(m, 1H), 4.02(s, 2H), 3.35-3.25(m, 2H), 3.18(t, J=6.0Hz, 2H), 2.88-2.78(m, 4H), 2.29-2.22(m, 2H), 2.02-1.92(m, 2H).

[0867] Compound 132.N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0868]

[0869] 1¹H NMR (300 MHz, chloroform-d) δ 7.99 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.54 (d, J = 1.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 6.96 (t, J = 1.8 Hz, 2H) 1.8Hz, 1H), 6.81 (s, 1H), 4.39-4.26 (m, 1H), 4.00 (s, 2H), 3.30 (d, J=12.7Hz, 2H), 3 .17(t, J=6.0Hz, 2H), 2.87-2.76(m, 4H), 2.25(d, J=12.6Hz, 2H), 2.05-1.92(m, 2H).

[0870] Compound 133.N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0871]

[0872] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.10–8.06 (m, 2H), 8.03 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 (s , 1H), 6.82 (s, 1H), 4.38-4.27 (m, 1H), 3.99 (s, 2H), 3.31 (d, J=12.6Hz, 2H), 3.18 (t, J=6.0Hz, 2H), 2.89-2.77 (m, 4H), 2.26 (d, J=12.7Hz, 2H), 2.07-1.96 (m, 2H).

[0873] Compound 134.N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0874]

[0875] 1¹H NMR (300 MHz, chloroform-d) δ 8.47–8.40 (m, ¹H), 8.02 (s, ¹H), 7.69 (s, ¹H), 7.61 (s, ¹H), 7.55 (s, ¹H), 7.28–7.26 (m, ¹H), 7.24 (s, ¹H), 7.13 (d, J = 2.9 Hz, ¹H), 7.09 (d, J = 10 Hz). 1Hz, 2H), 6.83 (s, 1H), 4.40-4.29 (m, 1H), 4.00 (s, 2H), 3.32 (d, J=13.0Hz, 2H), 3. 19 (t, J=6.0Hz, 2H), 2.92-2.78 (m, 4H), 2.27 (d, J=12.5Hz, 2H), 2.05-1.97 (m, 2H).

[0876] Compound 135.N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0877]

[0878] 1 HNMR (300MHz, chloroform-d) δ7.95 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.24-7.18 (m, 1H), 7.03 (d, J=8.1Hz, 1H), 6.80 (d .

[0879] Compound 136.N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0880]

[0881] 1HNMR (300MHz, chloroform-d) δ 8.06 (s, 2H), 8.01 (s, 1H), 7.99 (s, 1H), 7.66 (d, J = 0.8Hz, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.26 (d, J =2.3Hz, 1H), 7.05 (d, J = 8.1Hz, 2H), 6.82 (s, 1H), 4.04 (s, 3H), 3.96 (s, 2H), 3.16 (t, J = 6.0Hz, 2H), 2.80 (t, J = 5.9Hz, 2H).

[0882] Compound 137.N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0883]

[0884] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.96 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.22–7.12 (m, 4H), 7.09 (d, J = 8.2 Hz, 1H), 6.77 (s, 1H), 6.43–6.34 (m, 1H), 4.01 (s, 3H), 3.98 (s, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H).

[0885] Compound 138. 1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one

[0886]

[0887] 1 HNMR (300MHz, CDCl3) δ7.99 (s, 1H), 7.65 (d, J=0.8Hz, 1H), 7.53 (d, J=3.3Hz, 2H), 7.25 (d, J=8.4Hz, 1H), 7.17-7.08 (m, 2H), 6.81 (t, J=2 .3Hz, 3H), 6.22-6.15 (m, 1H), 4.73 (d, J = 15.1Hz, 2H), 4.03 (s, 3H), 3.95-3.83 (m, 2H), 3.75 (s, 4H), 3.73 (s, 2H), 2.95 (d, J = 6.5Hz, 2H).

[0888] Compound 139. 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one

[0889]

[0890] 1 HNMR (300MHz, CDCl3) δ8.15 (d, J=11.8Hz, 1H), 8.06 (d, J=2.1Hz, 2H), 8.02 (s, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.1 8-7.15 (m, 1H), 7.13-7.07 (m, 1H), 6.88 (s, 1H), 4.68 (d, J=15.0Hz, 2H), 4.05 (s, 3H), 3.93-3.79 (m, 2H), 2.94 (t, J=5.9Hz, 2H).

[0891] Compound 140. 1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one

[0892]

[0893] 1 HNMR (300MHz, CDCl3) δ8.01 (s, 1H), 7.67 (s, 1H), 7.56 (s, 2H), 7.41-7.33 (m, 1H), 7.24 (dd, J=10.0, 7.9Hz, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.85 (d, J=2.7Hz, 1H), 6.47-6.37 (m, 1H), 4.75 (d, J=13.0Hz, 2H), 4.04 (s, 3H), 3.95-3.84 (m, 2H), 2.98 (t, J=5.5Hz, 2H).

[0894] Compound 141. N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0895]

[0896] 1¹H NMR (300 MHz, chloroform-d) δ 8.01 (s, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28–7.23 (m, 1H), 7.21–7.16 (m, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 6.47–6.38 (m, 1H), 4.75 (d, J = 12.5 Hz, 1H). Hz, 2H), 4.68 (s, 1H), 4.59-4.47 (m, 1H), 4.23 (d, J=14.4Hz, 1H), 3.96-3.85 (m, 2H), 3.41 (t, J=12. 7Hz, 1H), 3.10 (t, J=12.7Hz, 1H), 2.98 (t, J=5.4Hz, 2H), 2.38 (d, J=13.4Hz, 2H), 2.25-2.11 (m, 2H).

[0897] Compound 142.N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0898]

[0899] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.01 (s, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.51 (d, J = 5.0 Hz, 3H), 7.41–7.30 (m, 1H), 7.25–7.17 (m, 1H), 6.98 (s, 1H), 6.81 (s, 1H), 4.76 (s, 2H), 4.70 (d, J = 12). 3Hz, 1H), 4.60-4.46 (m, 1H), 4.23 (d, J=14.2Hz, 1H), 3.95-3.83 (m, 2H), 3.41 (t, J=12.5 Hz, 1H), 3.11 (t, J=12.7Hz, 1H), 2.96 (s, 2H), 2.38 (d, J=13.0Hz, 2H), 2.26-2.09 (m, 2H).

[0900] Compound 143.N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0901]

[0902] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.06 (s, 2H), 8.03 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.15 (t, J = 10.5 Hz, 1H), 6.81 (s, 1H), 4.73 (s, 2H), 4.68 (s, 1H), 4.60-4. 47 (m, 1H), 4.28-4.19 (m, 1H), 3.89 (dt, J=12.2, 5.8Hz, 2H), 3.42 (t, J=12.9Hz, 1H), 3. 11 (t, J=12.8Hz, 1H), 2.97 (d, J=6.2Hz, 2H), 2.39 (d, J=13.0Hz, 2H), 2.25-2.09 (m, 2H).

[0903] Compound 144. N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine

[0904]

[0905] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.34 (t, J = 5.2 Hz, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.39–7.30 (m, 1H), 7.20 (s, 1H), 7.18–7.11 (m, 2H), 6.82 (s, 1H), 4. 73 (d, J=15.1Hz, 3H), 4.60-4.47 (m, 1H), 4.24 (d, J=13.6Hz, 1H), 3.96-3.86 (m, 2H), 3.41 (t, J=13. 0Hz, 1H), 3.11 (t, J=12.8Hz, 1H), 2.98 (t, J=5.7Hz, 2H), 2.38 (d, J=12.8Hz, 2H), 2.24-2.11 (m, 2H).

[0906] Compound 145.N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0907]

[0908] 1 HNMR (300MHz, CDCl3) δ7.98 (s, 1H), 7.66 (d, J = 0.8Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 11.3Hz, 1H), 7.25 (d, J = 8.5Hz, 2H), 7.13 ( d, J=4.6Hz, 2H), 6.78 (s, 1H), 6.70 (d, J=8.1Hz, 1H), 4.03 (s, 3H), 4.00 (s, 2H), 3.17 (t, J=6.0Hz, 2H), 2.81 (t, J=6.0Hz, 2H).

[0909] Compound 146.N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0910]

[0911] 1 HNMR (300MHz, CDCl3) δ7.99 (s, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 7.31 (s, 1H), 7.26 (d, J = 2.3Hz, 1H), 7.12 (d, J = 2.2Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.80-6.74 (m, 2H), 4.03 (d, J=1.1Hz, 3H), 3.95 (s, 2H), 3.74 (d, J=2.6Hz, 3H), 3.20-3.11 (m, 2H), 2.83-2.74 (m, 2H).

[0912] Compound 147. 2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[0913]

[0914] 1HNMR (300MHz, CDCl3) δ7.98 (s, 1H), 7.71 (d, J = 0.8Hz, 1H), 7.64 (s, 2H), 7.48 (s, 1H), 7.44 (s, 1H), 7.26 (d, J = 7.1Hz, 2H), 7.18 (s, 1H), 7.15 (s, 1H) ), 7.12(s, 1H), 6.79(s, 1H), 6.73-6.67(m, 1H), 4.40-4.35(m, 2H), 4.17 -4.09 (m, 3H), 4.00 (s, 2H), 3.17 (t, J = 6.0Hz, 2H), 2.81 (t, J = 6.0Hz, 2H).

[0915] Compound 148. 2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[0916]

[0917] 1 HNMR (300MHz, CDCl3) δ7.97 (d, J=1.5Hz, 1H), 7.71-7.67 (m, 1H), 7.62 (d, J=0.9Hz, 1H), 7.52 ( d, J=8.6Hz, 1H), 7.36 (d, J=14.9Hz, 2H), 7.26 (s, 1H), 7.15-7.04 (m, 2H), 6.78 (d, J=6.4Hz, 2H ), 4.39-4.31 (m, 2H), 4.10 (t, J=4.8Hz, 2H), 3.95 (s, 1H), 3.75 (s, 3H), 3.72 (s, 1H), 3.68 (d, J =5.5Hz, 1H), 3.16 (t, J = 6.0Hz, 1H), 2.88 (s, 1H), 2.80 (t, J = 6.0Hz, 2H), 2.06 (d, J = 4.4Hz, 3H).

[0918] Compound 149.N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0919]

[0920] 1HNMR (300MHz, CDCl3) δ7.97 (s, 1H), 7.79 (t, J = 2.1Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.36-7.30 (m, 1H), 7.23 (d, J = 6.1Hz, 1H), 7.19 (s, 1H), 7.17-7.09 (m, 2H), 6.99-6.93 (m, 1H), 6.78 (s, 1H), 4.03 (s, 3H), 3.99 (s, 2H), 3.16 (t, J=6.0Hz, 2H), 2.80 (t, J=5.9Hz, 2H).

[0921] Compound 150.N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0922]

[0923] 1 HNMR (300MHz, CDCl3) δ7.96 (s, 1H), 7.71 (t, J=2.3Hz, 1H), 7.68-7.64 (m, 2H), 7.54 (d, J=0.8Hz, 1H), 7.26-7.19 (m, 3H), 7.09 (t, J=8.5Hz, 2H), 6.78 (s, 1H), 6.72-6.65 (m, 1H), 4.03 (s, 3H), 4.02 (d, J=3.8Hz, 2H), 3.19 (t, J=6.0Hz, 2H), 2.82 (t, J=6.0Hz, 2H).

[0924] Compound 151. 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

[0925]

[0926] 1HNMR (300MHz, CDCl3) δ7.98 (d, J=3.2Hz, 1H), 7.84 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.67 -7.63(m, 1H), 7.55-7.51(m, 1H), 7.42(d, J=4.7Hz, 1H), 7.37(d, J=7.5Hz, 1H), 7.25(d, J=7.3Hz, 2H), 7.12(d, J=2.2Hz, 1H), 7.08(d, J=8.2Hz, 1H), 6.82-6.76(m, 1H), 4.03(d , J=2.7Hz, 3H), 3.97 (s, 2H), 3.17 (t, J=6.0Hz, 2H), 2.91 (s, 1H), 2.80 (t, J=5.9Hz, 1H).

[0927] Compound 152.N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0928]

[0929] 1 HNMR (300MHz, CDCl3) δ7.96 (d, J=2.7Hz, 1H), 7.64 (dd, J=2.3, 0.8Hz, 1H), 7.55-7.48 (m, 1H), 7.34 -7.29 (m, 1H), 7.27 (d, J=2.5Hz, 1H), 7.25-7.22 (m, 1H), 7.22-7.20 (m, 1H), 7.20-7.14 (m, 2H), 7.1 4-7.11 (m, 1H), 7.11-7.03 (m, 1H), 6.76 (s, 1H), 6.62-6.56 (m, 1H), 4.02 (d, J=2.7Hz, 3H), 3.97 (s, 1H), 3.73 (d, J=2.2Hz, 3H), 3.70 (s, 1H), 3.17 (t, J=6.0Hz, 1H), 2.90 (s, 2H), 2.80 (t, J=5.9Hz, 1H).

[0930] Compound 153. 5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0931]

[0932] 1HNMR (300MHz, CDCl3) δ7.96 (s, 1H), 7.65 (d, J=0.8Hz, 1H), 7.61-7.54 (m, 2H), 7.52 (s, 1H), 7.36-7.30 (m, 1H), 7.25 (dd, J=11.3, 3.2Hz, 2H), 7.11 (s, 1H), 7.09-7.00 (m, 2H), 6.76 (s, 1H), 4.03 (s, 3H), 3.99 (s, 2H), 3.17 (t, J=6.0Hz, 2H), 2.80 (t, J=5.9Hz, 2H).

[0933] Compound 154.N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0934]

[0935] 1 HNMR (300MHz, CDCl3) δ7.91 (d, J=3.2Hz, 1H), 7.78-7.72 (m, 1H), 7.62 (d, J=0.8Hz, 1H), 7.51 -7.46 (m, 1H), 7.38-7.31 (m, 1H), 7.26 (d, J=2.4Hz, 1H), 7.24-7.18 (m, 2H), 7.15-7.06 (m, 1H) , 6.95 (d, J = 8.3Hz, 1H), 6.76 (d, J = 5.2Hz, 2H), 4.02 (s, 3H), 3.83 (s, 2H), 3.24 (p, J = 6.8Hz, 1H ), 3.13 (t, J = 5.9Hz, 2H), 2.75 (t, J = 5.8Hz, 2H), 1.28 (d, J = 2.1Hz, 3H), 1.25 (d, J = 1.9Hz, 3H).

[0936] Compound 155. 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine

[0937]

[0938] 1HNMR (300MHz, CDCl3) δ7.86 (s, 1H), 7.63 (s, 1H), 7.61 (d, J=0.8Hz, 1H), 7.56 (t, J=8.5Hz, 2H), 7.50-7.45 (m, 2H), 7.20 (d, J=8.4Hz, 1H), 7.16 (s, 1 H), 6.97 (d, J=8.2Hz, 1H), 6.69 (s, 1H), 5.56 (s, 1H), 4.71 (d, J=6.2Hz, 2H ), 4.01 (s, 3H), 3.89 (s, 2H), 3.14 (t, J = 6.0Hz, 2H), 2.76 (t, J = 6.0Hz, 2H).

[0939] Compound 156. 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(o-tolyl)pyrimidine-2,4-diamine

[0940]

[0941] 1 HNMR (300MHz, CDCl3) δ7.91 (d, J=1.9Hz, 1H), 7.85 (d, J=7.8Hz, 1H), 7.60 (d, J=2.3Hz, 1H), 7.48 (s, 1H), 7.34-7.28 (m, 1H), 7.21 (d, J=7.6Hz, 1H), 7.18-7.01 (m, 3H), 6.97 (d, J=8.4Hz, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 3.99 (d, J=1.9Hz, 3H), 3.93 (s, 2H), 2.82 (t, J=5.9Hz, 4H), 2.36-2.27 (m, 3H).

[0942] Compound 157.N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidin-2,4-diamine

[0943]

[0944] 1HNMR (300MHz, CDCl3) δ7.92 (d, J=2.5Hz, 1H), 7.62 (d, J=0.8Hz, 1H), 7.49 (s, 1H), 7.27-7.16 (m, 2H), 7.16-7.08 (m, 1H), 7.01 (t, J=8.0Hz, 2H), 6.92 (d, J=8.2Hz, 1H), 6.76 (s, 1H), 4.02 (s, 3H), 3.87 (s, 2H), 3.14 (t, J=6.0Hz, 2H), 2.75 (t, J=6.0Hz, 2H).

[0945] Compound 158. 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine

[0946]

[0947] 1 HNMR (300MHz, CDCl3) δ7.95 (d, J=2.0Hz, 1H), 7.64 (t, J=1.3Hz, 1H), 7.52 (s, 1H), 7. 44 (d, J=8.1Hz, 1H), 7.34 (d, J=14.4Hz, 2H), 7.23-7.16 (m, 2H), 7.07 (d, J=7.2Hz, 2H) , 6.85 (d, J=7.9Hz, 1H), 6.75 (s, 1H), 4.03 (s, 3H), 4.00 (d, J=10.5Hz, 2H), 3.17 (t, J =6.0Hz, 1H), 2.89 (d, J = 6.1Hz, 1H), 2.80 (t, J = 6.0Hz, 1H), 2.33 (s, 3H), 2.29 (s, 1H).

[0948] Compound 159.N2-(5-fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0949]

[0950] 1HNMR (300MHz, CDCl3) δ8.01-7.97 (m, 1H), 7.96 (s, 1H), 7.95 (t, J=2.2Hz, 1H), 7 .67-7.62 (m, 1H), 7.56-7.50 (m, 1H), 7.24 (s, 1H), 7.20 (dd, J=8.0, 2.2Hz, 1H), 7.14-7.05(m, 2H), 6.87(s, 1H), 6.79(s, 1H), 6.71-6.63(m, 1H), 4.02(s, 3H), 4 .00 (d, J=8.1Hz, 2H), 3.19 (t, J=6.0Hz, 1H), 2.83 (t, J=5.9Hz, 2H), 2.29 (s, 3H).

[0951] Compound 160.N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0952]

[0953] 1 HNMR (300MHz, CDCl3) δ7.96 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.50 (d, J=1.9Hz , 2H), 7.44 (s, 1H), 7.30-7.26 (m, 1H), 7.11 (d, J=8.2Hz, 1H), 7.07 (d, J=2.2Hz, 1 H), 6.93 (t, J=1.8Hz, 1H), 6.81 (s, 1H), 4.66-4.54 (m, 1H), 3.98 (s, 2H), 3.95-3 .89 (m, 1H), 3.15 (t, J=6.0Hz, 2H), 2.78 (t, J=6.0Hz, 3H), 1.59 (d, J=6.7Hz, 6H).

[0954] Compound 161.N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0955]

[0956] 1HNMR (300MHz, CDCl3) δ8.19 (d, J=7.8Hz, 1H), 8.10 (s, 2H), 7.97-7.90 (m, 1H ), 7.68-7.62(m, 1H), 7.58-7.52(m, 1H), 7.38(s, 1H), 7.26-7.21(m, 1H), 7.1 5-7.04(m, 1H), 7.00(d, J=8.6Hz, 1H), 6.81(d, J=9.9Hz, 1H), 4.64-4.50(m, 1H), 4.09 (s, 2H), 3.19 (d, J=6.3Hz, 2H), 2.86 (s, 2H), 1.60 (d, J=6.7Hz, 6H).

[0957] Compound 162.N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0958]

[0959] 1 HNMR (300MHz, CDCl3) δ7.93 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.53 (d, J=1.8Hz , 2H), 7.42 (s, 1H), 7.31-7.27 (m, 1H), 7.12 (d, J = 8.1Hz, 1H), 7.08 (d, J = 2.1Hz, 1 H), 6.97 (t, J=1.8Hz, 1H), 6.84 (s, 1H), 4.68-4.56 (m, 1H), 3.99 (s, 2H), 3.96-3 .91 (m, 1H), 3.21 (t, J=6.0Hz, 2H), 2.79 (t, J=6.0Hz, 3H), 1.61 (d, J=6.7Hz, 6H);

[0960] LC / MS[M+H] + 462.3.

[0961] Compound 163.N2-(3-chloro-5-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0962]

[0963] 1HNMR (300MHz, chloroform-d) δ7.99-7.87 (m, 1H), 7.75-7.60 (m, 2H), 7.57 (d, J=2.9H z, 1H), 7.48-7.39 (m, 1H), 7.31 (d, J=13.3Hz, 1H), 7.24 (s, 1H), 7.19-7.03 (m , 2H), 6.90-6.79 (m, 1H), 6.72-6.57 (m, 1H), 4.59 (p, J=6.7Hz, 2H), 4.11 (d, J=11.7Hz, 1H), 3.32-3.14 (m, 2H), 2.94-2.84 (m, 2H), 1.59 (d, J=6.7Hz, 6H).

[0964] Compound 164. 5-(1-isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0965]

[0966] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.04–7.94 (m, ¹H), 7.65 (d, J = 3.3 Hz, ¹H), 7.56 (s, ¹H), 7.50 (s, ¹H), 7.46–7.35 (m, ¹H), 7.30 (s, ¹H), 7.21 (d, J = 13.3 Hz, 2H), 7.05 (t, J=7.9Hz, 1H), 6.81(s, 1H), 6.74(d, J=5.6Hz, 1H), 4.65-4.53(m, 1H), 4.03(s , 1H), 3.73 (s, 2H), 3.71 (s, 2H), 2.87 (d, J=6.6Hz, 2H), 1.59 (d, J=6.7Hz, 6H).

[0967] Compound 165.N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0968]

[0969] 1¹H NMR (300 MHz, chloroform-d) δ 7.94 (d, J = 3.3 Hz, 1H), 7.67–7.61 (m, 1H), 7.59–7.52 (m, 1H), 7.46–7.31 (m, 2H), 7.24 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6 .83-6.75(m, 3H), 6.15(q, J=2.2Hz, 1H), 4.58(p, J=6.6Hz, 1H), 3.75(s, 2H), 3.69(d, J=4.5Hz, 6H), 2.89 (d, J=10.9Hz, 2H), 2.08-1.97 (m, 2H), 1.59 (dd, J=6.7, 2.5Hz, 6H).

[0970] Compound 166.N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0971]

[0972] 1 HNMR (300MHz, chloroform-d) δ7.92 (d, J=5.4Hz, 1H), 7.64 (d, J=2.7Hz, 1H), 7.54 (d, J=1.2Hz, 1H), 7.39 (d, J=7.5Hz, 2H), 7.18 (s, 2H), 7.14-7.0 3 (m, 2H), 6.79 (s, 1H), 6.65 (s, 1H), 4.58 (p, J=6.7Hz, 1H), 3.97-3.82 (m, 2H), 2.86 (d, J=5.2Hz, 2H), 2.24 (s, 6H), 1.59 (d, J=6.7Hz, 6H).

[0973] Compound 167.N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0974]

[0975] 1HNMR (300MHz, chloroform-d) δ7.96 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.30 (d, J = 8.6Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 7.9Hz, 2H), 7.11 (d, J = 8.1Hz, 1H), 6.95 (d, J=7.0Hz, 1H), 6.80 (s, 1H), 4.66-4.51 (m, 1H), 4.02 (s, 1H), 3.19 (t, J=6.1Hz, 2H), 2.93-2.76 (m, 2H), 1.60 (d, J=6.7Hz, 6H).

[0976] Compound 168. 5-(1-isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0977]

[0978] 1 HNMR (300MHz, chloroform-d) δ7.96-7.91 (m, 1H), 7.65 (d, J=0.9Hz, 1H), 7.55 (d, J=0.9Hz, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.25-6.97 (m, 5H), 6.81 (s, 1H), 6.56 (d, J=7.7Hz, 1H), 4.58 (p, J=6.7Hz, 1H), 3.96-3.80 (m, 2H), 3.75-3.63 (m, 3H), 2.88 (s, 2H), 1.59 (d, J=6.7Hz, 6H).

[0979] Compound 169. 5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine

[0980]

[0981] 1HNMR (300MHz, chloroform-d) δ7.94 (d, J=2.3Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=0.8Hz, 1H), 7.4 2 (d, J=6.6Hz, 1H), 7.33 (s, 2H), 7.18 (d, J=7.8Hz, 2H), 7.13 (d, J=8.1Hz, 2H), 7.05 (d , J=8.2Hz, 1H), 6.83 (d, J=7.7Hz, 1H), 6.77 (s, 1H), 4.58 (p, J=6.8Hz, 1H), 3.97 (s, 2 H), 3.16 (t, J=6.0Hz, 2H), 2.79 (t, J=5.8Hz, 2H), 2.30 (s, 3H), 1.59 (d, J=6.7Hz, 6H).

[0982] Compound 170. 5-(1-isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0983]

[0984] 1 HNMR (300MHz, chloroform-d) δ7.95 (d, J=2.1Hz, 1H), 7.67-7.64 (m, 1H), 7.60-7.54 (m, 3H), 7.30 (d, J=7.5Hz, 3H), 7.18 (d, J=23.3Hz, 3H), 7.08-7 .00 (m, 2H), 6.79 (s, 1H), 4.58 (dt, J=13.5, 6.8Hz, 1H), 3.98 (s, 2H), 3.16 (t, J=6.0Hz, 2H), 2.80 (t, J=6.1Hz, 2H), 1.59 (d, J=6.7Hz, 6H).

[0985] Compound 171.N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0986]

[0987] 1HNMR (300MHz, chloroform-d) δ7.97 (d, J=3.6Hz, 1H), 7.65 (s, 1H), 7.57-7.47 (m, 3 H), 7.31 (d, J=5.9Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=8.4Hz, 1H), 7.07 (s, 1H) , 6.93 (t, J=1.7Hz, 1H), 6.80 (s, 1H), 4.17 (t, J=7.3Hz, 2H), 3.99-3.78 (m , 2H), 2.87 (d, J=5.1Hz, 2H), 1.98 (q, J=7.3Hz, 4H), 0.99 (t, J=7.4Hz, 3H).

[0988] Compound 172.N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0989]

[0990] 1 ¹H NMR (300 MHz, chloroform-d) δ 8.12–7.98 (m, 2H), 7.72–7.65 (m, 1H), 7.65–7.57 (m, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 18.9 Hz, 1H), 7.30 (s, 1H), 7.25–7.19 (m, 2H). 1H), 7.11-7.01(m, 1H), 6.96(s, 1H), 6.84(d, J=7.8Hz, 1H), 4.27-4.15(m, 2H ), 3.98-3.75 (m, 2H), 2.88 (s, 2H), 2.10-1.86 (m, 4H), 0.99 (t, J=7.5Hz, 3H).

[0991] Compound 173.N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0992]

[0993] 1HNMR (300MHz, chloroform-d) δ7.94 (t, J=2.5Hz, 1H), 7.67-7.62 (m, 1H), 7.55 (d, J=3.3Hz, 1H), 7.33 (s, 1H), 7.27-7.04 (m, 5H), 6.84 (d, J=11 .3Hz, 1H), 6.46-6.29 (m, 1H), 4.18 (td, J=7.0, 2.7Hz, 2H), 4.00-3.73 (m, 3H), 2.90 (s, 2H), 1.97 (h, J=7.3Hz, 4H), 1.04-0.92 (m, 3H).

[0994] Compound 174.N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0995]

[0996] 1 HNMR (300MHz, CDCl3) δ7.97 (s, 1H), 7.65 (d, J=0.8Hz, 1H), 7.54-7.50 (m, 2 H), 7.41 (s, 1H), 7.32 (s, 1H), 7.25-7.16 (m, 2H), 7.05 (d, J=8.1Hz, 1H), 6.7 6 (d, J=11.0Hz, 2H), 4.17 (t, J=7.1Hz, 2H), 3.99 (s, 2H), 3.73 (s, 3H), 3.22 -3.14(m, 2H), 2.85-2.77(m, 2H), 2.05-1.90(m, 3H), 0.99(t, J=7.4Hz, 3H).

[0997] Compound 175.N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[0998]

[0999] 1¹H NMR (300 MHz, chloroform-d) δ 7.95 (s, 1H), 7.64 (d, J = 0.8 Hz, 2H), 7.54 (d, J = 0.9 Hz, 1H), 7.44 (dt, J = 11.4, 2.2 Hz, 1H), 7.25–7.19 (m, 2H), 7.15 (dd, J = 8.3, 2.3 Hz, 1H), 7.07 (d, J = 8 .2Hz, 1H), 6.80 (s, 1H), 6.66-6.59 (m, 1H), 4.17 (t, J=7.2Hz, 2H), 4.05 (s, 2H), 3.21 ( t, J=6.1Hz, 2H), 2.85 (t, J=5.8Hz, 2H), 1.97 (q, J=7.3Hz, 2H), 0.99 (t, J=7.4Hz, 3H).

[1000] Compound 176.N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1001]

[1002] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.94 (s, 1H), 7.63 (d, J = 0.8 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H) .2Hz, 2H), 6.76 (s, 1H), 6.15 (t, J=2.2Hz, 1H), 4.16 (t, J=7.1Hz, 2H), 3.99 (s, 2H), 3.69 (s, 6H), 3.19 (t, J=6.0Hz, 2H), 2.82 (t, J=5.9Hz, 2H), 2.00-1.93 (m, 2H), 0.99 (t, J=7.4Hz, 3H).

[1003] Compound 177.N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1004]

[1005] 1¹H NMR (300 MHz, chloroform-d) δ 7.93 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.40 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (s, 2H), 7.15 (s, 1H), 7.10–7.02 (m, 2H), 6.7 4(s, 1H), 6.66(s, 1H), 4.19-4.13(m, 2H), 3.96(s, 2H), 3.16(t, J=6.1Hz, 2H), 2 .79 (t, J=5.9Hz, 2H), 2.25 (s, 6H), 1.97 (q, J=7.3Hz, 2H), 0.99 (t, J=7.4Hz, 3H).

[1006] Compound 178.N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1007]

[1008] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.96 (s, 1H), 7.77 (t, J = 2.1 Hz, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.33–7.27 (m, 2H), 7.19 (d, J = 7.9 Hz, 1H), 7.16–7.07 (m, 3H) ), 6.98-6.93 (m, 1H), 6.77 (s, 1H), 4.17 (t, J=7.2Hz, 2H), 3.98 (s, 2H), 3.15 (t, J =5.9Hz, 2H), 2.79 (t, J = 5.8Hz, 2H), 1.98 (q, J = 7.4Hz, 2H), 0.99 (t, J = 7.4Hz, 3H).

[1009] Compound 179.N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1010]

[1011] 1HNMR (300MHz, CDCl3) δ7.97 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.54-7.48 (m, 3H), 7.29 (d, J=2.3Hz, 1H), 7.11 (d, J=8.2Hz, 1H), 7.06 (d, J=2.2Hz, 1H), 6.93 (t, J=1.8Hz, 1H), 6.80 (s, 1H), 4.00 (d, J=7.2Hz, 2H), 3.97 (s, 2H), 3.15 (t, J =5.9Hz, 3H), 2.78 (t, J = 6.0Hz, 2H), 2.34-2.23 (m, 1H), 0.97 (d, J = 6.7Hz, 6H);

[1012] LC / MS[M+H] + 509.2.

[1013] Compound 180.N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1014]

[1015] 1 HNMR (300MHz, chloroform-d) δ8.12 (s, 1H), 8.10-7.99 (m, 2H), 7.96 (s, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.52 (d, J = 2.9Hz, 1H), 7.40 (d, J = 16.8Hz, 2H), 7.1 -6.95 (m, 2H), 6.82 (d, J = 9.1Hz, 1H), 4.14 (s, 2H), 4.01 (d, J = 7.2Hz, 2H), 3.21 (s, 2H), 2.88 (s, 2H), 2.33-2.24 (m, 1H), 0.98 (d, J = 6.7Hz, 6H);

[1016] LC / MS[M+H] + 576.3.

[1017] Compound 181.N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1018]

[1019] 1¹H NMR (300 MHz, chloroform-d) δ 7.92 (s, 1H), 7.65–7.59 (m, 1H), 7.51 (d, J = 5.6 Hz, 2H), 7.23–7.08 (m, 5H), 7.01 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 10.3 Hz, 1H). Hz, 1H), 6.32 (t, J=9.3Hz, 1H), 4.25 (s, 2H), 4.01-3.96 (m, 2H), 3.26 (d, J=6.4 Hz, 2H), 2.93 (d, J=6.9Hz, 2H), 2.31-2.23 (m, 1H), 0.96 (dd, J=6.7, 2.7Hz, 6H);

[1020] LC / MS[M+H] + 476.1.

[1021] Compound 182.N2-(3-chloro-5-fluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1022]

[1023] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.99 (d, J = 4.8 Hz, 1H), 7.92 (d, J = 7.4 Hz, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.51 (s, 2H), 7.40 (d, J = 10.4 Hz, 2H), 7.24–7.09 (m, 3H), 7.04 (s, 1H) , 6.80 (s, 1H), 6.65-6.57 (m, 1H), 4.15 (s, 2H), 3.99 (d, J=7.2Hz, 2H), 3.28 (d, J =6.1Hz, 2H), 2.92 (d, J = 16.4Hz, 2H), 2.31-2.23 (m, 1H), 0.96 (d, J = 6.6Hz, 6H);

[1024] LC / MS[M+H] + 493.1.

[1025] Compound 183. 5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1026]

[1027] 1HNMR (300MHz, chloroform-d) δ7.97 (s, 1H), 7.65 (s, 1H), 7.51 (d, J = 2.4Hz, 3H), 7.31 (s, 1H), 7.20 (d, J = 8.3Hz, 2H), 7.04 (d, J = 8.2Hz, 1H), 6.78 (s, 1H), 6. 74 (s, 1H), 4.00 (d, J = 7.0Hz, 4H), 3.72 (d, J = 4.5Hz, 3H), 3.17 (t, J = 6.1H z, 2H), 2.82 (q, J=6.6, 5.9Hz, 2H), 2.32-2.24 (m, 1H), 1.00-0.94 (m, 6H);

[1028] LC / MS[M+H] + 538.2.

[1029] Compound 184.N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1030]

[1031] 1 HNMR (300MHz, chloroform-d) δ7.95 (d, J=1.7Hz, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.30 (d, J=2.1Hz, 1H), 7.24-7.07 (m, 3H), 7.04 (d, J=8.1Hz, 1H), 6.83-6.69 (m, 3 H), 6.15 (t, J=2.1Hz, 1H), 4.04-3.95 (m, 4H), 3.69 (s, 6H), 3.18 (t, J=6.0Hz , 2H), 2.82 (q, J=7.8, 6.1Hz, 2H), 2.32-2.23 (m, 1H), 0.97 (d, J=6.7Hz, 6H);

[1032] LC / MS[M+H] + 500.1.

[1033] Compound 185.N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1034]

[1035] 1HNMR (300MHz, chloroform-d) δ7.93 (d, J=1.71Hz, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.3 6 (d, J=2.1Hz, 1H), 7.26-7.11 (m, 3H), 7.05 (d, J=8.1Hz, 1H), 6.81-6.64 (m, 3H), 6.14 (t, J=2.1Hz, 1H), 4.01-3.92 (m, 4H), 3.18 (t, J=6.0Hz, 2H), 2.82 ( q, J=7.8, 6.1Hz, 2H), 2.32-2.23 (m, 1H), 2.15 (s, 6H), 0.97 (d, J=6.7Hz, 6H);

[1036] LC / MS[M+H] + 468.1

[1037] Compound 186.N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1038]

[1039] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.96 (d, J = 1.6 Hz, 1H), 7.76 (t, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.33–7.27 (m, 1H), 7.24 (s, 1H), 7.17 (dd, J = 9.4, 6.6 Hz, 3H) , 7.09 (d, J=8.3Hz, 1H), 6.98-6.91 (m, 1H), 6.77 (s, 1H), 4.03-3.94 (m, 4H), 3.17 ( t, J=5.9Hz, 2H), 2.80 (t, J=5.9Hz, 2H), 2.33-2.23 (m, 1H), 0.97 (d, J=6.7Hz, 6H);

[1040] LC / MS[M+H] + 474.6.

[1041] Compound 187. 5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1042]

[1043] 1HNMR (300MHz, chloroform-d) δ7.95 (d, J=2.2Hz, 1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.33-7.27 (m, 1H), 7.25-7.12 (m, 4H), 7.09-7.01 (m, 2H), 6.76 (s, 1H), 6 .56 (d, J=8.0Hz, 1H), 4.03-3.93 (m, 4H), 3.73-3.66 (m, 3H), 3.17 (t, J=6 .1Hz, 2H), 2.91-2.77(m, 2H), 2.30-2.23(m, 1H), 0.97(d, J=6.7Hz, 6H);

[1044] LC / MS[M+H] + 467.1.

[1045] Compound 188. 5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine

[1046]

[1047] 1 HNMR (300MHz, chloroform-d) δ7.95 (s, 1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.33 (s, 2H), 7.18 (d, J=6.1Hz, 2H), 7.05 (d, J=7.8Hz, 2H), 6.83 (d, J=7.4Hz, 1H), 6.75(s, 1H), 4.02-3.96(m, 4H), 3.16(t, J=6.0Hz, 2H), 2.79( t, J=6.0Hz, 2H), 2.30 (s, 3H), 2.26 (d, J=6.4Hz, 1H), 0.97 (d, J=6.7Hz, 6H);

[1048] LC / MS[M+H] + 454.7.

[1049] Compound 189. 5-(1-isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1050]

[1051] 1HNMR (300MHz, chloroform-d) δ7.96 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 8.1Hz, 2H), 7.50 (s, 1H), 7.31 (d, J = 7.5Hz, 3H), 7.21 (d, J = 8.2Hz, 1H), 7.03 (q, J=7.8Hz, 3H), 6.76 (s, 1H), 4.00 (d, J=7.5Hz, 4H), 3.16 (t, J=5.9Hz, 2H), 2.79 (t, J=5.9Hz, 2H), 2.32-2.24 (m, 1H), 0.98 (d, J=6.7Hz, 6H);

[1052] LC / MS[M+H] + 454.7.

[1053] Compound 190.N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1054]

[1055] 1 HNMR (300MHz, chloroform-d) δ8.42-8.36 (m, 1H), 8.00 (s, 1H), 7.66 (d, J=0.8Hz, 1H), 7.52 (s, 2H), 7.22 (d, J=2.3Hz, 1H), 7.18-7.04 (m , 4H), 6.82 (s, 1H), 4.05-3.97 (m, 4H), 3.22 (t, J=6.0Hz, 2H), 2.87 (t, J=6.0Hz, 2H), 2.34-2.22 (m, 1H), 0.98 (d, J=6.7Hz, 6H);

[1056] LC / MS[M+H] + 509.1.

[1057] Compound 191.N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1058]

[1059] 1¹H NMR (300 MHz, chloroform-d) δ 8.30–8.14 (m, 1H), 8.00 (d, J = 3.4 Hz, 1H), 7.68 (d, J = 6.2 Hz, 1H), 7.55 (d, J = 10.4 Hz, 1H), 7.26 (d, J = 5.3 Hz, 2H), 7.20–7.09 (m, 2H), 7.05–6.92 (m, 1H), 6.80 (s, 1H), 6.56 (t, J=8.3Hz, 1H), 4.10 (s, 1H), 4.05-3.96 (m, 3H), 3.35 -3.20 (m, 2H), 2.96-2.85 (m, 2H), 2.33-2.25 (m, 1H), 0.98 (dd, J=6.7, 1.1Hz, 6H);

[1060] LC / MS[M+H] + 476.1.

[1061] Compound 192. 5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine

[1062]

[1063] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.92 (s, 1H), 7.76–7.70 (m, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.37–7.31 (m, 1H), 7.24–7.16 (m, 3H), 7.06 (dd, J = 8.3, 2.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 4.8Hz, 2H), 4.00 (d, J=7.3Hz, 3H), 3.82 (s, 2H), 3.21 (q, J=6.9Hz, 1H), 3.13 (t, J=6.0Hz, 3 H), 2.74 (t, J=5.9Hz, 2H), 2.32-2.22 (m, 1H), 1.24 (d, J=6.9Hz, 6H), 0.98 (d, J=6.7Hz, 6H);

[1064] LC / MS[M+H] + 482.5.

[1065] Compound 193. 2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1066]

[1067] 1 ¹H NMR (300 MHz, chloroform-d) δ 7.91 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 2.2 Hz, 2H), 6.77 (s, 1H) , 6.17 (t, J=2.2Hz, 1H), 4.33 (t, J=4.7Hz, 2H), 4.08 (t, J=4.7Hz, 2H), 3.94 (s , 2H), 3.71 (s, 6H), 3.17 (t, J=6.0Hz, 2H), 3.01 (s, 1H), 2.80 (t, J=5.9Hz, 2H);

[1068] LC / MS[M+H] + 488.2.

[1069] Compound 194. 2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1070]

[1071] 1 HNMR (300MHz, chloroform-d) δ7.95 (s, 1H), 7.68 (d, J = 0.8Hz, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.3Hz, 1H), 7.20 (d, J = 1.5Hz, 2H), 7.08 (d, J = 7.7Hz, 2H), 6.98 (s, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 4.38-4.31 (m, 2H), 4.13-4.07 (m, 2H) , 3.97 (s, 2H), 3.17 (t, J=6.0Hz, 2H), 2.81 (t, J=5.9Hz, 2H), 2.28 (s, 6H);

[1072] LC / MS[M+H] + 456.3.

[1073] Compound 195. 2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1074]

[1075] 1 HNMR (300MHz, chloroform-d) δ7.86 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=5.7Hz, 2H), 7.22 (d, J=2.2Hz, 1H), 7.15-7.09 (m, 2H), 7.03 (d, J=7.6Hz, 1H), 6.94 (d, J=8.3Hz , 1H), 6.78 (d, J=10.5Hz, 2H), 4.36-4.31 (m, 2H), 4.11-4.06 (m, 2H), 3.85 (s, 2H), 3.15 (t, J=6.0Hz, 2H), 2.77 (t, J=6.0Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H);

[1076] LC / MS[M+H] + 456.2.

[1077] Compound 196. 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1078]

[1079] 1 HNMR (300MHz, chloroform-d) δ7.95 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.5Hz, 1H), 7.18 (t, J = 8.0Hz, 2H), 7.09 (d, J = 7.3Hz, 3 H), 6.96 (d, J=7.9Hz, 1H), 6.75 (s, 1H), 4.38-4.32 (m, 2H), 4.09 (t, J=4.8Hz, 2H), 3.96 (s, 2H), 3.14 (t, J=5.9Hz, 2H), 2.78 (t, J=6.0Hz, 2H).

[1080] Compound 197. 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1081]

[1082] 1HNMR (300MHz, chloroform-d) δ7.93 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.31 (m, 1H), 7.16 (m, 1H), 7.07 (m, 2H), 6.9 3 (m, 1H), 6.78 (s, 1H), 4.36 (m, 2H), 4.08 (t, J = 4.8Hz, 2H), 3.95 (s, 2H), 3.15 (t, J = 5.9Hz, 2H), 2.78 (t, J = 6.0Hz, 2H);

[1083] LC / MS[M+H] + 496.51.

[1084] Compound 198.N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine

[1085]

[1086] 1 HNMR (300MHz, CDCl3) δ7.97 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.24-7.20 (m, 2H), 7.19-7.14 (m, 2H), 6.80 (s, 1H) ;

[1087] LC / MS(ESI) m / z 462.0 [M+H] + .

[1088] Compound 199.N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine

[1089]

[1090] 1HNMR (300MHz, CDCl3) δ7.99 (s, 1H), 7.66 (s, 1H), 7.61-7.53 (m, 3H), 7.44 (d, J = 8.2Hz, 2H), 7.24 (d, J = 6.1Hz, 2H), 6.98 (s, 1H), 6.85 (s, 1H), 4.03 (s, 3H), 3.27 (d, J=11.9Hz, 2H), 2.80 (t, J=12.0Hz, 2H), 2.65 (t, J=12.0Hz, 1H), 1.95-1.82 (m, 2H), 1.79-1.58 (m, 3H);

[1091] LC / MS(ESI) m / z 495.0 [M+H] + .

[1092] Compound 200.N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine

[1093]

[1094] 1 HNMR (300MHz, CDCl3) δ7.97 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.45 (t, J= 2.1Hz, 1H), 7.43-7.39 (m, 2H), 7.32 (s, 1H), 7.25 (s, 1H), 7.23 (s, 2H), 6.8 1(s, 1H), 6.70-6.66(m, 1H), 4.01(s, 3H), 3.21(d, J=11.9Hz, 2H), 2.83-2 .70(m, 2H), 2.69-2.56(m, 1H), 1.85(d, J=12.1Hz, 2H), 1.70-1.58(m, 3H);

[1095] LC / MS(ESI) m / z 478 [M+H] + .

[1096] Compound 201. 2-(4-(2-(3,5-dichlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1097]

[1098] 1HNMR (300MHz, MeOH-d4) δ7.98 (s, 1H), 7.92 (s, 1H), 7.70 (d, J=11.8Hz, 2H), 7.61-7.45 (m, 3H), 7.44-7.24 (m, 3H), 6.97-6.91 (m, 1H), 4 .33 (t, J=5.2Hz, 2H), 3.99 (t, J=5.3Hz, 2H), 3.65-3.59 (m, 1H), 3.58-3.54 (m, 1H), 3.09 (s, 1H), 2.18-2.04 (m, 2H), 1.93-1.80 (m, 3H);

[1099] LC / MS(ESI) m / z 525.0 [M+H] + .

[1100] Compound 202.N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidin-2,4-diamine

[1101]

[1102] 1 HNMR (300MHz, CDCl3) δ8.08 (s, 2H), 8.01 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.45 (d, J = 6.5Hz, 2H), 7.40 (d, J = 8.3Hz, 2H), 7.19 (d, J = 8.3Hz, 2 H), 6.85 (s, 1H), 4.02 (s, 3H), 3.28 (d, J = 12.2Hz, 2H), 2.81 (t, J = 12.1Hz, 2H), 2.69-2.57 (m, 1H), 1.88 (d, J = 12.9Hz, 2H), 1.79-1.67 (m, 2H);

[1103] LC / MS(ESI) m / z 562.0 [M+H] + .

[1104] Compound 203.N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine

[1105]

[1106] 1HNMR (300MHz, CDCl3) δ7.95 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.48-7.35 (m, 3H), 7.23 (s, 1H), 7.21-7.11 (m, 1H), 6.85 (s, 1H), 6. 77 (s, 1H), 4.35 (t, J=7.0Hz, 1H), 4.01 (s, 3H), 3.87 (t, J=6.0Hz, 1H), 3. 76 (s, 3H), 3.74-3.63 (m, 3H), 2.62-2.46 (m, 4H), 2.28 (q, J=7.4Hz, 2H).

[1107] Compound 204. 2-(4-(2-(3-chlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1108]

[1109] 1 HNMR (300MHz, MeOH-d4) δ7.95 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=2.2Hz, 1H), 7.71 ( s, 1H), 7.58-7.46 (m, 2H), 7.39 (d, J=8.2Hz, 1H), 7.34-7.22 (m, 2H), 7.17 (t, J=8. 1Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 4.33 (t, J=5.2Hz, 2H), 3.99 (t, J=5.2Hz, 2H), 3. 60 (t, J=6.4Hz, 2H), 3.56-3.47 (m, 2H), 2.38 (t, J=7.5Hz, 2H), 1.91-1.79 (m, 4H);

[1110] LC / MS(ESI) m / z 490.0 [M+H] + .

[1111] Compound 205. 2-(4-(2-(3,5-difluorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol-1-ol

[1112]

[1113] 1HNMR (300MHz, MeOH-d4) δ7.97 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.56-7.42 (m, 2H), 7.39-7.21 (m, 4H), 6.50-6.35 (m, 1H), 4.33 (t, J=5.2 Hz, 2H), 3.99 (t, J=5.2Hz, 2H), 3.60 (t, J=6.4Hz, 2H), 3.51 (q, J=7.0Hz, 1H), 2.58-2.48 (m, 1H), 2.38 (t, J=7.5Hz, 2H), 1.88-1.75 (m, 3H);

[1114] LC / MS(ESI) m / z 492.0 [M+H] + .

[1115] <Example 2. Confirmation of the inhibitory activity of TAM receptor inhibitory compounds against Tyro3, ​​Axl, and Mer>

[1116] To evaluate the inhibitory activity of the compounds of the present invention against Tyro3, ​​Axl and Mer, the following experiments were conducted.

[1117] The specific experimental methods were performed according to the methods provided by Cisbio. Compounds of various concentrations from the examples were prepared, and Tyro3, ​​Axl, or Mer and the substrate peptide were added. The reaction was initiated with ATP, and after one hour, a solution containing EDTA was added to terminate the reaction. The amount of phosphorylated peptide was then measured. The amount of phosphorylated peptide was then treated with an antibody that recognizes phosphorylated peptides containing europium (Eu). After one hour, light at wavelengths of 320 nm or 340 nm was excited using an Envision Reader. The degree of TAM receptor inhibition was confirmed by measuring the amount of light emitted at 665 nm, and the TAM receptor inhibitory activity (IC50) of each compound was analyzed using the GraphPad Prism program. 50 The values ​​are shown in Tables 1 to 3 below. At this time, the positive control group used LDC1267 (CAS no. 1361030-48-9, Calbiochem), which is a TAM receptor inhibitor compound.

[1118] [Chemical Formula 1]

[1119]

[1120] Table 1

[1121]

[1122]

[1123] Table 2

[1124]

[1125]

[1126] Table 3

[1127]

[1128]

[1129]

[1130]

[1131] As shown in Tables 1 to 3, Table 1 illustrates the following activities: In Formula 1, R1 is a phenyl or furanyl substituent, R2 is a phenyl, cycloalkyl, or heterocycloalkyl substituent, and R3 or R4 is a compound in which the substituent is replaced by a heteroaryl group containing a heteroatom, for Tyro3 IC 50 The value is above 0.5 μM.

[1132] Table 2 shows the compounds in Formula 1 where R1 substituents include pyrazolyl groups substituted with hydroxyalkyl or piperidinyl groups, R2 is phenyl, cycloalkyl, or heterocycloalkyl, and R3 or R4 substituents are substituted with phenyl or tetrahydroisoquinolinyl groups, for Tyro3 IC 50 The values ​​range from 0.000012 to 0.059 μM, exhibiting strong activity.

[1133] Table 3 shows the compounds in Formula 1 where R1 substituents include pyrazolyl groups substituted with alkyl, hydroxyalkyl, or piperidinyl groups, R2 substituents are tetrahydroisoquinolinyl groups, and R3 or R4 substituents are substituted with phenyl or tetrahydroisoquinolinyl groups, for Tyro3 IC 50 The values ​​range from 0.0000062 to 0.086 μM, exhibiting strong activity.

[1134] Therefore, it can be seen that the compounds in Tables 2 and 3 have more than 10 times better inhibitory activity against Tyro3 than the compounds in Table 1. The Tyro3 inhibitory activity varies greatly depending on the substituents of the pyrimidine derivatives. In particular, the compounds of the present invention have a better inhibitory effect on Tyro3 in the TAM receptor and can be effectively used as cancer prevention or treatment compositions without side effects.

[1135] <Example 3. Confirmation of hERG toxicity of TAM receptor inhibitory compounds>

[1136] In the development of therapeutic agents, drugs not only have therapeutic effects, but their toxicity also plays an important role. The most commonly used criterion for assessing drug toxicity is hEGR (human ether-a-go-go-related gene 2) toxicity. In most pharmaceutical companies, hEGR toxicity is... 50 A value less than 0.1 μM indicates high toxicity, and drug development should be terminated. Conversely, hERG IC 50 A value above 10 μM is considered non-toxic.

[1137] Therefore, in order to confirm the drug toxicity of the TAM receptor inhibitory compounds of the present invention, hERG (human ether-a-go-go-related gene) of compounds 29, 60, 73, 75, 84, 89 and 132 in Table 4 below were measured.

[1138] Table 4

[1139]

[1140] According to hERG assay results, in compounds 29 and 60 of Table 1, where the R1 substituent in chemical formula 1 is a methyl-substituted pyrazolyl or phenyl group, the hERG IC50 values ​​are... 50 The values ​​showed values ​​below 1 μM, confirming hERG toxicity.

[1141] Conversely, in compounds 73 and 75 of Table 2, where the R1 substituent in Formula 1 is a pyrazolyl group substituted with a hydroxyalkyl or piperidinyl group, hERG IC 50 The values ​​showed values ​​above 50 μM, confirming the absence of hERG toxicity.

[1142] In addition, in chemical formula 1, when the R1 substituent is a pyrazolyl group substituted with an alkyl, hydroxyalkyl or piperidinyl group, and the R2 substituent is a tetrahydroisoquinoline group, compounds 84, 89 and 132 in Table 3 were confirmed to have no hERG toxicity.

[1143] It can be seen that the R1 to R3 substituents in the structure of chemical formula 1 of the present invention have a great influence on Tyro3 inhibitory activity and hERG toxicity. Therefore, as shown in Tables 2 and 3, compounds with specific substituents are non-toxic and exhibit excellent anti-cancer effects.

[1144] <Formulation Example 1. Preparation of Powders>

[1145] 2g of compound 139 of the present invention and 1g of lactose were mixed and filled into an airtight cloth to prepare a powder.

[1146] <Formulation Example 2. Preparation of Tablets>

[1147] After mixing 100 mg of compound 139 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate, tablets were prepared by compression according to conventional tablet preparation methods.

[1148] <Formulation Example 3. Preparation of Capsules>

[1149] After mixing 100 mg of compound 139 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate, the above ingredients are mixed according to conventional capsule preparation methods and filled into gelatin capsules to prepare capsules.

[1150] <Formulation Example 4. Preparation of Pills>

[1151] A 100mg pill was prepared by mixing 90mg of compound 139 of the present invention, 5mg of glutinous rice starch, 5mg of purified water, and small amounts of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as hygroscopic inhibitors.

[1152] <Formulation Example 5. Preparation of Injectables>

[1153] The compound 139 of the present invention, 10 mg, an appropriate amount of sterile distilled water for injection, and an appropriate amount of pH adjuster are mixed and then prepared using conventional injection preparation methods to achieve the above-mentioned component content in each ampoule (2 mL).

Claims

1. A pyrimidine derivative compound or a pharmaceutically acceptable salt thereof, wherein, The pyrimidine derivative compounds are selected from the following compounds: 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 71), N2-(3,5-dichlorophenyl)-N4-(piperidin-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 73) 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 75), 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethyl ketone (compound 76), N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 95), 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 103), N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 108) N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 110), N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2,4-diamine (compound 111) 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 113), 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-bis(trifluoromethyl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethanol (compound 121), 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (compound 122), 2-(4-(2-(3,5-dichlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 201), 2-(4-(2-(3-chlorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethanol-1-ol (compound 204) and 2-(4-(2-(3,5-difluorophenylamino)-4-(4-(piperidin-4-yl)phenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 205).

2. A pyrimidine derivative compound represented by the following chemical formula 3, or a pharmaceutically acceptable salt thereof, [Chemical Formula 3] In the chemical formula 3, R 1″ It is hydrogen, substituted or unsubstituted C1-C 10 Alkyl or unsubstituted piperidin-4-yl, in, The substituted alkyl group is replaced by a hydroxyl group or a C1-C2 group. 10 Alkyl substitution; R 2″ It is an imino or trihaloacetamino group; and R 3″ It is a substituted or unsubstituted phenyl group. The substituted phenyl group is selected from halogens, C1-C... 10 Haloalkyl, C1-C 10 Alkyl or C1-C 10 One or more substituents in the group consisting of alkoxy groups are substituted.

3. A pyrimidine derivative compound or a pharmaceutically acceptable salt thereof, wherein, The pyrimidine derivative compounds are selected from the following compounds: 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 82), 1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 83), N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 84) N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 85) 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 87), 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 89), 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 93), 1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 94), 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 101), 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol (compound 102), 1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 123), 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 124), 1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 125), 1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethyl ketone (compound 126), 2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 127), 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 128), 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 129), 2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-ethanol (compound 130), N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 131) N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 132) N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 133) N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 134) N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 135) N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 136) N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 137) 1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 138), 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 139), 1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 140), N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 141), N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 142), N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 143), N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 144), N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 145) N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 146) 2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 147), 2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethanol (compound 148), N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 149) N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 150) 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine (compound 151) N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 152) 5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 153) N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 154) 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine (compound 155) 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(o-tolyl)pyrimidine-2,4-diamine (compound 156) N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 157) 5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 158) N2-(5-fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 159) N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 160) N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 161) N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 162) N2-(3-chloro-5-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 163) 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 164) N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 165) N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 166) N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 167) 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 168) 5-(1-Isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 169) 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 170) N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 171) N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 172) N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 173) N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 174) N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 175) N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 176) N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 177) N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 178) N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 179) N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 180) N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 181) N2-(3-chloro-5-fluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 182) 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 183) N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 184) N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazole-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 185) N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 186) 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 187) 5-(1-Isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-N2-(m-tolyl)pyrimidine-2,4-diamine (compound 188) 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 189) N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 190) N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 191) 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)pyrimidine-2,4-diamine (compound 192) 2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 193), 2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 194), 2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 195), 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 196) and 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethyl-1-ol (compound 197).

4. A pharmaceutical composition for the prevention or treatment of Tyro3-related diseases, characterized in that, The active ingredient comprises any one of the pyrimidine derivative compounds or pharmaceutically acceptable salts thereof as claimed in claims 1 to 3.

5. Use of a pyrimidine derivative compound or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 3, in the preparation of a pharmaceutical composition for the prevention or treatment of Tyro3-related diseases.

6. The use according to claim 5, characterized in that, The Tyro3-related disease is cancer.

7. The use according to claim 6, characterized in that, The cancers mentioned are selected from pseudomyxoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B-cell lymphoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal sinus cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, childhood lymphoma, childhood leukemia, and small bowel cancer. The group consists of meningioma, esophageal cancer, glioma, neuroblastoma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal carcinoma, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, chorioretinopathy of pregnancy, cervical cancer, endometrial cancer, prostate cancer, metastatic bone cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Paget's disease, tonsil cancer, squamous cell carcinoma, lung cancer, skin cancer, anal cancer, laryngeal cancer, pleural cancer, and thymic cancer.

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