KR20190027765A - Pyrazole 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

Since a pyrimidine derivative compound substituted with a pyrazole group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof has an excellent TAM receptor inhibitory effect, particularly a selective inhibitory effect on Tyro3, it is possible to be usefully used as a composition for preventing or treating cancer, which has excellent effects, without side effects caused by inhibiting other TAM receptors, Axl and Mer.

Description

TECHNICAL FIELD [0001] The present invention relates to a pyrimidine derivative substituted with a pyrazole group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer, < RTI ID = 0.0 > and / or < / RTI >

The present invention relates to a pyrimidine derivative compound substituted with a pyrazole 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 TAM receptor is called the TAM family and is a receptor tyrosine kinase (RTK), which collectively refers to three receptors, Tyro3, Axl and Mer (Mertk). The TAM receptor is a protein in the cell membrane that binds to and transmits signals to the outside of the cell. The TAM receptor activates a kinase inside the cell to transmit signals into the cell (Lemke, G., 2013 ).

TAM receptor signal transduction is involved in platelet aggregation and thrombus formation, erythropoiesis, and homeostasis of endothelial cells and vascular smooth muscle. In addition, the TAM-dependent pathway is known to be involved in spermatogenesis, retention of retinal and mammary function, bone physiology, atherosclerosis, nervous system biology, and permeability of vascular brain barriers (Linger, RMA, et al. , 2008; Paolino M., et al., 2016).

The phenotype of the TAM receptor, Tyro 3, Axl, and Mer knockout animal models, when Tyro 3, Axl, and Mer were knocked out alone, antigen-presenting cells , APC) and over-production of autoantibody production and protection of thrombosis. On the other hand, when Mer is knocked out, it causes excretion dysfunction of the apoptotic cell, retinitis pigmentosa, and inflammation. In addition, when Axl is knocked out, it is known that it exhibits serious side effects such as autoimmune encephalomyelitis, enhancement of dehydration, and excretion function deficiency of apoptotic cells. On the other hand, no specific problem was found when Tyro 3 was knocked out. Thus, the development of selective inhibitors of TAM receptors, particularly Tyro 3, has been noted as a way to overcome the side effects of TAM receptor inhibition.

So far, studies on TAM receptors have largely focused on the role of these two processes in cancer development and immune regulation. Recently, Tyro 3 target inhibitor has been proposed as a drug target for breast cancer treatment in relation to cancer development of TAM receptor. Tyro 3 is expressed twice more in liver cancer than normal tissue, and cancer growth, liver (Duan, Y., et al., 2016). Therefore, controlling the inhibition or overexpression of Tyro 3 may be an important target for the development of liver cancer treatment agents.

In the ovarian cancer stage 3, the survival rate is as low as 5 years. The expression of Tyro 3 RNA is increased in SKOV3 / TR, an ovarian cancer cell line resistant to taxol, which is known as an anticancer drug, It has been reported that RNA expression of Mer is decreased. This increase in the expression level of Tyro 3 increases the survival of cancer cells in SKOV3 / TR and leads to drug resistance to taxol (Lee, C., 2015). In addition, it has been shown that expression of Tyro3 is increased in skin cancer, and that knockdown of Tyro 3 in melanoma cells inhibits cell proliferation and colony formation.

Therefore, the development of selective inhibitor of Tyro 3 is expected to develop a cancer treatment agent which is excellent in cancer treatment effect while minimizing side effects and capable of overcoming resistance to anticancer drugs.

Korean Patent Laid-Open No. 10-2009-0121399 discloses a dianilinopyrimidine derivative, a pharmaceutical composition containing the same, and a process for producing the same. International Publication No. 2017-059280 discloses a novel PAN-TAM Inhibitors and MER / AXL dual inhibitors are disclosed, and Chinese Patent Publication No. 106588885 discloses 2-substituted aromatic ring-pyrimidine derivatives, their preparation methods and uses.

The inventors of the present invention discovered a pyrimidine derivative compound as a novel TAM receptor inhibitory compound in the course of studying TAM receptor inhibitory compounds and confirmed the TAM receptor inhibitory activity and hERG toxicity according to a specific substituent of pyrimidine derivatives and found that there was no hERG toxicity Of the present invention is also excellent in the selective inhibitory effect of Tyro3 among TAM receptors.

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

Duan, Y., et al., Overexpression of Tyro3 and its implications in hepatocellular carcinoma progression, International Journal of Oncology, 48 (1), 358-366, 2016. Lee, C., Overexpression of tyrosine 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.

It is an object of the present invention to provide a pyrimidine derivative compound substituted with a pyrazole 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 represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R < ¹ > is hydroxy, or substituted or unsubstituted piperidinyl,

Wherein the substituted piperidinyl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (= O), hydroxy, cyano, nitro, amino, acetamido, amino, acetamido tree halogen amino, tri-acetyl halogen, C ₁ - ₁ > is selected from the group consisting of 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. Lt; / RTI > or more substituents;

R ² is a substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl, or a substituted or unsubstituted C ₄ -C ₁₀ heteroaryl,

Wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is optionally substituted with at least _one substituent selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, Acetic amino, tri-amino-acetamide halogen, tri-acetyl halogen, 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 heteroaryl;

R ³ is a substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl group, a substituted or unsubstituted C ₄ - C ₁₀ heteroaryl, and aryl, or C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl alkyl fused substituted or unsubstituted fused ring,

Wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano , nitro, amino, acetamido, amino, acetamido tree halogen amino, tri-acetyl halogen, 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 heteroaryl; And

n is an integer of 0 to 4;

The term " alkyl " refers to a straight or branched chain hydrocarbon group of a single bond, for example, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl and 1-methylpropyl.

The term " alkoxy " refers to an oxygen group to which a single bond of a saturated or a branched saturated hydrocarbon is bonded, and includes, for example, methoxy, ethoxy, propoxy, n-butoxy, .

The term " cycloalkyl " refers to a saturated, single bond saturated hydrocarbon group, depending on the number of carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term " heterocycloalkyl " refers to a saturated monocyclic saturated hydrocarbon group containing at least one heteroatom such as N, O, or S, and includes the number and kind of heteroatoms contained in the ring, Pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

The term " aryl " means an aromatic substituent having at least one ring having a covalent pi electron system, such as phenyl, benzyl, and the like.

The term " heteroaryl " refers to an aromatic ring compound containing at least one heteroatom such as N, O, or S, and includes, depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, pyrrolyl, furanyl, Pyrimidinyl, pyranyl, and the like.

Preferably, in Formula 1,

R ¹ is hydroxy, or substituted or unsubstituted piperidin-4-yl,

Wherein said substituted piperidin-4-yl is substituted with at least one substituent selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ alkoxy;

R ² is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, or substituted or unsubstituted C ₄ -C ₁₀ aryl,

Here, the substituted cycloalkyl, substituted heterocycloalkyl, or substituted aryl is a halogen, C ₁ -C ₁₀ haloalkyl, oxo (= O), hydroxy, cyano, nitro, amino, acetamido, amino, halogen tree Acetic amino, tri-acetyl halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, or C ₄ -C ₈ heterocycloalkyl is substituted with one or more substituents selected from the group consisting of alkyl;

R ³ is a substituted or unsubstituted C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl is a substituted or unsubstituted fused ring fusion,

Wherein said substituted aryl or substituted fused ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, , C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ alkoxy;

n is an integer of 0 to 4;

More specifically, the compound of formula (1)

Pyrazol-4-yl) pyrimidin-4-ylamino) piperidine-l-carboxylic acid ethyl ester was prepared in accordance with the general method of example 1 from 1- (4- (2- (3,5- 1-yl) -2,2,2-trifluoroethanone (Compound 1);

(Piperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine- 2,4-diamine (Compound 2);

Yl) -1H-pyrazol-1-yl) ethanol (compound (2)) was obtained in the same manner as in 3);

Pyrazol-4-yl) -2- (2- (2,2,2-trifluoroacetyl) -1,2- , 3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) piperidin-l-yl) -2,2,2-trifluoroethanone (Compound 4);

1 - (4- (2- (3-methyl-4-chlorophenylamino) -5- (1- (2- hydroxyethyl) -lH- pyrazol-4- yl) pyrimidin- Piperidin-1-yl) -2,2,2-trifluoroethanone (Compound 5);

Pyrazol-4-yl) -2- (4-methoxyphenylamino) pyrimidin-4-ylamino) piperidine The title compound was prepared from 1- (4- (5- (1- -1-yl) -2,2,2-trifluoroethanone (Compound 6);

Ylamino) -2- (l, 2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin- Pyrazol-1-yl) ethanol (Compound 7);

Yl) -lH-pyrazol-l-yl) ethanol [0252] < EMI ID = (Compound 8);

Yl) -1H-pyrazol-1-yl) ethanol (compound 9 (2-methyl-4- );

N - ((1 s, 4s) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2- hydroxyethyl) -1 H- pyrazol- -Ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 10);

N - ((ls, 4s) -4- (5- (1- (2-hydroxyethyl) -lH-pyrazol- Acetyl) -1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 11);

1 - (2-hydroxyethyl) -1 H-pyrazol-4-yl) pyrimidin-4-yl Amino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 12);

2- (3,5-Dichlorophenylamino) pyrimidin-5-yl) -1H-pyrazol-1-yl ) Ethanol (Compound 13);

2- (4- (4 - ((1S, 4S) -4-aminocyclohexylamino) -2- (1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin- ) -LH-pyrazol-l-yl) ethanol (Compound 14);

Yl) - lH-pyrazol-l-yl) ethanol To a solution of 2- (4- (4 - ((1S, 4S) -4-aminocyclohexylamino) -2- (Compound 15);

(1 - (2-hydroxyphenyl) -1H-pyrazol-4-yl) -N- ((1S, 4S) -4 - Pyrimidin-4-yl) amino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 16);

2- (3-methyl-4-chlorophenylamino) pyrimidin-5-yl) -1H-pyrazole-1 -Yl) ethanol (Compound 17);

4- (2- (3,5-Dichlorophenylamino) -5- (1- (1- (2,2,2-trifluoroacetyl) piperidin-4- Yl) -1H-pyrazol-4-yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 18);

N - ((lr, 4r) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2- hydroxyethyl) -1H- pyrazol-4-yl) pyrimidin- -Ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 19);

N4- ((ls, 4s) -4-aminocyclohexyl) -N2- (3,5-dichlorophenyl) -5- (1- (piperidin- ) Pyrimidine-2,4-diamine (Compound 20);

2- (3,5-Dichlorophenylamino) pyrimidin-5-yl) -1H-pyrazol-1-yl ) Ethanol (Compound 21);

N - ((lr, 4r) -4- (2- (3,5-Difluorophenylamino) -5- (1- (2- hydroxyethyl) -lH-pyrazol-4-yl) pyrimidine -4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 22);

2- (3,5-Difluorophenylamino) pyrimidin-5-yl) -1H-pyrazole-1 Yl) ethan-1-ol (Compound 23);

4- (2- (3,5-bis (trifluoromethyl) phenylamino) -5- (1- (2-hydroxyethyl) -1H-pyrazol- Yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 24);

2- (3,5-bis (trifluoromethyl) phenylamino) pyrimidin-5-yl) -1H-pyrazolo [3,4- Yl) ethan-1-ol (Compound 25);

Pyrazol-4-yl) pyrimidin-4-ylamino) - < / RTI & Cyclohexyl) -2,2,2-trifluoroacetamide (Compound 26);

4-yl) phenylamino) pyrimidin-5-yl) -1H-pyrazole-l- Yl) ethan-1-ol (Compound 27);

4-yl) phenylamino) pyrimidin-5-yl) -lH-pyrazol-l-yl) Ethan-1-ol (Compound 28); And

4- (4- (piperidin-4-yl) phenylamino) pyrimidin-5-yl) -1H-pyrazole- Yl) ethan-1-ol (Compound 29); And 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 following Reaction Scheme 1, which is a method disclosed in Korean Patent Application No. 10-2017-0056002.

Reacting a compound represented by the formula (B) with NH ₂ R ² to prepare a compound represented by the formula (C) (step 1);

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

(Step 3) of producing a compound represented by the compound A from the compound represented by the compound D prepared in the step 2 above.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ^{1 '} is a pyrazole derivative, R ² and R ³ are as defined in Formula 1;

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 step by step.

In the process for producing a compound represented by the formula 1 (or the compound A) according to the present invention, the step 1 of Scheme 1 may be carried out by reacting the compound represented by the compound B with NH ₂ R ² to prepare a compound represented by the compound C .

In this case, step 1 may be understood as a step of introducing -NH-R ² substituent to the parent compound of the compound of the present invention. The compound represented by the formula ( ¹⁾ can be prepared by introducing an -NH-R ² substituent at the X ¹ position of the compound represented by the formula (B) to prepare a compound represented by the formula (C) , 4-dioxane with a compound represented by DIPEA (N, N-diisopropylethylamine) and compound B can be carried out.

The solvent used for the reaction may be any solvent which can dissolve the compound represented by the compound B and DIPEA. Examples of the solvent include tetrahydrofuran (THF); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Lower alcohols including methanol, ethanol, propanol and butanol; But are not limited to, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, Naphthalene-2-sulphonate, mandelate, and naphthalene-2-sulphonate, and salts and esters thereof, such as phenylbutyrate, chitrate, lactate, A mixture thereof, and 1,4-dioxane can be used.

Further, the reaction temperature is not particularly limited, but can be preferably carried out at 0 캜 to 100 캜, for example, at room temperature. Furthermore, the reaction time is not particularly limited, but can be set to, for example, 2 hours to 10 hours. As another example, the reaction can be carried out for 20 minutes to 8 hours in the case of heating.

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

In this case, step 2 can be understood as a step of introducing an R ^{1 '} substituent into a compound represented by the compound C, and R ^1' is selectively introduced according to a desired compound to prepare a compound represented by the formula .

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.As one example, but not limited thereto, as a method for introducing R ^{1 '} , DMF is mixed with Na ₂ CO ₃ and a compound represented by C,

, And Pd (dppf) ₂ Cl ₂ , but the compound represented by the compound D can be prepared in a similar manner to the step 2 of the present invention by a method used in a state of the art Are included in the present invention without limitation as long as they can be carried out as a step.

Examples of the solvent that can be used in the reaction include but are not limited to dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazenesulfonate, toluene Sulfonates, chlorobenzene sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, secrates, lactates,? -Hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, Ether solvents including methanol, ethanol, propanol, isopropanol, n-butanol, n-butanol, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran, dioxane, Lower alcohols including propanol and butanol, and mixtures thereof, and DMF can preferably be used.

In addition, the reaction temperature is not particularly limited, but can be preferably carried out at 50 to 150 캜, for example, at 90 캜. Further, the reaction time is not particularly limited, but can be set to, for example, 10 hours to 40 hours, and still another example can be carried out over 20 hours to 30 hours.

In the process for producing the compound represented by the formula 1 (or the compound A) according to the present invention, the step 3 of the above reaction scheme 1 is a process for producing a compound represented by the formula 1 (or the compound A) from the compound represented by the compound D prepared in the above step 2 Is prepared.

In this case, step 3 can be understood as a step of introducing a -NHR ³ substituent into a compound represented by the compound D, and selectively introducing an -NHR ³ substituent according to a desired compound to obtain a compound represented by the formula (1) To produce the compound of the present invention to be displayed.

Examples of the solvent that may be used in the reaction include but are not limited to ethoxyethanol, 1,4-dioxane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM) But are not limited to, dichloroethane, water, acetonazenesulfonate, toluene sulfonate, chlorobenzene sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, secrate, lactate,? -Hydroxybutyrate, glycolate, (Methanesulfonate), methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane , Lower alcohols including methanol, ethanol, propanol and butanol, and mixtures thereof, and preferably ethoxyethanol is used There.

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

Meanwhile, in the process for preparing the compound represented by the formula 1 (or the compound A) according to the present invention, proceed as in the reaction scheme 1, and as a preferable example, the following scheme 2 can be performed.

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ^{1 '} is a pyrazole derivative, and R ² and R ³ are as defined in the above formula (1).

Further, in the process for preparing the compound represented by the formula (1) according to the present invention, more preferred examples include the process for preparing the compounds of the following examples of the present invention. The method for preparing the compound represented by the formula (1) according to the present invention, which is shown in the above Reaction Scheme 1, Reaction Scheme 2 and the method for preparing the compound of the present invention, should be understood as an example of a method for preparing the compound of the present invention, Any method capable of producing the compound represented by the formula (1), which the present invention is producing, is included in the present invention without limitation. Also, it should be understood that the methods presented in the specification of the present invention and manufacturing methods that can be easily modified and modified by those skilled in the art are also included in the scope of the present invention, ≪ / RTI >

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from 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 sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, bromides, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene sulfonate, chlorobenzene Propionate, naphthalene-1, < / RTI > < RTI ID = 0.0 & -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, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

The present invention also relates to a pharmaceutical composition for preventing or treating cancer, which comprises as an active ingredient a pyrimidine derivative compound substituted with a pyrazole group represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

The cancer is also referred to as a malignant tumor. It is an abnormally grown mass due to autonomous overgrowth of the body tissue. It is a mass that rapidly grows as it infiltrates into surrounding tissues and diffuses or transitions to various parts of the body, , And includes carcinoma and sarcoma. More specifically, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition selected from the group consisting of psoriatic myxoma, intrahepatic bile duct carcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, Cholangiocarcinoma, cholangiocarcinoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Barter's bulge, ovarian cancer, ovarian cancer, ovarian cancer cell, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, Cancer, bladder cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Neuroblastoma, renal cancer, renal cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovary, vulvar cancer, ureter cancer Cancer, uterine cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic breast cancer, breast cancer, sarcoma, penile cancer, pancreatic cancer, uterine cancer, uterine cancer, endometrial cancer, uterine cancer, Cancer of the lungs, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acne vulgaris, pancreatic cancer, salivary gland cancer, Kaposi sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, Cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma.

The pharmaceutical composition according to the present invention can be formulated into a suitable form together with a commonly used pharmaceutically acceptable carrier. &Quot; Pharmaceutically acceptable " refers to a composition that is physiologically acceptable and, when administered to humans, does not normally cause an allergic reaction such as gastrointestinal disorders, dizziness, or the like. In addition, the compositions can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method.

Examples of carriers, excipients and diluents that can be contained in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, But are not limited to, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using diluents or excipients such as fillers, stabilizers, binders, disintegrants, surfactants and the like which are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, microcrystalline cellulose, sucrose or lactose, Low-substituted hydroxypropylcellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used. In order to formulate parenteral administration formulations, the pyrimidine derivative compound substituted with a pyrazole group of the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof may be sterilized and / or used as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, And / or adjuvants such as buffers, and other therapeutically useful substances in water to prepare solutions or suspensions, which may be prepared in ampoules or vial unit dosage forms.

The pharmaceutical composition comprises a pyrimidine derivative compound substituted with a pyrazole group of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% by weight to 50% by weight, more preferably 0.001% by weight to 40% by weight, and most preferably 0.001% by weight to 30% by weight, based on the total weight of the composition.

The pharmaceutical composition comprising the compound of formula (I) as an active ingredient of the present invention can be administered to mammals such as rats, livestock, and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. The dosage will depend on the age, sex, body weight, the particular disease or condition being treated, the severity of the disease or condition, the time of administration, the route of administration, the absorption, distribution and excretion of the drug, It depends on judgment. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several doses. The dose is not intended to limit the scope of the invention in any way.

Since the pyrimidine derivatives substituted with the pyrazole group according to the present invention, its optical isomers, or pharmaceutically acceptable salts thereof are excellent in the TAM receptor inhibitory effect, particularly the selective inhibitory effect on Tyro3, other TAM receptors Axl and Mer The present invention can be effectively used as a composition for preventing or treating cancer, which has an excellent effect without any adverse effects caused by inhibition of cancer.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.

≪ Example 1: Synthesis of pyrimidine derivative substituted with pyrazole group and identification of physicochemical properties >

The compounds 1 to 29 of the present invention were prepared by referring to the method disclosed in Korean Patent Application No. 10-2017-0056002, and their physicochemical properties are as follows.

Compound 1. 1- (4- (2- (3,5- Dichlorophenylamino ) -5- (1- (2- Hydroxyethyl ) -1H-pyrazol-4-yl) pyrimidin-4-ylamino) piperidin- 1 -yl) -2,2,2-trifluoroethanone

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.82 (s, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.58 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H ), 6.99 (d, J = 1.9 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H), 4.56 (t, J = 12.3 Hz, 3H), 3.75 (s, 1H), 3.38 (q, J = 12.1 Hz, 2H).

Compound 2. N2- (3,5-Dichlorophenyl) -N4- (piperidin-4-yl) -5- (1- (piperidin- Pyrimidine-2,4-diamine

^{1 H NMR (300 MHz, MeOH} -d 4) δ 7.85 (s, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 6.97 ( J = 1.9 Hz, 1H), 4.42-4.29 (m, 1H), 4.29-4.09 (m, 1H), 3.19 (dd, J = 21.9,13.0 Hz, 4H), 2.83 11.6 Hz, 4H), 2.15 (t, J = 13.1 Hz, 3H), 2.09-1.94 (m, 3H), 1.63-1.43 (m, 3H).

Compound 3. 2- (4- (2- (3,5-Dichlorophenylamino) -4- (piperidin-4-ylamino) pyrimidin- ethanol

¹ H NMR (300 MHz, MeOH-d ₄ )? 7.81 (t, J = 2.2 Hz, 4H), 7.64 J = 8.9 Hz, 2H), 2.84 (dd, J = 13.6, 2H), 3.19 (d, J = 11.0 Hz, 2H), 2.11-1.99 (m, 2H), 1.59-1.40 (m, 3H).

Compound 4. 1- (4- (5- (1- (2-Hydroxyethyl) -1H-pyrazol-4-yl) -2- (2- (2,2,2-trifluoroacetyl) 7-ylamino) pyrimidin-4-ylamino) piperidin-l-yl) -2,2,2-trifluoroethanone

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.79 (d, J = 2.6 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.50-7.38 (m, 3H), 7.10 (t J = 7.3 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 4.76 (d, J = = 4.8 Hz, 3H), 4.06 (t, J = 4.7 Hz, 3H), 3.88 (dt, J = 11.5, 6.0 Hz, 2H), 3.31 = 12.5 Hz, 1H), 2.92 (q, J = 6.3 Hz, 2H), 2.20 (s, 2H), 1.44 (d, J = 21.2 Hz, 3H).

Compound 5. 1- (4- (2- (3-Methyl-4-chlorophenylamino) -5- (1- (2- hydroxyethyl) -1H-pyrazol-4-yl) pyrimidin- Ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.81 (s, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.42 (dd, J (M, 2H), 4.25 (d, J = 7.3 Hz, 1H) (d, J = 4.1 Hz, 1H), 4.11-4.03 (m, 2H), 4.00 (s, 1H), 3.29 (t, J = 13.0 Hz, , 2.37 (s, 3H), 2.19 (s, 2H), 1.56 - 1.35 (m, 2H).

Compound 6. 1- (4- (5- (1- (2-Hydroxyethyl) -1H-pyrazol-4-yl) -2- (4-methoxyphenylamino) pyrimidin- Piperidin-1-yl) -2,2,2-trifluoroethanone

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.73 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.45 (d, J J = 7.2 Hz, 1 H), 4.49 (dd, J = 11.2, 6.7 Hz, 1 H), 4.34 3H), 3.80 (s, 3H), 3.26 (ddd, J = 14.4, 11.9, 2.7 Hz, 2H), 2.96 (t, J = 12.5 Hz, 1H), 2.27-2.11 (m, 2H), 1.52-1.33 (m, 3H).

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

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.32-7.27 (m (D, J = 7.7 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.91 2H), 3.19-3.05 (m, 5H), 2.80-2.70 (m, 4H), 2.06 (d, J = 12.5 Hz, 3H), 1.41-1.28 (m, 5H).

Compound 8. 2- (4- (2- (3-Methyl-4-chlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- 1) ethanol

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.73 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.41 (dd, J = 8.6, 2.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.14 (s, 1H), 4.94 (d, J = 7.6 Hz, 1H) J = 5.6, 4.0 Hz, 2H), 3.08 (dt, J = 12.7, 3.7 Hz, 2H), 2.99-2.79 (m, 1H), 2.73 (td, J = 12.4, 11.9, 2.6 Hz, 3H), 2.36 (s, 3H), 2.10-1.99 (m, 2H), 1.41-1.26 (m, 3H).

Compound 9. 2- (4- (2- (4-Methoxyphenylamino) -4- (piperidin-4-ylamino) pyrimidin-

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.76 (s, 1H), 7.57 (s, 1H), 7.51 (d, J = 2.1 Hz, 2H), 7.49 (d, J = 2.1 Hz, 1H), 2H), 6.85 (d, J = 2.2 Hz, 1H), 4.89 (d, J = 7.5 Hz, 1H), 4.37-4.25 ), 4.05 (dd, J = 5.5, 4.0 Hz, 2H), 3.80 (s, 3H), 3.12 (d, J = 12.8 Hz, 2H), 2.76 , J = 13.3 Hz, 3H), 1.43-1.29 (m, 3H).

Compound 10. N - ((ls, 4s) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2- hydroxyethyl) 4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

¹ H NMR (300 MHz, Chloroform-d)? 7.82 (s, IH), 7.66-7.59 (m, 4H), 6.97 , 4.40 (s, 1H), 1.90 (dd, J = 10.5, 5.3 Hz, 2H), 4.40-4.31 (m, 2H), 4.24 5H), 1.70 (ddd, J = 14.0, 6.8, 4.3 Hz, 5H).

Compound 11. N - ((ls, 4s) -4- (5- (1- (2-hydroxyethyl) Trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.72 (d, J = 3.8 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 2H), 7.51 (s, 1H), 7.37 (t, J = 9.2 Hz, IH), 7.09 (t, J = 7.3 Hz, IH), 6.92 (s, IH), 5.34-5.22 (m, 2H), 4.24 (s, 1H), 4.05 (d, J = 5.5 Hz, 2H), 3.94 J = 5.9 Hz, 2H), 1.80 (s, 6H), 1.61 (d, J = 10.6 Hz, 2H).

Compound 12. N - ((ls, 4s) -4- (2- (3-Chlorophenylamino) -5- (1- (2- hydroxyethyl) -1H- pyrazol- 4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

¹ H NMR (300 MHz, Chloroform-d) 8 8.06 (s, IH), 7.77 (s, IH), 7.63 (D, J = 7.5 Hz, 1H), 4.40-4.31 (m, 1H) 2H), 4.25 (s, IH), 4.07 (t, J = 4.7 Hz, 2H), 3.99 (s, IH), 3.36-2.93 = 14.6, 7.9 Hz, 4H).

2- (3,5-Dichlorophenylamino) pyrimidin-5-yl) -1H-pyrazole- 1-yl) ethanol

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.85 (s, 1H), 7.78 (s, 1H), 7.65 (d, J = 1.9 Hz, 2H), 7.55 (d, J = 0.9 Hz, 1H), (M, 2H), 4.31 (s, 1H), 4.00-3.92 (m, 2H) 2H), 2.95 (d, J = 9.6 Hz, 1H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 4H), 1.26 (s, 2H).

Compound 14 2- (4- (4 - ((ls, 4s) -4-aminocyclohexylamino) -2- (l, 2,3,4-tetrahydroisoquinolin- Yl) -1H-pyrazol-1-yl) ethanol

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.82 (d, J = 1.0 Hz, 1H), 7.76 (s, 1H), 7.53 (s, 1H), 7.44 (d, J = 2.2 Hz, 1H), 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.89 (s, (M, 2H), 1.80 (d, J = 11.4 Hz, 2H), 3.98-3.91 , 3H), 1.63 (t, J = 13.2 Hz, 4H), 1.26 (t, J = 11.6 Hz, 3H).

Compound 15 2- (4- (4 - ((1s, 4s) -4-aminocyclohexylamino) -2- (3- chlorophenylamino) pyrimidin- 1) ethanol

^{1 H NMR (300 MHz, Chloroform} -d) δ 8.05 (t, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.24-7.22 (m, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.94 (dt, J = 7.6, 1.6 Hz, 1H), 5.28 2H), 2.96 (dt, J = 5.3, 3.9 Hz, 2H), 3.96 (dd, J = 5.3, 3.9 Hz, 2H) 1.75 (m, 2H), 1.74-1.60 (m, 4H), 1.26 (dd, J = 9.0, 4.6 Hz, 3H).

Compound 16. N - ((lS, 4S) -4 - ((2- ((4-Chloro-3- methylphenyl) amino) -5- (1- (2- hydroxyphenyl) Yl) pyrimidin-4-yl) amino) cyclohexyl) -2,2,2-trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.78 (s, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.40 (dd, J = 8.7, 2.7 Hz, 1H), 7.25 (s, 1H), 7.06 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.10 (m, 2H), 4.23 (d, J = 6.6 Hz, 1H), 4.12-4.03 (m, 2H), 3.96 (s, 1.76 (d, J = 6.8 Hz, 2H), 1.62 (s, 2H).

Compound 17 2- (4- (4- ((1S, 4S) -4-aminocyclohexylamino) -2- (3-methyl-4-chlorophenylamino) pyrimidin- 1-yl) ethanol

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.84 (s, 1H), 7.77 (s, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.40 (dd, J = 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H) = 5.3, 3.9 Hz, 2H), 4.31 (s, 1H), 4.00-3.90 (m, 2H), 2.94 (dt, J = 10.0, 5.7 Hz, 1H) m, 3H), 1.64 (t, J = 13.4 Hz, 5H), 1.24 (d, J = 10.9 Hz, 3H).

Compound 18. N - ((ls, 4s) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (1- (2,2,2- trifluoroacetyl) piperidine Yl) -1H-pyrazol-4-yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2- trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.84 (s, 1H), 7.63 (d, J = 1.8 Hz, 3H), 7.58 (s, 1H), 7.29 (s, 1H), 6.98 (t, J = 1.8 Hz, 1H), 6.32 (s, 1H), 5.10 (d, J = 7.0 Hz, 1H), 4.67 (d, J = 13.4 Hz, 1H), 4.59-4.42 J = 13.0 Hz, 2H), 2.22-2.08 (m, 1H), 3.99 (s, (m, 2H), 2.03-1.86 (m, 5H), 1.82 (s, 2H), 1.67 (s, 2H).

Compound 19. N - ((lr, 4r) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2-hydroxyethyl) 4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.80 (s, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (s, 1H), J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.98 (t, J = 1.8 Hz, 1H), 6.10 ), 4.07 (d, J = 4.7 Hz, 2H), 4.05-3.94 (m, IH), 3.83 (s, IH), 2.24 , 2H), 1.78-1.61 (m, 1H), 1.52 (q, J = 12.4 Hz, 3H), 1.36 (d, J = 12.4 Hz, 2H).

Compound 20. N4 - ((ls, 4s) -4-aminocyclohexyl) -N2- (3,5-dichlorophenyl) -5- (1- (piperidin- 4-yl) pyrimidine-2,4-diamine

¹ H NMR (300 MHz, Chloroform-d)? 7.82 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.59 (s, ), 6.94 (t, J = 1.8 Hz, 1H), 5.19 (d, J = 7.3 Hz, 1H), 4.28 J = 12.5 Hz, 2H), 3.03 (s, 1H), 2.86-2.74 (m, 2H), 2.22 , 1.80 (d, J = 3.6 Hz, 6H), 1.44 (d, J = 16.6 Hz, 5H).

Compound 21. 2- (4- (4 - (( 1r, 4r )-4- Aminocyclohexylamino ) -2- (3,5- Dichlorophenylamino ) Pyrimidin-5-yl) -1H-pyrazol-1-yl) ethanol

¹ H NMR (300 MHz, Chloroform-d) [delta] 7.78 (s, IH), 7.66 (d, J = 1.8 Hz, 2H), 7.60 ), 6.98 (d, J = 1.8 Hz, 1 H), 4.93 (d, J = 7.7 Hz, 1 H), 4.38-4.30 (m, J = 12.1 Hz, 2H), 1.94 (d, J = 13.0 Hz, 2H), 1.39 (q, J = 12.1 Hz, 3H), 1.30-1. 15 (m, 3H).

Compound 22. N - ((lr, 4r) -4- (2- (3,5-Difluorophenylamino) -5- (1- (2- hydroxyethyl) ) Pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 7.81 (s, 1H), 7.52 (d, J = 0.9 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 3H), 3.92 (dd, J = 7.4, 3.6 Hz, IH), 7.30-7.23 (m, 2H), 6.45-6.35 , 2.73-2.60 (m, 1H), 2.14 (d, J = 11.9 Hz, 2H), 1.98-1.86 (m, 2H), 1.48-1.13 (m, 6H).

Compound 23 2- (4- (4 - ((lr, 4r) -4- aminocyclohexylamino) -2- (3,5- difluorophenylamino) pyrimidin- Yl) ethan-1-ol < / RTI >

¹ H NMR (300 MHz, Chloroform-d)? 7.77 (d, J = 1.0 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 2.2 Hz, IH), 7.28 (s, IH), 7.25 (s, IH), 6.46-6.36 2H), 4.07 (dd, J = 5.4,4.0 Hz, 2H), 4.00-3.87 (m, 1H), 2.71-2.60 , 1.94 (d, J = 12.5 Hz, 3H), 1.40-1.13 (m, 6H).

Compound 24. N - ((lr, 4r) -4- (2- (3,5-bis (trifluoromethyl) phenylamino) -5- (1- (2-hydroxyethyl) Yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide

^{1 H NMR (300 MHz, Chloroform} -d) δ 8.20 (s 2H), 7.81 (s 1H), 7.60 (s 1H), 7.54 (s 1H), 7.45 (s 1H), 7.41 (s 1H), 4.91 ( 1H, J = 6.0 Hz), 4.06 (m, 1H), 4.32 (m, 2H), 4.06 (m, 2H), 4.01 1.96 (m, 2 H), 1.43 (m, 3 H).

Compound 25. 2- (3,5-Bis (trifluoromethyl) phenylamino) pyrimidin-5-yl) -2- (4- (4- -1H-pyrazol-1-yl) ethan-l-ol

^{1 H NMR (300 MHz, Chloroform} -d) δ 8.24 (s 2H), 7.82 (s 1H), 7.61 (s 1H), 7.56 (s 1H), 7.47 (s 1H), 7.42 (s 1H), 4.91 ( 2H), 4.08 (m, 2H), 4.02 (m, 1H), 2.62 (m, 1.98 (m, 2 H), 1.42 (m, 3 H).

Compound 26. 1- (4- (2- (3,5-Dichlorophenylamino) -5- (1- (piperidin-4-yl) Amino) cyclohexyl) -2,2,2-trifluoroacetamide

¹ H NMR (300 MHz, CDCl ₃ )? 7.84 (s, IH), 7.62 (d, J = 1.8 Hz, 2H), 7.58 (s, J = 8.6 Hz, 2H), 6.99 (d, J = 7.9 Hz, 2H) J = 12.3 Hz, 1H), 4.32 (dd, J = 7.5, 3.9 Hz, 1H), 4.20 J = 12.4 Hz, 2H), 3.06 (q, J = 11.7 Hz, 2H), 2.28 (q, J = 12.3, 10.7 Hz, 4H), 2.20-2.06 ).

Compound 27. 2- (4- (2- (3,5-Dichlorophenylamino) -4- (4- (piperidin-4-yl) phenylamino) pyrimidin- -1-yl) ethan-1-ol

^{1 H NMR (300 MHz, MeOH} -d 4) δ 7.98 (s, 1H), 7.92 (s, 1H), 7.70 (d, J = 11.8 Hz, 2H), 7.61-7.45 (m, 3H), 7.44- 2H), 3.99 (t, J = 5.3 Hz, 2H), 3.65-3.59 (m, 1H), 3.58 -3.54 (m, IH), 3.09 (s, IH), 2.18-2.04 (m, 2H), 1.93-1.80 (m, 3H);

LC / MS (ESI) m / z 525.0 [M + H] < ⁺ >.

Compound 28. 2- (4- (2- (3-Chlorophenylamino) -4- (4- (piperidin-4-yl) phenylamino) pyrimidin- Yl) ethan-1-ol

^{1 H NMR (300 MHz, MeOH} -d 4) δ 7.95 (s, 1H), 7.90 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.58-7.46 ( 8.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.34-7.22 (m, 2H), 7.17 2H), 3.38 (t, J = 5.2 Hz, 2H), 3.38 (t, J = = 7.5 Hz, 2H), 1.91-1.79 (m, 4H);

LC / MS (ESI) m / z 490.0 [M + H] < ⁺ >.

Compound 29. 2- (4- (2- (3,5-Difluorophenylamino) -4- (4- (piperidin-4-yl) phenylamino) pyrimidin- Yl) ethan-l-ol < / RTI >

^{1 H NMR (300 MHz, MeOH} -d 4) δ 7.97 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.56-7.42 (m, 2H), 7.39-7.21 (m, 4H (T, J = 6.4 Hz, 2H), 3.51 (q, 2H), 6.50-6.35 J = 7.0 Hz, 1H), 2.58-2.48 (m, 1H), 2.38 (t, J = 7.5 Hz, 2H), 1.88-1.75 (m, 3H);

LC / MS (ESI) m / z 492.0 [M + H] < ⁺ >.

Example 2. Identification of Inhibitory Activity of TAM Receptor Inhibitory Compounds on Tyro3, AxI and Mer [

The following experiments were conducted to evaluate the inhibitory activity of the compound of the present invention against Tyro3, Axl and Mer.

Specific experimental methods were performed according to the method provided by Cisba. The compounds of the Examples were prepared at various concentrations, tryto3, AxI, or Mer and substrate peptide were added thereto, and then the reaction was started by adding ATP. After 1 hour, a solution containing EDTA was added to stop the reaction, The amount of peptides was measured. At this time, the amount of the phosphorylated peptide was treated with an antibody recognizing the phosphorylated peptide having Eu (Eu), and after 1 hour, light of 320 nm or 340 nm was emitted using an Envision Reader ), And the amount of light emitted at 665 nm was measured to confirm the degree of TAM receptor inhibition. The TAM receptor inhibitory activity (IC ₅₀ value) of each compound was analyzed using a GraphPad Prism program Are shown in Table 1 below. At this time, a TAM receptor inhibitor LDC1267 was used as a positive control.

Condition IC ₅₀ ([mu] M) Tyro3 Axl Mer Compound 1 0.0035 > 10 1.1 Compound 2 0.0018 4.5 0.032 Compound 3 0.00006 3.6 0.03 Compound 4 0.045 2.4 > 10 Compound 8 0.059 10.8 0.048 Compound 10 0.0065 > 10 > 10 Compound 12 0.0009 0.032 0.00091 Compound 13 0.00019 0.7 0.025 Compound 15 0.0024 0.33 0.0033 Compound 17 0.013 0.2 0.0044 Compound 18 0.0087 0.89 0.3 Compound 19 0.00028 0.92 0.028 Compound 20 0.00048 0.38 0.045 Compound 21 0.00037 0.23 0.0069 Compound 22 0.052 0.19 0.0009 Compound 23 0.0016 0.52 0.001 Compound 25 0.003 0.37 0.01 Compound 26 0.017 > 10 > 10 Compound 27 0.000012 0.15 0.85 Compound 28 0.0013 2.35 0.15 Compound 29 0.00014 0.87 0.032 The positive control (LDC1267) 0.0048 0.0049 0.068

Comparative compound 1

0.0001 14.2 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 29 of the present invention include a pyrazole group in which the R ₁ substituent group is substituted with a hydroxy group or a piperidine group, and the R ₂ substituent group is a phenyl group, a cycloalkyl group, a heterocycloalkyl group , And when the R ₃ substituent was substituted with a phenyl group or a tetrahydroisoquinoline group, the compound showed a strong activity with an IC ₅₀ value of 0.000012 to 0.059 μM for Tyro 3.

However, unlike Compounds 1 to 29 of the present invention, Comparative Compound 3 is a compound in which the R ₁ substituent in Formula 1 is substituted with a pyridine group instead of a pyrazole group substituted with a hydroxy group or a piperidine group, Compounds of the formula 1 in which the R ₁ substituent is a pyrazole group substituted by a methyl group instead of a hydroxy group or a piperidine group and the R ₃ substituent is substituted by an aryl group containing a hetero atom, Comparative Compounds 3 to 5 showed that the TAM receptor inhibitory activity was remarkably low, and that the inhibitory activity against Tyro 3 was particularly low at 1 μM or more.

Therefore, it was found that the TAM receptor inhibitory activity was significantly different depending on the substituents of the pyrimidine derivatives. In particular, the compound of the present invention was more excellent in the inhibitory effect on Tyro3 among the TAM receptors, It can be seen that it can be usefully used as a composition for a liquid crystal display device.

≪ Example 3: Identification of hERG toxicity of TAM receptor-inhibiting compounds &

In the development of therapeutic agents, not only therapeutic effects but also toxicity by drugs are important. The most commonly used criteria for drug-induced toxicity are toxicity to human ether-a-go-go-related gene (hEGR) and most pharmaceutical companies believe that the hERG IC ₅₀ value is less than 0.1 μM To stop the development of drugs. On the other hand, when the hERG IC ₅₀ value is more than 10 μM, it is considered to be not toxic.

Thus, a hERG (human ether-a-go-related gene) assay was performed on compounds 2 and 3 of the present invention to confirm the degree of drug toxicity by the TAM receptor-inhibiting compound of the present invention.

As a result of the hERG assays analysis, the inventive Compounds 2 and 3 showed hERG IC ₅₀ value of 50 μM or more, indicating that hERG toxicity was not present.

However, unlike the compound of the present invention, in the case of Comparative Compounds 1 to 5 in which the R ₁ substituent is substituted with a methyl group or a pyridine group other than hydroxy or piperidinyl group, the hERG IC ₅₀ value is 1 μM or less, .

Therefore, since the R ₁ substituent to R ₃ substituent of the present invention has a large influence on the TAM receptor inhibitory activity and hERG toxicity, 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 &

The compound of the present invention 3 (2- (4- (2- (3,5-dichlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- 1) ethanol) and 1 g of lactose were mixed and filled in airtight bags to prepare powders.

≪ Preparation Example 2 > Preparation of Tablets >

The compound of the present invention 3 (2- (4- (2- (3,5-dichlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- 1) ethanol), 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate were mixed, and tablets were prepared by tableting according to a conventional preparation method .

≪ Formulation Example 3: Preparation of capsules >

The compound of the present invention 3 (2- (4- (2- (3,5-dichlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- 1) ethanol), 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropylcellulose and 2 mg of magnesium stearate were mixed, and the above components were mixed according to a conventional capsule preparation method And filled in a gelatin capsule to prepare a capsule preparation.

≪ Formulation Example 4: Preparation of pill &

The compound of the present invention 3 (2- (4- (2- (3,5-dichlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- Maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives for inhibiting hygroscopicity were mixed in a small amount, and then 100 mg of a pellet was added according to a conventional method. .

< Formulation example  5. Preparation of injections>

The compound of the present invention 3 (2- (4- (2- (3,5-dichlorophenylamino) -4- (piperidin-4- ylamino) pyrimidin- (Ethanol) (10 mg), sterilized distilled water suitable for injection, and pH adjuster were mixed, and the contents of the components were adjusted to the above contents (2 ml) per ampoule according to the usual injection preparation method.

Claims (5)

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

In Formula 1,
R &lt; ¹ &gt; is hydroxy, or substituted or unsubstituted piperidinyl,
Wherein the substituted piperidinyl is halogen, C ₁ -C ₁₀ haloalkyl, oxo (= O), hydroxy, cyano, nitro, amino, acetamido, amino, acetamido tree halogen amino, tri-acetyl halogen, C ₁ - ₁ &gt; is selected from the group consisting of 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. Lt; / RTI &gt; or more substituents;
R ² is a substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl, or a substituted or unsubstituted C ₄ -C ₁₀ heteroaryl,
Wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is optionally substituted with at least _one substituent selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, Acetic amino, tri-amino-acetamide halogen, tri-acetyl halogen, 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 heteroaryl;
R ³ is a substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₀ aryl group, a substituted or unsubstituted C ₄ - C ₁₀ heteroaryl, and aryl, or C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl alkyl fused substituted or unsubstituted fused ring,
Wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano , nitro, amino, acetamido, amino, acetamido tree halogen amino, tri-acetyl halogen, 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 heteroaryl; And
n is an integer from 0 to 4; to be. The method according to claim 1,
In Formula 1,
R ¹ is hydroxy, or substituted or unsubstituted piperidin-4-yl,
Wherein said substituted piperidin-4-yl is substituted with at least one substituent selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ alkoxy;
R ² is substituted or unsubstituted C ₄ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ heterocycloalkyl, or substituted or unsubstituted C ₄ -C ₁₀ aryl,
Here, the substituted cycloalkyl, substituted heterocycloalkyl, or substituted aryl is a halogen, C ₁ -C ₁₀ haloalkyl, oxo (= O), hydroxy, cyano, nitro, amino, acetamido, amino, halogen tree Acetic amino, tri-acetyl halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, or C ₄ -C ₈ heterocycloalkyl is substituted with one or more substituents selected from the group consisting of alkyl;
R ³ is a substituted or unsubstituted C ₄ -C ₁₀ aryl, or C ₄ -C ₁₀ aryl and C ₄ -C ₈ heterocycloalkyl is a substituted or unsubstituted fused ring fusion,
Wherein said substituted aryl or substituted fused ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₁₀ haloalkyl, oxo (═O), hydroxy, cyano, nitro, amino, acetamino, trihalogenacetamino, , C ₁ -C ₁₀ alkyl, or C ₁ -C ₁₀ alkoxy; And
n is an integer from 0 to 4;
Or an optically active isomer thereof, or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 or 2,
The compound of formula (1)
Pyrazol-4-yl) pyrimidin-4-ylamino) piperidine-l-carboxylic acid ethyl ester was prepared in accordance with the general method of example 1 from 1- (4- (2- (3,5- 1-yl) -2,2,2-trifluoroethanone (Compound 1);
(Piperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine- 2,4-diamine (Compound 2);
Yl) -1H-pyrazol-1-yl) ethanol (compound (2)) was obtained in the same manner as in 3);
Pyrazol-4-yl) -2- (2- (2,2,2-trifluoroacetyl) -1,2- , 3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) piperidin-l-yl) -2,2,2-trifluoroethanone (Compound 4);
1 - (4- (2- (3-methyl-4-chlorophenylamino) -5- (1- (2- hydroxyethyl) -lH- pyrazol-4- yl) pyrimidin- Piperidin-1-yl) -2,2,2-trifluoroethanone (Compound 5);
Pyrazol-4-yl) -2- (4-methoxyphenylamino) pyrimidin-4-ylamino) piperidine The title compound was prepared from 1- (4- (5- (1- -1-yl) -2,2,2-trifluoroethanone (Compound 6);
Ylamino) -2- (l, 2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin- Pyrazol-1-yl) ethanol (Compound 7);
Yl) -lH-pyrazol-l-yl) ethanol [0252] &lt; EMI ID = (Compound 8);
Yl) -1H-pyrazol-1-yl) ethanol (compound 9 (2-methyl-4- );
N - ((1 s, 4s) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2- hydroxyethyl) -1 H- pyrazol- -Ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 10);
N - ((ls, 4s) -4- (5- (1- (2-hydroxyethyl) -lH-pyrazol- Acetyl) -1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 11);
1 - (2-hydroxyethyl) -1 H-pyrazol-4-yl) pyrimidin-4-yl Amino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 12);
2- (3,5-Dichlorophenylamino) pyrimidin-5-yl) -1H-pyrazol-1-yl ) Ethanol (Compound 13);
2- (4- (4 - ((1S, 4S) -4-aminocyclohexylamino) -2- (1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin- ) -LH-pyrazol-l-yl) ethanol (Compound 14);
Yl) - lH-pyrazol-l-yl) ethanol To a solution of 2- (4- (4 - ((1S, 4S) -4-aminocyclohexylamino) -2- (Compound 15);
(1 - (2-hydroxyphenyl) -1H-pyrazol-4-yl) -N- ((1S, 4S) -4 - Pyrimidin-4-yl) amino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 16);
2- (3-methyl-4-chlorophenylamino) pyrimidin-5-yl) -1H-pyrazole-1 -Yl) ethanol (Compound 17);
4- (2- (3,5-Dichlorophenylamino) -5- (1- (1- (2,2,2-trifluoroacetyl) piperidin-4- Yl) -1H-pyrazol-4-yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 18);
N - ((lr, 4r) -4- (2- (3,5-Dichlorophenylamino) -5- (1- (2- hydroxyethyl) -1H- pyrazol-4-yl) pyrimidin- -Ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 19);
N4- ((ls, 4s) -4-aminocyclohexyl) -N2- (3,5-dichlorophenyl) -5- (1- (piperidin- ) Pyrimidine-2,4-diamine (Compound 20);
2- (3,5-Dichlorophenylamino) pyrimidin-5-yl) -1H-pyrazol-1-yl ) Ethanol (Compound 21);
N - ((lr, 4r) -4- (2- (3,5-Difluorophenylamino) -5- (1- (2- hydroxyethyl) -lH-pyrazol-4-yl) pyrimidine -4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 22);
2- (3,5-Difluorophenylamino) pyrimidin-5-yl) -1H-pyrazole-1 Yl) ethan-1-ol (Compound 23);
4- (2- (3,5-bis (trifluoromethyl) phenylamino) -5- (1- (2-hydroxyethyl) -1H-pyrazol- Yl) pyrimidin-4-ylamino) cyclohexyl) -2,2,2-trifluoroacetamide (Compound 24);
2- (3,5-bis (trifluoromethyl) phenylamino) pyrimidin-5-yl) -1H-pyrazolo [3,4- Yl) ethan-1-ol (Compound 25);
Pyrazol-4-yl) pyrimidin-4-ylamino) - &lt; / RTI & Cyclohexyl) -2,2,2-trifluoroacetamide (Compound 26);
4-yl) phenylamino) pyrimidin-5-yl) -1H-pyrazole-l- Yl) ethan-1-ol (Compound 27);
4-yl) phenylamino) pyrimidin-5-yl) -lH-pyrazol-l-yl) Ethan-1-ol (Compound 28); And
4- (4- (piperidin-4-yl) phenylamino) pyrimidin-5-yl) -1H-pyrazole- Yl) ethan-1-ol (Compound 29);
, Or an optical isomer thereof or a pharmaceutically acceptable salt thereof. 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 may be selected from the group consisting of a cancer selected from the group consisting of a cancer selected from the group consisting of a caudal myxoma, an intrahepatic bile duct cancer, a hepatoblastoma, a liver cancer, a thyroid cancer, a colon cancer, a testicular cancer, a myelodysplastic syndrome, a glioblastoma, a oral cancer, a larynx cancer, a bacterial sarcoma, an acute lymphocytic leukemia, Cholangiocarcinoma, cholangiocarcinoma, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B cell lymphoma, Barter's bulge, ovarian cancer, ovarian cancer, ovarian cancer cell, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, Cancer, bladder cancer, peritoneal cancer, pituitary cancer, adenocarcinoma, non-sinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small bowel cancer, Malignant melanoma, malignant lymphoma, malignant mesothelioma, malignant melanoma, ovarian cancer, vulvar cancer, ureter cancer, urethral cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, Cancer of the uterus, uterine cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, uterine cancer, breast cancer, sarcoma, penile cancer, Cancer of the lungs, squamous cell carcinoma of the lung, squamous cell carcinoma of the lung, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, neuroendocrine tumor, pancreatic cancer, salivary cancer, Kaposi sarcoma, Paget's disease, Skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymic carcinoma.