KR102383561B1 - Tetrahydroisoquinoline substituted pyrimidine derivative, optical isomer thereof, or pharmaceutically acceptable salts thereof, and composition comprising its same for preventing or treating of cancer - Google Patents

Abstract

The pyrimidine derivative compound substituted with a tetrahydroisoquinoline group according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof has an excellent TAM receptor inhibitory effect, in particular a selective inhibitory effect on Tyro3, And it can be usefully used as a composition for preventing or treating cancer having excellent effects without side effects appearing through the inhibition of Mer.

Description

A pyrimidine derivative compound substituted with a tetrahydroisoquinoline group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the same as an active ingredient {Tetrahydroisoquinoline substituted pyrimidine derivative, optical isomer thereof, or pharmaceutically acceptable salts thereof, and composition comprising its same for preventing or treating of cancer}

The present invention relates to a pyrimidine derivative compound substituted with a tetrahydroisoquinoline group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the same as an active ingredient.

TAM receptor (receptor) is called a TAM family (family), Tyro3, Axl and Mer (Mertk) is a tyrosine kinase receptor (receptor tyrosine kinase, RTK) that collectively refers to three receptors. The TAM receptor is a protein present in the cell membrane that binds to a signal material outside the cell and transmits a signal to the inside. ).

TAM receptor signaling is involved in platelet aggregation and thrombus formation, erythropoiesis, and homeostasis regulation of endothelial cells and vascular smooth muscle. In addition, the TAM-dependent pathway is known to be involved in spermatogenesis, maintenance of retina and function of the lactating mammary gland, bone physiology, atherosclerosis, neurological biology and permeability of the vascular brain barrier (Linger, R. M. A., et al. , 2008; Paolino M., et al., 2016).

Looking at the phenotype by an animal model in which the TAM receptor Tyro 3, Axl and Mer genes are knocked out, when Tyro 3, Axl and Mer are knocked out alone, antigen-presenting cells are commonly , APC) and hyperactivity of autoantibody production were observed, and protection against thrombosis was observed. On the other hand, when Mer is knocked out, the excretory function of apoptotic cells is impaired, retinitis pigmentosa, an increase in inflammation, and the like are induced. In addition, it is known that when Axl is knocked out, side effects such as severe autoimmune encephalomyelitis, enhancement of demyelination, and defect in excretory function of apoptotic cells are exhibited. On the other hand, when Tyro 3 was knocked out, no specific problem was found. Accordingly, the development of a TAM receptor, in particular, a selective inhibitor of Tyro 3 is attracting attention as a way to overcome the side effects caused by TAM receptor inhibition.

So far, most of the research on TAM receptors has been on their roles in two processes: cancer development and immune regulation. In relation to the development of TAM receptor cancer, recently Tyro 3 target inhibitor has been proposed as a drug target for the treatment of breast cancer, and Tyro 3 is expressed more than twice as strongly in liver cancer patients as compared to normal tissues, cancer growth, liver Research results have been reported that it is importantly involved in destruction, etc., and accordingly, controlling the inhibition or overexpression of Tyro 3 can be an important target for the development of a therapeutic agent for liver cancer (Duan, Y., et al., 2016).

When diagnosed with stage 3 ovarian cancer, the survival rate is as low as 5 years or less. In SKOV3/TR, an ovarian cancer cell line that is resistant to taxol, known as an anticancer drug, RNA expression of Tyro 3 increases, and Axl, It has been reported that the RNA expression of Mer is reduced. This increase in the expression level of Tyro 3 increases the survival of cancer cells in SKOV3/TR and acquires drug resistance to taxol (Lee, C., 2015). In addition, it was known that the expression of Tyro3 is increased in skin cancer, and when Tyro 3 is knocked down in melanoma cells, cell proliferation and colony formation are inhibited.

Therefore, through the development of a Tyro 3 selective inhibitor, it is expected that the development of a cancer therapeutic agent capable of overcoming anticancer drug resistance and having excellent cancer treatment effect while minimizing side effects is expected.

As a prior art, Korean Patent Application Laid-Open No. 10-2009-0121399 discloses a dianilinopyrimidine derivative, a pharmaceutical composition containing the same, and a method for preparing the same, and International Patent Publication No. 2017-059280 discloses a novel PAN-TAM Inhibitors and MER/AXL dual inhibitors are disclosed, and Chinese Patent Laid-Open No. 106588885 discloses a 2-substituted aromatic ring-pyrimidine derivative, a preparation method thereof, and a use thereof.

The present inventors discovered a pyrimidine derivative compound as a novel TAM receptor inhibitory compound in the course of researching a TAM receptor inhibitory compound. Also, it was possible to complete the present invention by confirming that the TAM receptor, in particular, the Tyro3 selective inhibitory effect was excellent.

Korean Patent Publication No. 10-2009-0121399, compound, November 25, 2009, published International Patent Publication No. 2017-059280, NOVEL PAN-TAM INHIBITORS AND MER/AXL DUAL INHIBITORS, published on April 06, 2017 Chinese Laid-Open Patent No. 106588885, 2-substituted aromatic ring-pyrimidine derivative, and preparation and application thereof, published on April 26, 2017

Duan, Y., et al., Overexrepssion of Tyro3 and its implications on hepatocellular carcinoma progression, International Journal of Oncology, 48(1), 358-366, 2016. Lee, C., Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells, Mol. Med. Rep., 12(1), 1458-1492, 2015. Lemke, G., Biology of the TAM Receptors, Cold Spring Harb Perspect Biol., 5, a009076, 2013. Linger, R.M.A., et al., TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potenetial Thereapetic Targeting in Human Cancer, Adv. Cancer Res., 100, 35-83, 2008. Paolino, M., et al., The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy, Cancer, 8, 97, 2016.

An object of the present invention is to provide a pyrimidine derivative compound substituted with a tetrahydroisoquinoline group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the same as an active ingredient.

The present invention relates to a pyrimidine derivative compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ¹ is hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, or substituted or unsubstituted piperidinyl,

wherein said substituted alkyl, or substituted piperidinyl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, trihalogen consisting of acetyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ heterocycloalkyl, C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl substituted with one or more substituents selected from the group;

R ² is amino, acetamino, or trihalogenacetamino; and

R ³ is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl, substituted or unsubstituted C ₄ - C ₁₀ heteroaryl, or a substituted or unsubstituted fused ring in which C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl are fused;

wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is halogen, C ₁ -C ₁₀ haloalkyl, oxo(=O), hydroxy, cyano , nitro, amino, acetamino, trihalogenacetamino, trihalogenacetyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ cycloalkyl, C ₄ -C ₈ heterocycloalkyl, C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ is substituted with one or more substituents selected from the group consisting of heteroaryl.

The term “alkyl” refers to a single-bonded straight-chain or branched hydrocarbon group, for example, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, and the like.

The term “alkoxy” refers to an oxygen group to which a single bond straight or branched saturated hydrocarbon is bonded, for example, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy etc.

The term “cycloalkyl” refers to a saturated hydrocarbon group of a single cyclic bond, and includes cyclobutyl, cyclopentyl, cyclohexyl, etc. depending on the number of carbon atoms.

The term “heterocycloalkyl” refers to a saturated hydrocarbon group of a single cyclic bond containing one or more heteroatoms such as N, O, or S, and may vary depending on the number and type of heteroatoms included in the ring, and the number of carbon atoms. Ridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term “aryl” refers to an aromatic substituent having at least one ring having a shared pi electron system, for example, phenyl, benzyl, or the like.

The term “heteroaryl” refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and pyrrolyl, furanyl, pyridine according to the number and type of heteroatoms included in the ring, and carbon number yl, pyrimidinyl, pyranyl, and the like.

Preferably, in Formula 1,

R ¹ is hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, or substituted or unsubstituted piperidin-4-yl,

wherein said substituted alkyl, or substituted piperidin-4-yl, is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino , trihalogenacetyl, C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ substituted with one or more substituents selected from the group consisting of alkoxy;

R ² is amino, acetamino, or trihalogenacetamino; and

R ³ is substituted or unsubstituted C ₄ -C ₁₀ aryl,

wherein said substituted aryl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, trihalogenacetyl, C ₁ -C ₁₀ It is substituted with one or more substituents selected from the group consisting of alkyl, or C ₁ -C ₁₀ alkoxy.

When the compound of Formula 1 of the present invention is more specifically illustrated,

1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroiso quinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 1);

1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-di hydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 2);

N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 3);

N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 4);

1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 5);

2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethanol (Compound 6);

1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4 -dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (compound 7);

1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3, 4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 8);

2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol- 1-yl)ethanol (Compound 9);

2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazole -1-yl)ethanol (Compound 10);

1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) -3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 11);

1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 12);

1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 13);

1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) -3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 14);

2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -Pyrazol-1-yl)-ethan-1-ol (Compound 15);

2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5 -yl)-1H-pyrazol-1-yl)-ethan-1-ol (Compound 16);

2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)-ethan-1-ol (Compound 17);

2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -Pyrazol-1-yl)-ethan-1-ol (Compound 18);

N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetra hydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 19);

N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 20);

N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(1-(piperidin-4- yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 21);

N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 22);

N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 23);

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 24);

N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 25);

1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydro Isoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 26);

1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 27);

1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-di hydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 28);

N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5 -(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 29);

N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 30);

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 31);

N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 32);

N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 33);

N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 34);

2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-Pyrazol-1-yl)ethan-1-ol (Compound 35);

2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin- 5-yl)-1H-pyrazol-1-yl)ethan-1-ol (Compound 36);

N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2 ,4-diamine (Compound 37);

N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 38);

5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoromethyl)phenyl ) pyrimidine-2,4-diamine (Compound 39);

N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 40);

5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine ( compound 41);

N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 42);

5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoromethyl)benzyl ) pyrimidine-2,4-diamine (Compound 43);

5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(o-tolyl)pyrimidine-2, 4-diamine (Compound 44);

N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 45);

5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2, 4-diamine (Compound 46);

N2-(5-Fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 47);

N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 48);

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 49);

N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 50);

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 51);

5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 52);

N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 53);

N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 54);

N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 55);

5-(1-isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 56);

5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2 ,4-diamine (Compound 57);

5-(1-isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 58);

N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 59);

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 60);

N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 61);

N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 62);

N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 63);

N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 64);

N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 65);

N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2 ,4-diamine (Compound 66);

N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 67);

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 68);

N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 69);

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 70);

5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 71);

N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 72);

N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 73);

N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 74);

5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 75);

5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2 ,4-diamine (Compound 76);

5-(1-isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 77);

N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 78);

N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl )pyrimidine-2,4-diamine (Compound 79);

5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 80);

2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethan-1-ol (Compound 81);

2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 82);

2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 83);

2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol- 1-yl)ethan-1-ol (Compound 84); and

2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 85); It is at least one selected from the group consisting of.

In addition, the compound represented by Formula 1 of the present invention is prepared by the method of Scheme 1, which is a method disclosed in Korean Patent Application No. 10-2017-0056002.

reacting the compound represented by compound B and NH ₂ R ^{2 '} to prepare a compound represented by compound C (step 1);

preparing a compound represented by compound D from the compound represented by compound C prepared in step 1 (step 2); and

Preparing a compound represented by compound A from the compound represented by compound D prepared in step 2 (step 3).

[Scheme 1]

In Scheme 1,

R ^1′ is a pyrazole derivative, R ^2′ is a tetrahydroisoquinoline derivative, and R ³ is as defined in Formula 1 above;

X ¹ , X ² and X ³ are halogen.

Hereinafter, a method for preparing the compound represented by Formula 1 (or Compound A) according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Formula 1 (or Compound A) according to the present invention, step 1 of Scheme 1 reacts a compound represented by Compound B with NH ₂ R ^{2 '} to obtain a compound represented by Compound C This is the manufacturing step.

In this case, step 1 may be understood as a step of introducing a -NH-R ^2' substituent into the parent nucleus structure of the compound of the present invention. Any method capable of preparing a compound represented by Compound C by introducing a -NH-R ^2' substituent at the X ¹ position of the compound represented by Compound B is included in the present invention without limitation, and is preferably It can be carried out by reacting the compound represented by DIPEA (N,N-diisopropylethylamine) and compound B with 1,4-dioxane.

In this case, as a solvent that can be used for the reaction, any solvent capable of dissolving the compound represented by Compound B and DIPEA may be used without limitation, and examples thereof include tetrahydrofuran (THF); dioxane; ether solvents including ethyl ether and 1,2-dimethoxyethane; lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate , phenylbutyrate, cicrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and Mixtures thereof may be used, and 1,4-dioxane may be used.

In addition, the reaction temperature is not particularly limited, but may preferably be carried out at 0° C. to 100° C., for example, at room temperature. Furthermore, the reaction time is not particularly limited, but may be set, for example, to 2 hours to 10 hours, and as another example, may be reacted over 20 minutes to 8 hours when heating.

In the method for preparing a compound represented by Formula 1 (or Compound A) according to the present invention, Step 2 of Scheme 1 is to prepare a compound represented by Compound D from the compound represented by Compound C prepared in Step 1. is a step

In this case, step 2 may be understood as a step of introducing a R ^1' substituent to the compound represented by Compound C, and selectively introducing R ^1' according to the desired compound to prepare a compound represented by Compound D is a step

로 표시되는 화합물 및 Pd(dppf)₂Cl₂를 반응시켜 수행될 수 있으나, 이와 상등한 당분야 통상의 기술로 사용되는 방법으로 본 발명의 단계 2와 같이 화합물 D로 표시되는 화합물을 제조할 수 있는 단계로 수행될 수 있는 것이라면 제한없이 본 발명에 포함된다.On the other hand, although not limited thereto, as an example, as part of a method for introducing the R ^{1 '} , a compound represented by Na ₂ CO ₃ and Compound C in DMF,

It may be carried out by reacting the compound represented by and Pd(dppf) ₂ Cl ₂ , but the compound represented by the compound D can be prepared as in step 2 of the present invention by a method used in a conventional technique equivalent to this. It is included in the present invention without limitation as long as it can be carried out in the following steps.

In this case, the solvent that can be used in the reaction may be used without particular limitation, but for example, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazensulfonate, toluene Sulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfo ether solvents including nitrate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, methanol, ethanol, Lower alcohols including propanol and butanol, and mixtures thereof may be used, and DMF may be preferably used.

In addition, the reaction temperature is not particularly limited, but may preferably be carried out at 50 °C to 150 °C, for example, at 90 °C. Furthermore, the reaction time is not particularly limited, but, for example, may be set to 10 to 40 hours, and as another example, may be reacted over 20 to 30 hours.

In the method for preparing a compound represented by Formula 1 (or Compound A) according to the present invention, step 3 of Scheme 1 is represented by Formula 1 (or Compound A) from the compound represented by Compound D prepared in Step 2 It is a step for preparing the compound.

In this case, step 3 may be understood as a step of introducing a -NHR ³ substituent into the compound represented by Compound D, and selectively introducing a -NHR ³ substituent according to a desired compound to obtain Formula 1 (or Compound A) The indicated steps are for preparing the compound of the present invention.

In this case, the solvent that can be used for the reaction may be used without particular limitation, but for example, ethoxyethanol, 1,4-dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), Dichloroethane, water, acetonazensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, horse Late, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane It is possible to use an ether solvent containing such as, a lower alcohol containing methanol, ethanol, propanol and butanol, and mixtures thereof, preferably ethoxyethanol.

In addition, the reaction temperature is not particularly limited, but may preferably be carried out at 50° C. to 150° C., for example, at 100° C. Further, the reaction time is not particularly limited, but may be set to, for example, 10 to 40 hours, and in another example, may be reacted over 10 to 20 hours.

Meanwhile, in the method for preparing a compound represented by Formula 1 (or Compound A) according to the present invention, it proceeds as in Scheme 1, but as a preferred example, it may be carried out as in Scheme 2 below.

[Scheme 2]

In Scheme 2,

R ^1' is a pyrazole derivative, R ^2' is a tetrahydroisoquinoline derivative, and R ³ is as defined in Formula 1 above.

Further, in the method for preparing the compound represented by Formula 1 according to the present invention, as a more preferred embodiment, the following method for preparing the compound of the present invention may be mentioned. The method for preparing the compound represented by Formula 1 according to the present invention shown in Scheme 1, Scheme 2, and the method for preparing the compound of the example of the present invention below should be understood as an example of a method for preparing the compound of the present invention, As long as it is a method capable of preparing the compound represented by Formula 1, which is being prepared in the present invention, it is included in the present invention without limitation. In addition, it should be understood that the method presented in the present specification and the manufacturing method that those skilled in the art can easily change and modify therefrom are also included in the scope of the present invention, which is obvious to those skilled in the art. can be understood as

In the present invention, the compound represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The cancer is also called a malignant tumor, and is an abnormally grown mass due to the autonomous overgrowth of body tissues, rapidly growing while infiltrating the surrounding tissues, and spreading or metastasizing to each part of the body, thereby endangering life. means, and includes carcinoma and sarcoma. More specifically, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial 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 myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, ampulla Barter's Cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, nerve Glioma, neuroblastoma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant melanoma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, Gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer , rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic 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 thymus cancer.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate and mineral oil may be included, but are not limited thereto. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, for example, starch, microcrystalline cellulose, sucrose or lactose, to the compound of the present invention; It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, and the like can be used. In order to formulate a formulation for parenteral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and/or an adjuvant such as a preservative, a stabilizer, a wetting agent or an emulsification accelerator, a salt for regulating the osmotic pressure, and/or a buffer; and other therapeutically useful substances to prepare a solution or suspension by mixing in water, which may be prepared in ampoules or vial unit dosage form.

The pharmaceutical composition provides a pharmaceutical composition comprising the compound of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight based on the total weight of the composition.

The pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection. The dosage may be determined by the age, sex, weight, specific disease or pathology to be treated, the severity of the disease or pathology, administration time, administration route, absorption, distribution and excretion rate of the drug, the type of other drugs used, and the prescriber's It will depend on judgment, etc. Dosage determination based on these factors is within the level of one of ordinary skill in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or divided into several administrations. The above dosage does not limit the scope of the present invention in any way.

The pyrimidine derivative compound substituted with a tetrahydroisoquinoline group according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof has an excellent TAM receptor inhibitory effect, in particular a selective inhibitory effect on Tyro3, And it can be usefully used as a composition for preventing or treating cancer having excellent effects without side effects appearing through the inhibition of Mer.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Confirmation of the synthesis and physicochemical properties of a pyrimidine derivative compound substituted with a tetrahydroisoquinoline group>

Compounds 1 to 85 of the present invention were prepared with reference to the method disclosed in Patent Application No. 10-2017-0056002, and their physicochemical properties are as follows.

Compound 1. 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4- Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H 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).

compound 2. 1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3, 4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H 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).

Compound 3. N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.64 (s, 1H), 7.51 (d, J = 2.1 Hz, 3H), 7.31 (d, J = 2.5 Hz, 1H), 7.28 (d, J = 5.9 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.94 (t, J = 1.9 Hz, 1H), 6.76 ( s, 1H), 4.01 (s, 3H), 3.96 (s, 2H), 3.13 (t, J = 5.9 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 1.73 (s, 1H).

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

¹ H 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 = 2.4 Hz, 1H), 7.07 (s) , 1H), 7.04 (d, J = 4.0 Hz, 1H), 6.73 (s, 1H), 4.01 (s, 3H), 3.95 (s, 2H), 3.15 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.30 (s, 3H), 1.70 (s, 1H).

Compound 5. 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino )-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H 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), 6.85 (s, 1H), 4.71 (d, J = 10.5 Hz, 2H) , 4.35 (t, J = 4.7 Hz, 2H), 4.10 (t, J = 4.7 Hz, 2H), 3.85 (q, J = 7.1, 5.8 Hz, 2H), 3.41-3.04 (m, 1H), 2.94 ( d, J = 6.6 Hz, 2H).

Compound 6. 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethanol

¹ H 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, 1H), 6.78 (s, 1H), 4.32 (t, J = 4.7 Hz, 2H), 4.07 (t, J = 4.7 Hz, 2H), 3.91 (s, 2H), 3.12 (t, J = 5.9 Hz, 2H), 2.76 (t, J = 6.0 Hz) , 2H), 1.35-1.28 (m, 1H), 0.87 (d, J = 7.3 Hz, 1H).

Compound 7. 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H NMR (300 MHz, Chloroform-d) δ 7.92 (d, J = 0.9 Hz, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.39 (d, J = 4.7 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 3.3 Hz, 1H), 7.25-7.21 (m, 1H), 7.20-7.16 (m) , 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.98 (dq, J = 7.5, 1.8 Hz, 1H), 6.84 (s, 1H), 4.69 (d, J = 10.5 Hz, 2H), 4.37 -4.31 (m, 2H), 4.12-4.06 (m, 2H), 3.88 (t, J = 6.0 Hz, 1H), 3.83 (t, J = 5.9 Hz, 1H), 2.92 (t, J = 5.8 Hz, 2H).

Compound 8. 1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) -3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H 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 = 12.3 Hz, 2H), 4.39-4.31 (m, 2H), 4.13-4.07 (m, 2H), 3.87 (dd, J = 13.6, 7.0 Hz, 2H), 3.31-3.12 (m, 1H) ), 2.97 (s, 2H).

Compound 9. 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethanol

¹ H 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, 1.0 Hz, 1H), 6.75 (s, 1H), 4.31 (dd, J = 5.4, 4.0 Hz, 2H), 4.06 (t, J = 4.8 Hz, 2H), 3.92 (s, 2H), 3.12 (t, J = 5.9) Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.49-2.08 (m, 2H).

Compound 10. 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -Pyrazol-1-yl)ethanol

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.20 (d, J = 9.0 Hz, 3H) ), 7.07 (t, J = 8.9 Hz, 3H), 6.74 (s, 1H), 6.67 (t, J = 7.3 Hz, 1H), 4.37-4.30 (m, 2H), 4.14-4.05 (m, 2H) , 3.97 (s, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H).

Compound 11. 1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4- ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H NMR (300 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.35 (d, J = 2.5 Hz, 1H) ), 7.26 (dd, J = 8.1, 2.2 Hz, 1H), 7.20-7.13 (m, 3H), 6.87 (s, 1H), 6.47-6.39 (m, 1H), 4.75 (d, J = 11.2 Hz, 2H), 4.38 (dd, J = 5.5, 4.0 Hz, 2H), 4.14-4.09 (m, 2H), 3.90 (dt, J = 12.3, 5.9 Hz, 2H), 3.03-2.92 (m, 4H).

Compound 12. 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri Midin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H NMR (300 MHz, Chloroform-d) δ 8.06 (d, J = 3.0 Hz, 2H), 8.03 (s, 1H), 7.81 (d, J = 13.9 Hz, 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 = 15.3 Hz, 2H), 4.43 -4.33 (m, 2H), 4.17-4.08 (m, 2H), 3.94-3.82 (m, 2H), 2.95 (t, J = 6.0 Hz, 2H).

Compound 13. 1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) )-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H NMR (300 MHz, Chloroform-d) δ 8.38-8.30 (m, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.39 (d, J = 18.1 Hz, 1H), 7.32 (d, J = 7.0 Hz, 0H) ), 7.18-7.15 (m, 1H), 7.14-7.08 (m, 1H), 4.71 (d, J = 14.2 Hz, 2H), 4.40-4.33 (m, 2H), 4.14-4.04 (m, 2H), 3.87 (dd, J = 13.0, 6.4 Hz, 2H), 2.95 (t, J = 5.5 Hz, 2H).

Compound 14. 1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4- ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

¹ H 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= 7.9 Hz, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 4.59 (d, J = 14.3 Hz, 2H), 4.37 (dd, J = 5.6, 4.0 Hz, 2H), 4.15-4.08 (m, 2H) ), 3.91-3.80 (m, 2H), 2.90 (q, J = 5.5 Hz, 2H), 2.37 (s, 3H).

Compound 15. 2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl )-1H-pyrazol-1-yl)-ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.97 (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 = 5.9 Hz, 2H), 2.81 (t, J) = 5.9 Hz, 2H).

Compound 16. 2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyri Midin-5-yl)-1H-pyrazol-1-yl)-ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 8.05 (d, J = 1.5 Hz, 2H), 8.00 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 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 = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H) .

Compound 17. 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-Pyrazol-1-yl)-ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 8.43-8.35 (m, 1H), 7.96 (s, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 0.8 Hz, 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 = 5.9 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H).

Compound 18. 2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl )-1H-pyrazol-1-yl)-ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.57 (d, J = 0.8) Hz, 1H), 7.21-7.07 (m, 4H), 6.96 (d, J = 8.3 Hz, 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 = 6.0 Hz, 2H), 2.74 (t, J = 5.9 Hz, 2H), 2.35 (s, 3H).

Compound 19. N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3, 4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.24-7.09 (m, 6H), 6.80 (s, 1H), 6.41 (d, J = 8.9 Hz, 1H), 4.36-4.27 (m, 1H), 4.02 (s, 2H), 3.35-3.25 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.88- 2.78 (m, 4H), 2.29-2.22 (m, 2H), 2.02-1.92 (m, 2H).

Compound 20. N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H 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, 1H), 6.81 (s, 1H) ), 4.39-4.26 (m, 1H), 4.00 (s, 2H), 3.30 (d, J = 12.7 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.87-2.76 (m, 4H) , 2.25 (d, J = 12.6 Hz, 2H), 2.05-1.92 (m, 2H).

Compound 21. N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(1-(piperidine) -4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

¹ H 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 = 12.6 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.89-2.77 (m, 4H), 2.26 (d, J = 12.7) Hz, 2H), 2.07-1.96 (m, 2H).

Compound 22. N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H 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 = 10.1 Hz, 2H), 6.83 (s, 1H), 4.40-4.29 ( m, 1H), 4.00 (s, 2H), 3.32 (d, J = 13.0 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 2.92-2.78 (m, 4H), 2.27 (d, J) = 12.5 Hz, 2H), 2.05-1.97 (m, 2H).

Compound 23. N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (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 = 8.1 Hz, 1H), 6.80 (d, J = 2.2 Hz, 2H), 6.76 (s, 1H), 6.16 (t, J = 2.2 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 2H), 3.69 (s, 6H), 3.14 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H).

Compound 24. N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine

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

Compound 25. N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H 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).

Compound 26. 1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4 -dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 3.3 Hz, 2H), 7.25 (d, J = 8.4 Hz) , 1H), 7.17-7.08 (m, 2H), 6.81 (t, J = 2.3 Hz, 3H), 6.22-6.15 (m, 1H), 4.73 (d, J = 15.1 Hz, 2H), 4.03 (s, 3H), 3.95-3.83 (m, 2H), 3.75 (s, 4H), 3.73 (s, 2H), 2.95 (d, J = 6.5 Hz, 2H).

Compound 27. 1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino) )-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (d, J = 11.8 Hz, 1H), 8.06 (d, J = 2.1 Hz, 2H), 8.02 (s, 1H), 7.68 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.18-7.15 (m, 1H), 7.13-7.07 (m, 1H), 6.88 (s, 1H), 4.68 (d, J = 15.0 Hz, 2H), 4.05 (s, 3H), 3.93-3.79 (m, 2H), 2.94 (t, J = 5.9 Hz, 2H).

Compound 28. 1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3, 4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.67 (s, 1H), 7.56 (s, 2H), 7.41-7.33 (m, 1H), 7.24 (dd, J = 10.0, 7.9 Hz, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.85 (d, J = 2.7 Hz, 1H), 6.47-6.37 (m, 1H), 4.75 (d, J = 13.0 Hz, 2H) ), 4.04 (s, 3H), 3.95-3.84 (m, 2H), 2.98 (t, J = 5.5 Hz, 2H).

Compound 29. N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl )-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

¹ H 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, 2H), 4.68 (s, 1H), 4.59-4.47 (m, 1H), 4.23 (d, J = 14.4 Hz, 1H), 3.96-3.85 (m, 2H), 3.41 (t, J = 12.7 Hz) , 1H), 3.10 (t, J = 12.7 Hz, 1H), 2.98 (t, J = 5.4 Hz, 2H), 2.38 (d, J = 13.4 Hz, 2H), 2.25-2.11 (m, 2H).

Compound 30. N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

¹ H 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 = 12.3 Hz, 1H), 4.60-4.46 ( m, 1H), 4.23 (d, J = 14.2 Hz, 1H), 3.95-3.83 (m, 2H), 3.41 (t, J = 12.5 Hz, 1H), 3.11 (t, J = 12.7 Hz, 1H), 2.96 (s, 2H), 2.38 (d, J = 13.0 Hz, 2H), 2.26-2.09 (m, 2H).

Compound 31. 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

¹ H 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, 5.8 Hz, 2H), 3.42 (t, J = 12.9 Hz, 1H), 3.11 (t, J = 12.8 Hz, 1H), 2.97 (d, J = 6.2) Hz, 2H), 2.39 (d, J = 13.0 Hz, 2H), 2.25-2.09 (m, 2H).

Compound 32. N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- 5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

¹ H 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 = 15.1 Hz, 3H), 4.60-4.47 (m, 1H), 4.24 (d, J = 13.6 Hz, 1H), 3.96-3.86 (m, 2H), 3.41 (t, J = 13.0) Hz, 1H), 3.11 (t, J = 12.8 Hz, 1H), 2.98 (t, J = 5.7 Hz, 2H), 2.38 (d, J = 12.8 Hz, 2H), 2.24-2.11 (m, 2H).

Compound 33. N2-(3-Chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 11.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 4.6 Hz, 2H), 6.78 (s, 1H), 6.70 (d, J = 8.1 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.81 (t, J) = 6.0 Hz, 2H).

Compound 34. N2-(3-Methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 7.31 (s, 1H), 7.26 (d, J = 2.3 Hz, 1H) , 7.12 (d, J = 2.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.80-6.74 (m, 2H), 4.03 (d, J = 1.1 Hz, 3H), 3.95 (s, 2H), 3.74 (d, J = 2.6 Hz, 3H), 3.20-3.11 (m, 2H), 2.83-2.74 (m, 2H).

Compound 35. 2-(4-(2-(3-Chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5- yl)-1H-pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.64 (s, 2H), 7.48 (s, 1H), 7.44 (s, 1H) , 7.26 (d, J = 7.1 Hz, 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 = 6.0 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H).

Compound 36. 2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-5-yl)-1H-pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (d, J = 1.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.62 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 14.9 Hz, 2H), 7.26 (s, 1H), 7.15-7.04 (m, 2H), 6.78 (d, J = 6.4 Hz, 2H), 4.39-4.31 ( m, 2H), 4.10 (t, J = 4.8 Hz, 2H), 3.95 (s, 1H), 3.75 (s, 3H), 3.72 (s, 1H), 3.68 (d, J = 5.5 Hz, 1H), 3.16 (t, J = 6.0 Hz, 1H), 2.88 (s, 1H), 2.80 (t, J = 6.0 Hz, 2H), 2.06 (d, J = 4.4 Hz, 3H).

Compound 37. N2-(3-Chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (t, J = 2.1 Hz, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.36-7.30 (m, 1H), 7.23 (d, J = 6.1 Hz, 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 = 6.0 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H).

Compound 38. N2-(3-Fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.71 (t, J = 2.3 Hz, 1H), 7.68-7.64 (m, 2H), 7.54 (d, J = 0.8 Hz, 1H) , 7.26-7.19 (m, 3H), 7.09 (t, J =8.5 Hz, 2H), 6.78 (s, 1H), 6.72-6.65 (m, 1H), 4.03 (s, 3H), 4.02 (d, J) = 3.8 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H).

Compound 39. 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoro methyl)phenyl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, J = 3.2 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.67-7.63 (m, 1H) , 7.55-7.51 (m, 1H), 7.42 (d, J = 4.7 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.82-6.76 (m, 1H), 4.03 (d, J = 2.7 Hz, 3H), 3.97 (s, 2H), 3.17 ( t, J = 6.0 Hz, 2H), 2.91 (s, 1H), 2.80 (t, J = 5.9 Hz, 1H).

Compound 40. N2-(3-Methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 2.3, 0.8 Hz, 1H), 7.55-7.48 (m, 1H), 7.34-7.29 ( m, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.25-7.22 (m, 1H), 7.22-7.20 (m, 1H), 7.20-7.14 (m, 2H), 7.14-7.11 (m, 1H), 7.11-7.03 (m, 1H), 6.76 (s, 1H), 6.62-6.56 (m, 1H), 4.02 (d, J = 2.7 Hz, 3H), 3.97 (s, 1H), 3.73 (d) , J = 2.2 Hz, 3H), 3.70 (s, 1H), 3.17 (t, J = 6.0 Hz, 1H), 2.90 (s, 2H), 2.80 (t, J = 5.9 Hz, 1H).

compound 41. 5-(1- methyl -1H- pyrazole -4-yl) -N2-phenyl-N4- (1,2,3,4- tetrahydroisoquinoline -7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.52 (s, 1H), 7.36-7.30 ( m, 1H), 7.25 (dd, J = 11.3, 3.2 Hz, 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 = 6.0 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H).

Compound 42. N2-(2-Isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, J = 3.2 Hz, 1H), 7.78-7.72 (m, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.51-7.46 (m, 1H), 7.38-7.31 (m, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.24-7.18 (m, 2H), 7.15-7.06 (m, 1H), 6.95 (d, J = 8.3 Hz) , 1H), 6.76 (d, J = 5.2 Hz, 2H), 4.02 (s, 3H), 3.83 (s, 2H), 3.24 (p, J = 6.8 Hz, 1H), 3.13 (t, J = 5.9 Hz) , 2H), 2.75 (t, J = 5.8 Hz, 2H), 1.28 (d, J = 2.1 Hz, 3H), 1.25 (d, J = 1.9 Hz, 3H).

Compound 43. 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoro methyl)benzyl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.63 (s, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.56 (t, J = 8.5 Hz, 2H), 7.50 -7.45 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 5.56 (s, 1H), 4.71 (d, J = 6.2 Hz, 2H), 4.01 (s, 3H), 3.89 (s, 2H), 3.14 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H).

Compound 44. 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(o-tolyl)pyrimidine -2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.48 (s) , 1H), 7.34-7.28 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.18-7.01 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 3.99 (d, J = 1.9 Hz, 3H), 3.93 (s, 2H), 2.82 (t, J = 5.9 Hz, 4H), 2.36-2.27 (m, 3H).

Compound 45. N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.49 (s, 1H), 7.27-7.16 (m, 2H) , 7.16-7.08 (m, 1H), 7.01 (t, J = 8.0 Hz, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 4.02 (s, 3H), 3.87 ( s, 2H), 3.14 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H).

Compound 46. 5-(1-Methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine -2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (d, J = 2.0 Hz, 1H), 7.64 (t, J = 1.3 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.1 Hz) , 1H), 7.34 (d, J = 14.4 Hz, 2H), 7.23-7.16 (m, 2H), 7.07 (d, J = 7.2 Hz, 2H), 6.85 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 4.03 (s, 3H), 4.00 (d, J = 10.5 Hz, 2H), 3.17 (t, J = 6.0 Hz, 1H), 2.89 (d, J = 6.1 Hz, 1H), 2.80 (t, J = 6.0 Hz, 1H), 2.33 (s, 3H), 2.29 (s, 1H).

Compound 47. N2-(5-Fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01-7.97 (m, 1H), 7.96 (s, 1H), 7.95 (t, J = 2.2 Hz, 1H), 7.67-7.62 (m, 1H), 7.56 7.50 (m, 1H), 7.24 (s, 1H), 7.20 (dd, J = 8.0, 2.2 Hz, 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 = 8.1 Hz, 2H), 3.19 (t, J = 6.0 Hz, 1H), 2.83 (t, J = 5.9 Hz, 2H), 2.29 (s, 3H).

Compound 48. N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 1.9 Hz, 2H), 7.44 (s, 1H) , 7.30-7.26 (m, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.93 (t, J = 1.8 Hz, 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 = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 3H) ), 1.59 (d, J = 6.7 Hz, 6H).

Compound 49. N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetra Hydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.19 (d, J = 7.8 Hz, 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), 7.15-7.04 (m, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 4.64-4.50 (m, 1H), 4.09 (s, 2H), 3.19 (d, J = 6.3 Hz, 2H), 2.86 (s, 2H), 1.60 (d, J = 6.7 Hz, 6H).

Compound 50. N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.53 (d, J = 1.8 Hz, 2H), 7.42 (s, 1H) , 7.31-7.27 (m, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.97 (t, J = 1.8 Hz, 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 = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 3H) ), 1.61 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 462.3.

Compound 51. N2-(3-Chloro-5-fluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline -7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.99-7.87 (m, 1H), 7.75-7.60 (m, 2H), 7.57 (d, J = 2.9 Hz, 1H), 7.48-7.39 (m, 1H) , 7.31 (d, J = 13.3 Hz, 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 = 6.7 Hz, 2H), 4.11 (d, J = 11.7 Hz, 1H), 3.32-3.14 (m, 2H), 2.94-2.84 (m, 2H), 1.59 (d, J = 6.7 Hz, 6H) .

Compound 52. 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4 -tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H 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 = 7.9 Hz, 1H), 6.81 (s, 1H), 6.74 (d, J = 5.6 Hz, 1H), 4.65-4.53 (m, 1H), 4.03 (s, 1H), 3.73 (s, 2H), 3.71 (s, 2H), 2.87 (d, J = 6.6 Hz, 2H), 1.59 ( d, J = 6.7 Hz, 6H).

Compound 53. N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H 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 = 2.2 Hz, 1H), 4.58 (p, J = 6.6 Hz, 1H), 3.75 (s, 2H), 3.69 (d, J = 4.5 Hz, 6H), 2.89 (d, J = 10.9 Hz, 2H) , 2.08-1.97 (m, 2H), 1.59 (dd, J = 6.7, 2.5 Hz, 6H).

Compound 54. N2-(3,5-Dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.92 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.39 ( d, J = 7.5 Hz, 2H), 7.18 (s, 2H), 7.14-7.03 (m, 2H), 6.79 (s, 1H), 6.65 (s, 1H), 4.58 (p, J = 6.7 Hz, 1H) ), 3.97-3.82 (m, 2H), 2.86 (d, J = 5.2 Hz, 2H), 2.24 (s, 6H), 1.59 (d, J = 6.7 Hz, 6H).

Compound 55. N2-(3-Chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H) ), 7.20 (s, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 6.80 (s, 1H) ), 4.66-4.51 (m, 1H), 4.02 (s, 1H), 3.19 (t, J = 6.1 Hz, 2H), 2.93-2.76 (m, 2H), 1.60 (d, J = 6.7 Hz, 6H) .

Compound 56. 5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.96-7.91 (m, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.36 (s, 1H) ), 7.30 (s, 1H), 7.25-6.97 (m, 5H), 6.81 (s, 1H), 6.56 (d, J = 7.7 Hz, 1H), 4.58 (p, J = 6.7 Hz, 1H), 3.96 -3.80 (m, 2H), 3.75-3.63 (m, 3H), 2.88 (s, 2H), 1.59 (d, J = 6.7 Hz, 6H).

Compound 57. 5-(1-Isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyri midine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.94 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 6.6) Hz, 1H), 7.33 (s, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.83 ( d, J = 7.7 Hz, 1H), 6.77 (s, 1H), 4.58 (p, J = 6.8 Hz, 1H), 3.97 (s, 2H), 3.16 (t, J = 6.0 Hz, 2H), 2.79 ( t, J = 5.8 Hz, 2H), 2.30 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H).

compound 58. 5-(1-isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2, 4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (d, J = 2.1 Hz, 1H), 7.67-7.64 (m, 1H), 7.60-7.54 (m, 3H), 7.30 (d, J = 7.5 Hz) , 3H), 7.18 (d, J = 23.3 Hz, 3H), 7.08-7.00 (m, 2H), 6.79 (s, 1H), 4.58 (dt, J = 13.5, 6.8 Hz, 1H), 3.98 (s, 2H), 3.16 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.1 Hz, 2H), 1.59 (d, J = 6.7 Hz, 6H).

Compound 59. N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.97 (d, J = 3.6 Hz, 1H), 7.65 (s, 1H), 7.57-7.47 (m, 3H), 7.31 (d, J = 5.9 Hz, 1H) ), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.93 (t, J = 1.7 Hz, 1H), 6.80 (s, 1H), 4.17 (t) , J = 7.3 Hz, 2H), 3.99-3.78 (m, 2H), 2.87 (d, J = 5.1 Hz, 2H), 1.98 (q, J = 7.3 Hz, 4H), 0.99 (t, J = 7.4 Hz) , 3H).

Compound 60. N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H 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, 1H), 7.11-7.01 (m, 1H), 6.96 (s, 1H), 6.84 (d, J = 7.8 Hz, 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 = 7.5 Hz, 3H).

Compound 61. N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.94 (t, J = 2.5 Hz, 1H), 7.67-7.62 (m, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.33 (s, 1H) ), 7.27-7.04 (m, 5H), 6.84 (d, J = 11.3 Hz, 1H), 6.46-6.29 (m, 1H), 4.18 (td, J = 7.0, 2.7 Hz, 2H), 4.00-3.73 ( m, 3H), 2.90 (s, 2H), 1.97 (h, J = 7.3 Hz, 4H), 1.04-0.92 (m, 3H).

Compound 62. N2-(3-Methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4- Tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.54-7.50 (m, 2H), 7.41 (s, 1H), 7.32 (s, 1H), 7.25-7.16 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 11.0 Hz, 2H), 4.17 (t, J = 7.1 Hz, 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 = 7.4 Hz, 3H) .

Compound 63. N2-(3-Chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)pyrimidine-2,4-diamine

¹ H 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 = 8.2 Hz, 1H), 6.80 (s, 1H), 6.66 -6.59 (m, 1H), 4.17 (t, J = 7.2 Hz, 2H), 4.05 (s, 2H), 3.21 (t, J = 6.1 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H) , 1.97 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Compound 64. N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H 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 = 2.2 Hz, 2H), 6.76 (s, 1H), 6.15 (t, J = 2.2 Hz, 1H), 4.16 (t, J = 7.1 Hz, 2H), 3.99 (s, 2H), 3.69 (s, 6H), 3.19 ( t, J = 6.0 Hz, 2H), 2.82 (t, J = 5.9 Hz, 2H), 2.00-1.93 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Compound 65. N2-(3,5-Dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine

¹ H 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), 6.74 (s, 1H), 6.66 (s, 1H), 4.19-4.13 (m, 2H), 3.96 (s, 2H), 3.16 (t, J = 6.1 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.25 (s, 6H), 1.97 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Compound 66. N2-(3-Chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine

¹ H 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 = 7.2 Hz, 2H), 3.98 (s, 2H), 3.15 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 5.8 Hz, 2H), 1.98 (q, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Compound 67. N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.54-7.48 (m, 3H), 7.29 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.93 (t, J = 1.8 Hz, 1H), 6.80 (s, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 3.15 (t, J = 5.9 Hz, 3H), 2.78 (t, J = 6.0 Hz, 2H), 2.34-2.23 (m, 1H), 0.97 ( d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 509.2.

Compound 68. N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetra Hydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.10-7.99 (m, 2H), 7.96 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (d , J = 2.9 Hz, 1H), 7.40 (d, J = 16.8 Hz, 2H), 7.1-6.95 (m, 2H), 6.82 (d, J = 9.1 Hz, 1H), 4.14 (s, 2H), 4.01 (d, J = 7.2 Hz, 2H), 3.21 (s, 2H), 2.88 (s, 2H), 2.33-2.24 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 576.3.

Compound 69. N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)pyrimidine-2,4-diamine

¹ H 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), 6.32 (t, J = 9.3 Hz, 1H), 4.25 (s) , 2H), 4.01-3.96 (m, 2H), 3.26 (d, J = 6.4 Hz, 2H), 2.93 (d, J = 6.9 Hz, 2H), 2.31-2.23 (m, 1H), 0.96 (dd, J = 6.7, 2.7 Hz, 6H);

LC/MS [M+H] ⁺ 476.1.

Compound 70. N2-(3-Chloro-5-fluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline -7-yl)pyrimidine-2,4-diamine

¹ H 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 = 7.2 Hz, 2H), 3.28 (d, J = 6.1 Hz, 2H), 2.92 (d, J = 16.4 Hz, 2H), 2.31-2.23 (m, 1H) , 0.96 (d, J = 6.6 Hz, 6H);

LC/MS [M+H] ⁺ 493.1.

Compound 71. 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4 -tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.65 (s, 1H), 7.51 (d, J = 2.4 Hz, 3H), 7.31 (s, 1H), 7.20 (d, J) = 8.3 Hz, 2H), 7.04 (d, J= 8.2 Hz, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 4.00 (d, J = 7.0 Hz, 4H), 3.72 (d, J) = 4.5 Hz, 3H), 3.17 (t, J = 6.1 Hz, 2H), 2.82 (q, J = 6.6, 5.9 Hz, 2H), 2.32-2.24 (m, 1H), 1.00-0.94 (m, 6H) ;

LC/MS [M+H] ⁺ 538.2.

Compound 72. N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 -yl) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (d, J = 1.7 Hz, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.24-7.07 (m, 3H), 7.04 (d, J = 8.1 Hz, 1H), 6.83-6.69 (m, 3H), 6.15 (t, J = 2.1 Hz, 1H), 4.04-3.95 (m, 4H) , 3.69 (s, 6H), 3.18 (t, J = 6.0 Hz, 2H), 2.82 (q, J = 7.8, 6.1 Hz, 2H), 2.32-2.23 (m, 1H), 0.97 (d, J = 6.7) Hz, 6H);

LC/MS [M+H] ⁺ 500.1.

Compound 73. N2-(3,5-Dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.93 (d, J = 1.71 Hz, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.26-7.11 (m, 3H), 7.05 (d, J = 8.1 Hz, 1H), 6.81-6.64 (m, 3H), 6.14 (t, J = 2.1 Hz, 1H), 4.01-3.92 (m, 4H) , 3.18 (t, J = 6.0 Hz, 2H), 2.82 (q, J = 7.8, 6.1 Hz, 2H), 2.32-2.23 (m, 1H), 2.15 (s, 6H), 0.97 (d, J = 6.7) Hz, 6H);

LC/MS [M+H] ⁺ 468.1.

Compound 74. N2-(3-Chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) Pyrimidine-2,4-diamine

¹ H 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 = 8.3 Hz, 1H), 6.98-6.91 (m, 1H), 6.77 (s, 1H), 4.03-3.94 (m, 4H), 3.17 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H), 2.33-2.23 ( m, 1H), 0.97 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 474.6.

Compound 75. 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) ) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (d, J = 2.2 Hz, 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 = 8.0 Hz, 1H), 4.03-3.93 (m, 4H), 3.73-3.66 (m, 3H) ), 3.17 (t, J = 6.1 Hz, 2H), 2.91-2.77 (m, 2H), 2.30-2.23 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 467.1.

Compound 76. 5-(1-Isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyri midine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (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 = 6.1 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 7.4 Hz, 1H), 6.75 (s, 1H), 4.02-3.96 (m) , 4H), 3.16 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H), 2.26 (d, J = 6.4 Hz, 1H), 0.97 (d) , J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 454.7.

compound 77. 5-(1-isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2, 4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.50 (s, 1H), 7.31 (d, J) = 7.5 Hz, 3H), 7.21 (d, J = 8.2 Hz, 1H), 7.03 (q, J = 7.8 Hz, 3H), 6.76 (s, 1H), 4.00 (d, J = 7.5 Hz, 4H), 3.16 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.32-2.24 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 454.7.

Compound 78. N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- Day) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d) δ 8.42-8.36 (m, 1H), 8.00 (s, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.52 (s, 2H), 7.22 (d , J = 2.3 Hz, 1H), 7.18-7.04 (m, 4H), 6.82 (s, 1H), 4.05-3.97 (m, 4H), 3.22 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.34-2.22 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 509.1.

Compound 79. N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline- 7-yl)pyrimidine-2,4-diamine

¹ H 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 = 8.3 Hz, 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, 1.1 Hz, 6H);

LC/MS [M+H] ⁺ 476.1.

Compound 80. 5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) ) pyrimidine-2,4-diamine

¹ H 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 = 4.8 Hz, 2H), 4.00 ( d, J = 7.3 Hz, 3H), 3.82 (s, 2H), 3.21 (q, J = 6.9 Hz, 1H), 3.13 (t, J = 6.0 Hz, 3H), 2.74 (t, J = 5.9 Hz, 2H), 2.32-2.22 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H), 0.98 (d, J = 6.7 Hz, 6H);

LC/MS [M+H] ⁺ 482.5.

Compound 81. 2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl) -1H-pyrazol-1-yl)ethan-1-ol

¹ H 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 = 2.2 Hz, 1H), 4.33 (t, J) = 4.7 Hz, 2H), 4.08 (t, J = 4.7 Hz, 2H), 3.94 (s, 2H), 3.71 (s, 6H), 3.17 (t, J = 6.0 Hz, 2H), 3.01 (s, 1H) ), 2.80 (t, J = 5.9 Hz, 2H);

LC/MS [M+H] ⁺ 488.2.

Compound 82. 2-(4-(2-(3,5-Dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.68 (d, J = 0.8 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 1.5 Hz, 2H), 7.08 (d, J = 7.7 Hz, 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 = 6.0 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.28 (s, 6H) ;

LC/MS [M+H] ⁺ 456.3.

Compound 83. 2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.63 (s, 1H), 7.57 (d, J = 5.7 Hz, 2H), 7.22 (d, J = 2.2 Hz, 1H), 7.15-7.09 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 10.5 Hz, 2H), 4.36-4.31 (m) , 2H), 4.11-4.06 (m, 2H), 3.85 (s, 2H), 3.15 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H) , 2.22 (s, 3H);

LC/MS [M+H] ⁺ 456.2.

Compound 84. 2-(4-(2-(3-Chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H) ), 7.18 (t, J = 8.0 Hz, 2H), 7.09 (d, J = 7.3 Hz, 3H), 6.96 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 4.38-4.32 (m) , 2H), 4.09 (t, J = 4.8 Hz, 2H), 3.96 (s, 2H), 3.14 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H).

Compound 85. 2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethan-1-ol

¹ H NMR (300 MHz, Chloroform-d) δ 7.93 (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), 6.93 (m, 1H), 6.78 (s, 1H), 4.36 (m, 2H), 4.08 (t, J = 4.8 Hz, 2H), 3.95 (s, 2H) , 3.15 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H);

LC/MS [M+H] ⁺ 496.51.

<Example 2. Confirmation of inhibitory activity on Tyro3, Axl and Mer of TAM receptor inhibitory compounds>

In order to evaluate the inhibitory activity of the compound according to the present invention to Tyro3, Axl and Mer, the following experiment was performed.

The specific experimental method was performed according to the method provided by cisbio. Prepare the compounds of Examples at various concentrations, add Tryo3, Axl, or Mer and substrate peptides to start the reaction, and add a solution containing EDTA after 1 hour to stop the reaction, and then phosphorylation The amount of the peptide was measured. At this time, the amount of phosphorylated peptide is treated with an antibody that recognizes the phosphorylated peptide with europium (Eu) attached, and after 1 hour, using an Envision Reader, light is emitted at a wavelength of 320 nm or 340 nm for excitation (excitation). ), and by measuring the amount of light emitted at 665 nm, the degree of TAM receptor inhibition was confirmed, and the TAM receptor inhibitory activity (IC ₅₀ value) of each compound was analyzed using the GraphPad Prism program. Thus, it is shown in Table 1 below. In this case, LDC1267, a TAM receptor inhibitor compound, was used as a positive control group.

condition IC ₅₀ (μM) Tyro 3 Axl Mer compound 1 0.025 0.066 0.012 compound 3 0.000041 0.067 0.012 compound 4 0.0023 0.044 0.0014 compound 5 0.016 0.21 0.016 compound 6 0.000041 0.21 0.016 compound 7 0.028 1.9 0.24 compound 8 0.016 0.44 0.023 compound 9 0.000012 0.73 0.026 compound 10 0.00042 0.033 0.00036 compound 11 0.055 3.8 0.057 compound 12 0.075 >10 >10 compound 13 0.061 >10 1.8 compound 14 0.013 5.2 1.5 compound 15 0.000052 0.082 >10 compound 16 0.0024 7.07 0.33 compound 17 0.0035 1.15 0.0013 compound 18 0.0094 1.5 0.0019 compound 19 0.00016 0.041 >10 compound 20 0.0002 0.27 0.0049 compound 21 0.0018 4.7 0.74 compound 22 0.017 0.5 0.0043 compound 23 0.004 4.5 0.35 compound 24 0.017 >10 3.6 compound 25 0.000097 0.043 0.00078 compound 26 0.05 >10 2.1 compound 27 0.0000062 >10 8.0 compound 28 0.023 2.7 0.32 compound 29 0.0091 3.6 0.091 compound 30 0.008 6.2 0.033 compound 31 0.052 8.2 >10 compound 32 0.086 6.4 0.16 compound 33 0.0003 1.16 0.39 compound 34 0.0018 2.15 1.25 compound 35 0.00013 1.12 2.53 compound 36 0.00013 0.59 2.35 compound 37 0.001 2.35 5.26 compound 38 0.0023 5.67 2.35 compound 39 0.0016 2.56 1.25 compound 40 0.0086 8.16 5.46 compound 41 0.0097 2.56 1.25 compound 43 0.064 2.57 6.54 compound 44 0.00034 0.86 1.25 compound 45 0.018 4.56 3.65 compound 46 0.0039 1.25 0.87 compound 47 0.00017 2.35 0.23 compound 48 0.00016 1.65 0.15 compound 49 0.0041 4.56 0.54 compound 50 0.00014 0.99 0.13 compound 51 0.00023 1.46 0.087 compound 52 0.0014 3.56 0.64 compound 53 0.0083 4.87 0.58 compound 54 0.00034 2.36 1.25 compound 55 0.0001 5.65 3.25 compound 56 0.009 4.58 0.23 compound 57 0.00017 6.59 0.19 compound 58 0.0016 2.73 0.25 compound 59 0.000012 0.99 0.15 compound 60 0.000012 0.9 0.33 compound 61 0.00013 0.77 0.13 compound 62 0.0073 4.65 0.52 compound 63 0.00032 5.78 0.47 compound 64 0.0042 4.56 0.89 compound 65 0.0017 1.25 0.98 compound 66 0.00027 1.11 0.96 compound 67 0.00017 1.05 0.85 compound 68 0.0043 2.35 0.54 compound 69 0.00016 0.96 0.85 compound 70 0.00027 2.45 0.65 compound 71 0.0057 1.25 0.87 compound 72 0.025 5.65 0.98 compound 73 0.0028 4.89 0.32 compound 74 0.0012 1.25 0.18 compound 75 0.0088 1.65 0.52 compound 76 0.0094 2.36 0.68 compound 77 0.013 4.65 0.56 compound 79 0.019 10 6.21 compound 81 0.0036 2.36 0.35 compound 82 0.00058 1.58 0.15 compound 84 0.0006 3.65 0.054 compound 85 0.00001 1.25 0.065 Positive control (LDC1267) 0.0048 0.0049 0.068

Comparative compound 1

0.0001 14.21 0.21 Comparative compound 2

0.001 1.5 0.1 Comparative compound 3

>1 >5 >0.1 Comparative compound 4

>10 >10 >0.1 Comparative compound 5

>10 >10 >0.1

As shown in Table 1, the compounds 1 to 85 of the present invention in the [Formula 1] structure, R ₁ substituent includes a pyrazole group substituted with an alkyl group, a hydroxyalkyl group or a piperidine group, R ₂ substituent is an amino group, an acetamino group Or it contains a trihalogenacetamino group, R ₃ As a compound when the substituent is substituted with a phenyl group, the IC ₅₀ value for Tyro 3 showed a strong activity of 0.0000062 ~ 0.086 μM.

However, unlike compounds 1 to 85 of the present invention, Comparative Compound 3 is substituted with a pyridine group instead of a pyrazole group substituted with an alkyl group, a hydroxyalkyl group or a piperidine group in [Formula 1] in which the R ₁ substituent has a tetrahydroisoquinoline structure. In the case of not, Comparative Compounds 4 and 5 include a pyrazole group in which the R ₁ substituent is substituted with a methyl group in [Formula 1], but does not include a tetrahydroisoquinoline structure, and the R ₃ substituent contains a hetero atom instead of a phenyl group As a compound in the case of being substituted with an aryl group including, it was confirmed that Comparative Compounds 3 to 5 had significantly lower TAM receptor inhibitory activity compared to compounds 1 to 85 of the present invention, and in particular, the inhibitory activity against Tyro 3 was as low as 1 μM or more. .

Therefore, it was found that there is a large difference in the TAM receptor inhibitory activity depending on the substituent of the pyrimidine derivative. In particular, in the case of the compound of the present invention, the inhibitory effect on Tyro3 among the TAM receptors was more excellent, preventing or treating cancer without side effects It was found that it can be usefully used as a composition for

<Example 3. Confirmation of hERG toxicity of TAM receptor inhibitory compound>

In the development of a therapeutic agent, not only the therapeutic effect but also the toxicity of the drug plays an important role. Human ether-a-go-go-related gene (hEGR) toxicity is the most commonly used as a criterion for judging drug toxicity, and most pharmaceutical companies judge that toxicity is high when hERG IC ₅₀ is less than 0.1 μM and stop drug development. On the other hand, when the hERG IC ₅₀ value is 10 μM or more, it is judged that there is no toxicity.

Accordingly, human ether-a-go-go-related gene (hERG) assays for compounds 3, 6 and 20 were performed to confirm the degree of drug toxicity caused by the TAM receptor inhibitory compound of the present invention.

As a result of hERG assay, compounds 3, 6, and 20 of the present invention exhibited hERG IC ₅₀ values of 50 μM or more, confirming that there is no hERG toxicity.

However, unlike the compounds of the present invention, in the case of Comparative Compounds 1 to 5 that do not include the tetrahydroisoquinoline structure in [Formula 1], the hERG IC ₅₀ value was 1 μM or less, confirming that hERG toxicity was present.

Therefore, the R ₁ substituents to R ₃ substituents of the structure of the present invention [Formula 1] have a significant effect on TAM receptor inhibitory activity and hERG toxicity, so that the compound having a substituent according to the present invention has no toxicity and exhibits excellent anticancer effect Could know.

<Formulation Example 1. Preparation of powder>

Compound 3 (N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 of the present invention) -yl) pyrimidine-2,4-diamine) 2 g and lactose 1 g were mixed and filled in an airtight bag to prepare a powder.

<Formulation Example 2. Preparation of tablets>

Compound 3 (N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 of the present invention) -yl) pyrimidine-2,4-diamine) 100 mg, microcrystalline cellulose 100 mg, lactose hydrate 60 mg, low-substituted hydroxypropyl cellulose 20 mg, and magnesium stearate 2 mg Therefore, tablets were prepared by tableting.

<Formulation Example 3. Preparation of capsules>

Compound 3 (N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 of the present invention) -yl) pyrimidine-2,4-diamine) 100 mg, microcrystalline cellulose 100 mg, lactose hydrate 60 mg, low-substituted hydroxypropyl cellulose 20 mg, and magnesium stearate 2 mg Accordingly, the above ingredients were mixed and filled in a gelatin capsule to prepare a capsule.

<Formulation Example 4. Preparation of Pills>

Compound 3 (N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 of the present invention) -yl) pyrimidine-2,4-diamine) 90 mg, glutinous rice starch 5 mg, purified water 5 mg, and dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as an additive to inhibit hygroscopicity are mixed in small amounts, and then usually 100 mg of pills were made according to the method of

< Formulation example 5. Preparation of Injection>

Compound 3 (N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7 of the present invention) -yl) pyrimidine-2,4-diamine) 10 mg, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjuster were mixed, and the content of the above components per 1 ampoule (2 ml) was prepared according to a conventional injection preparation method. .

Claims (5)

A pyrimidine derivative compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ¹ is hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, or substituted or unsubstituted piperidinyl,
wherein said substituted alkyl, or substituted piperidinyl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, trihalogen consisting of acetyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ heterocycloalkyl, C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl substituted with one or more substituents selected from the group;
R ² is amino, acetamino, or trihalogenacetamino; and
R ³ is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl, substituted or unsubstituted C ₄ - C ₁₀ heteroaryl, or a substituted or unsubstituted fused ring in which C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl are fused;
wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is halogen, C ₁ -C ₁₀ haloalkyl, oxo(=O), hydroxy, cyano , nitro, amino, acetamino, trihalogenacetamino, trihalogenacetyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₄ -C ₁₀ cycloalkyl, C ₄ -C ₈ heterocycloalkyl, C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ substituted with one or more substituents selected from the group consisting of heteroaryl; do. According to claim 1,
In Formula 1,
R ¹ is hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, or substituted or unsubstituted piperidin-4-yl,
wherein said substituted alkyl, or substituted piperidin-4-yl, is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino , trihalogenacetyl, C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ substituted with one or more substituents selected from the group consisting of alkoxy;
R ² is amino, acetamino, or trihalogenacetamino; and
R ³ is substituted or unsubstituted C ₄ -C ₁₀ aryl,
wherein said substituted aryl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (=O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, trihalogenacetyl, C ₁ -C ₁₀ substituted with one or more substituents selected from the group consisting of alkyl, or C ₁ -C ₁₀ alkoxy;
A pyrimidine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is 3. The method of claim 1 or 2,
The compound of Formula 1 is,
1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydroiso quinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 1);
1-(7-(2-(3-methyl-4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-di hydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 2);
N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 3);
N2-(3-methyl-4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 4);
1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 5);
2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethanol (Compound 6);
1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4 -dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (compound 7);
1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3, 4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 8);
2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol- 1-yl)ethanol (Compound 9);
2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazole -1-yl)ethanol (Compound 10);
1-(7-(2-(3,5-difluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) -3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 11);
1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 12);
1-(7-(2-(2,3-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 13);
1-(7-(2-(2-methyl-3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) -3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (Compound 14);
2-(4-(2-(3,5-difluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -Pyrazol-1-yl)-ethan-1-ol (Compound 15);
2-(4-(2-(3,5-bis(trifluoromethyl)phenylamino)-4-((1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5 -yl)-1H-pyrazol-1-yl)-ethan-1-ol (Compound 16);
2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)-ethan-1-ol (Compound 17);
2-(4-(2-(2-methyl-3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -Pyrazol-1-yl)-ethan-1-ol (Compound 18);
N2-(3,5-difluorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetra hydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 19);
N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 20);
N2-(3,5-bis(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(1-(piperidin-4- yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 21);
N2-(2,3-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 22);
N2-(3,5-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 23);
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 24);
N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 25);
1-(7-(2-(3,5-dimethoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydro Isoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 26);
1-(7-(2-(3,5-bis(trifluoromethyl)phenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 ,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 27);
1-(7-(2-(3,5-difluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-di hydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 28);
N2-(3,5-difluorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5 -(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 29);
N2-(3,5-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 30);
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 31);
N2-(2,3-dichlorophenyl)-N4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (Compound 32);
N2-(3-chloro-5-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 33);
N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 34);
2-(4-(2-(3-chloro-5-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-Pyrazol-1-yl)ethan-1-ol (Compound 35);
2-(4-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin- 5-yl)-1H-pyrazol-1-yl)ethan-1-ol (Compound 36);
N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2 ,4-diamine (Compound 37);
N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 38);
5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoromethyl)phenyl ) pyrimidine-2,4-diamine (Compound 39);
N2-(3-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 40);
5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine ( compound 41);
N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 42);
5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(3-(trifluoromethyl)benzyl ) pyrimidine-2,4-diamine (Compound 43);
5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(o-tolyl)pyrimidine-2, 4-diamine (Compound 44);
N2-(2,6-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 45);
5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2, 4-diamine (Compound 46);
N2-(5-Fluoro-2-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 47);
N2-(3,5-dichlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 48);
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 49);
N2-(3,5-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 50);
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 51);
5-(1-Isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 52);
N2-(3,5-dimethoxyphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 53);
N2-(3,5-dimethylphenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 54);
N2-(3-chlorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 55);
5-(1-isopropyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 56);
5-(1-isopropyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2 ,4-diamine (Compound 57);
5-(1-isopropyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 58);
N2-(3,5-dichlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 59);
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 60);
N2-(3,5-difluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 61);
N2-(3-methoxy-5-(trifluoromethyl)phenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine (Compound 62);
N2-(3-chloro-5-fluorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 63);
N2-(3,5-dimethoxyphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 64);
N2-(3,5-dimethylphenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 65);
N2-(3-chlorophenyl)-5-(1-propyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2 ,4-diamine (Compound 66);
N2-(3,5-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 67);
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 68);
N2-(3,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl ) pyrimidine-2,4-diamine (Compound 69);
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 70);
5-(1-Isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxy-5-(trifluoromethyl)phenyl)-N4-(1,2,3,4-tetrahydro Isoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 71);
N2-(3,5-dimethoxyphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl) pyrimidine-2,4-diamine (Compound 72);
N2-(3,5-dimethylphenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 73);
N2-(3-chlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine- 2,4-diamine (Compound 74);
5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(3-methoxyphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 75);
5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-N2-(m-tolyl)pyrimidine-2 ,4-diamine (Compound 76);
5-(1-isobutyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine (Compound 77);
N2-(2,3-dichlorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyri midine-2,4-diamine (Compound 78);
N2-(2,5-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl )pyrimidine-2,4-diamine (Compound 79);
5-(1-isobutyl-1H-pyrazol-4-yl)-N2-(2-isopropylphenyl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine -2,4-diamine (Compound 80);
2-(4-(2-(3,5-dimethoxyphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethan-1-ol (Compound 81);
2-(4-(2-(3,5-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 82);
2-(4-(2-(2,3-dimethylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 83);
2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol- 1-yl)ethan-1-ol (Compound 84); and
2-(4-(2-(2,3-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyra zol-1-yl)ethan-1-ol (Compound 85);
A pyrimidine derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that at least one selected from the group consisting of A pharmaceutical composition for preventing or treating cancer comprising the pyrimidine derivative compound of claim 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The method of claim 4,
The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial 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 myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse giant B-cell lymphoma, ampulla Barter's Cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, nerve Glioma, neuroblastoma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant melanoma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, Gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer , rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic 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, A pharmaceutical composition for preventing or treating cancer, characterized in that it is selected from the group consisting of rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer.