KR102382641B1 - Novel TYRO 3 inhibitory compounds, preparation method thereof, pharmaceutical composition for use in preventing or treating TYRO 3 relating diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel TYRO 3 inhibitory compound, a method for preparing the same, and a pharmaceutical composition for preventing or treating TYRO 3 related diseases containing the same as an active ingredient, and the novel TYRO 3 inhibitory compound according to the present invention, its three-dimensional structure Isomers or pharmaceutically acceptable salts thereof not only excellently inhibit TYRO 3 (Tyrosine-protein kinase receptor) in nanomolar units, but also AXL (Tyrosine-protein kinase receptor UFO) and MERTK (Proto-oncogene tyrosine- Protein kinase MER) compared to TYRO 3 inhibitory activity bar, it has a useful effect as a pharmaceutical composition and health functional food composition for the prevention or treatment of TYRO 3 related diseases that can significantly reduce side effects from TYRO 3 selective inhibitory activity.

Description

Novel TYRO 3 inhibitory compound, a preparation method thereof, and a pharmaceutical composition for preventing or treating TYRO 3 related diseases containing the same as an active ingredient TECHNICAL FIELD [0002] Novel TYRO 3 inhibitory compounds, preparation method thereof, pharmaceutical composition for use in preventing or treating TYRO 3 relating diseases containing the same as an active ingredient}

The present invention relates to a novel TYRO 3 inhibitory compound, a method for preparing the same, and a pharmaceutical composition for preventing or treating TYRO 3 related diseases containing the same as an active ingredient.

A large number of tumor-associated macrophages (TAM) are infiltrated into cancer tissues. In particular, it is known that the prognosis of malignant tumors is poor in many types when the number of macrophages having the M2 phenotype increases. In several types of cancer, the presence of high-density TAM or M2 TAM results in cancer cell proliferation and increase in T regulatory cells. In cancer, autocrine and paracrine ligands and apoptotic cells are abundant, providing a microenvironment for survival signals and anti-inflammatory and immune suppression of cancer cells. Therefore, inhibition of TAM kinase can enhance anticancer immunity, decrease the survival of cancer cells, enhance sensitivity to anticancer drugs, and prevent metastasis.

TAM knockout mice show various phenotype (trait, phenotype) changes. Tyrosine-protein kinase receptor (TYRO 3), Tyrosine-protein kinase receptor UFO (AXL). MERTK (Proto-oncogene tyrosine-protein kinase MER) is overlappingly distributed in various tissues, and TYRO 3 is most abundantly expressed in the nervous system, and ovarian, testis, breast, lung, kidney, osteoclast, It is also found in the retina.

TAM receptor knockout develops autoimmune diseases including arthritis and lupus. This is more pronounced in double knockout and most severe in triple knockout. This phenotype leads to the accumulation of apoptotic cells and thus tissue necrosis to the result of combining with the structural activity of the immune system (Non-Patent Document 1).

The physiological properties of TAM RTK (TYRO 3, AXL. MERTK) are well known. The characteristics of the phenotype by the gene knockout animal model can be examined. When MERTK, AXL, and TYRO 3 were knocked out alone, they commonly exhibit hyperactivity of APC (antigen-presenting cells) and autoantibody production, and thrombosis ( thrombosis) has been observed. On the other hand, in the case of knockout of MERTK, dysfunction of excretory function of apoptotic cells, 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 fetal autoimmune encephalomyeliti, enhancement of demyelination, defect in excretory function of apoptotic cells, and increase in viral infection, etc. Not found.

Accordingly, as the development of a selective inhibitor of TYRO 3 is noted as a way to overcome the side effects of existing anticancer drugs, immunosuppressants, etc., the development of a TYRO 3 inhibitor is more demanded than ever.

Until now, many RTK inhibitors have been developed, but the effect on TYRO 3 activity in cells is insignificant, so the development of novel TYRO 3 inhibitors is required.

TYRO 3 target inhibitors have been proposed as drug targets for breast cancer treatment, TYRO 3 is expressed more than twice as strongly in liver cancer patients as compared to normal tissues, and TYRO 3 is importantly involved in cancer growth and liver destruction. . Therefore, controlling the inhibition or overexpression of TYRO 3 can be an important target for the development of a treatment for liver cancer (Non-Patent Document 2).

Ovarian cancer has a low survival rate of 5 years or less when cancer is diagnosed at stage 3/4. In the taxol-resistant cell line SKOV3/TR, RNA expression of TYRO 3 is increased and RNA expression of AXL and MER is increased. was found to decrease. This increase in the expression level of TYRO 3 increases the survival of cancer cells in SKOV3/TR and allows the acquisition of drug resistance to Taxol. Taxol resistance acquisition in ovarian cancer is obtained by regulating ROS signal according to TYRO 3 expression and then activating Akt. In addition, it was known that the expression of TYRO 3 is increased in skin cancer, and when TYRO 3 is knocked down in melanoma cells, it was found to inhibit cell proliferation and colony formation. TYRO 3 knockdown in melanoma cells inhibits cancer progression in vivo. Therefore, TYRO 3 is more important as a target for the treatment of melanoma.

Accordingly, development of a new drug capable of minimizing side effects is required by developing a TYRO 3 selective targeting agent, and the development of a selective inhibitor of TYRO 3 can achieve an excellent effect that can greatly contribute to overcoming resistance to anticancer drugs. The development of novel TYRO 3 selective inhibitors is more demanded than ever.

Accordingly, the present inventors have excellent TYRO 3 inhibitory activity, and in particular, a compound having a TYRO 3 selective inhibitory effect, preferably a compound having a selective inhibitory effect on TYRO 3 rather than AXL and MERTK While trying to find a compound, according to the present invention It was confirmed that the novel TYRO 3 inhibitory compound exhibits an excellent TYRO 3 inhibitory effect as well as a TYRO 3 selective inhibitory effect, thereby confirming that it can be usefully used for the prevention or treatment of cancer, thereby completing the present invention .

Advances in CANCER RESEARCH, 35-83 (2008) INTERNATIONAL JOURNAL OF ONCOLOGY, 48, 358-366 (2016)

It is an object of the present invention to provide novel TYRO 3 inhibitory compounds.

Another object of the present invention is to provide a method for preparing the TYRO 3 inhibitory compound.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating TYRO 3 (Tyrosine-protein kinase receptor)-related diseases containing the TYRO 3 inhibitory compound as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving TYRO 3 (Tyrosine-protein kinase receptor) related diseases containing the TYRO 3 inhibitory compound as an active ingredient.

Another object of the present invention is to provide a method for treating, preventing or improving a TYRO 3 (Tyrosine-protein kinase receptor) related disease comprising administering the TYRO 3 inhibitory compound to a subject in need of treatment. .

In order to achieve the above purpose,

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ¹ is halogen, substituted or unsubstituted C _1-10 straight-chain or branched alkyl, substituted or unsubstituted C _1-10 straight-chain or branched alkoxy, substituted or unsubstituted C _6-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S;

wherein the substituted alkyl, substituted alkoxy, substituted aryl, or substituted heteroaryl is halogen, hydroxy, cyano, amino, nitro, substituted or unsubstituted C _1-10 straight-chain or branched alkyl and substituted or unsubstituted C _1-10 substituted with one or more substituents selected from the group consisting of straight-chain or branched alkoxy,

again wherein said substituted alkyl or substituted alkoxy is substituted with one or more substituents selected from the group consisting of halogen, oxo (=O) and hydroxy;

R ² is a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S; A substituted or unsubstituted C _6-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S;

Or C _6-10 aryl and C _3-10 cycloalkyl or 5 to 10-membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S is fused (fused) , a substituted or unsubstituted fused ring,

wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is substituted or unsubstituted amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted The group consisting of substituted or unsubstituted C _1-10 straight or branched chain alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, or substituted or unsubstituted C _6-10 arylC _1-10 alkyl substituted with one or more substituents selected from

Again, wherein said substituted amino, substituted alkyl, substituted alkoxy, substituted C _6-10 arylC _1-10 alkyl is a substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) is substituted with one or more substituents selected from the group consisting of,

Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O); and

R ³ and R ⁴ are each independently —H, halogen, substituted or unsubstituted C _3-10 cycloalkyl, N, O, and a substitution containing one or more heteroatoms selected from the group consisting of S Or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of unsubstituted 5 to 10-membered heterocycloalkyl, substituted or unsubstituted C _6-10 aryl, N, O, and S 5- to 10-membered ring heteroaryl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of N, O, and S A 5- to 10-membered ring heteroaryl C _1-10 alkyl, or C _6-10 aryl and C _3-10 cycloalkyl or N, O, and S It contains one or more heteroatoms selected from the group consisting of When the 5- to 10-membered heterocycloalkyl is a fused, substituted or unsubstituted fused ring,

wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or substituted fused ring is amino, halogen, hydroxy, cyano , nitro, oxo (=O), substituted or unsubstituted C _1-10 straight or branched chain alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, or substituted or unsubstituted C substituted with one or more substituents selected from the group consisting of _6-10 aryl,

Here again, substituted alkyl, substituted alkoxy, substituted C _6-10 aryl is selected from the group consisting of substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) substituted with one or more substituents,

Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O),

Or, when R ³ and R ⁴ together form a 5- to 10-membered substituted or unsubstituted heterocycloalkyl with the nitrogen atom to which they are connected,

The heterocycloalkyl may be a heterocycloalkyl further comprising at least one hetero atom selected from the group consisting of N, O, and S in addition to the nitrogen atom to which R ³ and R ⁴ are connected,

wherein the substituted heterocycloalkyl is amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted C _{6-10 arylC 1-10 alkyl , or} from the group consisting of N, O, and S Substituted with one or more substituents selected from the group consisting of substituted or unsubstituted 5- to _{10 -} membered heteroarylC _1-10 alkyl containing one or more heteroatoms selected,

Here again, the substituted C _{6-10 arylC 1-10 alkyl} , or a substituted 5- _{to 10- membered heteroaryl} C _1-10 alkyl is _one selected from the group consisting of halogen and oxo (=O) It is substituted with more than one substituent.

In addition, the present invention, as shown in Scheme 1 below,

reacting the compound represented by Formula 2 with NH ₂ R ² to prepare a compound represented by Formula 3 (step 1);

preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and

It provides a method for preparing a compound represented by the formula (1) of claim 1, including; preparing a compound represented by formula (1) from the compound represented by formula (4) prepared in step 2 (step 3).

[Scheme 1]

In Scheme 1,

R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1 above;

X ¹ , X ² and X ³ are halogen.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a TYRO 3 (Tyrosine-protein kinase receptor)-related disease containing the compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

In addition, the present invention is a health functional food composition for preventing or improving TYRO 3 (Tyrosine-protein kinase receptor)-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient provides

The novel TYRO 3 inhibitory compound according to the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, not only excellently inhibits TYRO 3 (Tyrosine-protein kinase receptor) in nanomolar units or less, but also AXL (Tyrosine- As it shows superior TYRO 3 inhibitory activity compared to protein kinase receptor UFO) and MERTK (Proto-oncogene tyrosine-protein kinase MER), pharmaceutical for preventing or treating TYRO 3 related diseases that can significantly reduce side effects from TYRO 3 selective inhibitory activity There is a useful effect as a composition and a health functional food composition.

Hereinafter, the present invention will be described in detail.

The following description is provided to help the understanding of the present invention, and the present invention is not limited to the content of the following description.

The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ¹ is halogen, substituted or unsubstituted C _1-10 straight-chain or branched alkyl, substituted or unsubstituted C _1-10 straight-chain or branched alkoxy, substituted or unsubstituted C _6-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S;

wherein the substituted alkyl, substituted alkoxy, substituted aryl, or substituted heteroaryl is halogen, hydroxy, cyano, amino, nitro, substituted or unsubstituted C _1-10 straight-chain or branched alkyl and substituted or unsubstituted C _1-10 substituted with one or more substituents selected from the group consisting of straight-chain or branched alkoxy,

again wherein said substituted alkyl or substituted alkoxy is substituted with one or more substituents selected from the group consisting of halogen, oxo (=O) and hydroxy;

R ² is a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S; A substituted or unsubstituted C _6-10 aryl, or a substituted or unsubstituted 5- to 10-membered heteroaryl containing one or more hetero atoms selected from the group consisting of N, O, and S;

Or C _6-10 aryl and C _3-10 cycloalkyl or 5 to 10-membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S is fused (fused) , a substituted or unsubstituted fused ring,

wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, or substituted fused ring is substituted or unsubstituted amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted The group consisting of substituted or unsubstituted C _1-10 straight or branched chain alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, or substituted or unsubstituted C _6-10 arylC _1-10 alkyl substituted with one or more substituents selected from

Again, wherein said substituted amino, substituted alkyl, substituted alkoxy, substituted C _6-10 arylC _1-10 alkyl is a substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) is substituted with one or more substituents selected from the group consisting of,

Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O); and

R ³ and R ⁴ are each independently —H, halogen, substituted or unsubstituted C _3-10 cycloalkyl, N, O, and a substitution containing one or more heteroatoms selected from the group consisting of S Or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of unsubstituted 5 to 10-membered heterocycloalkyl, substituted or unsubstituted C _6-10 aryl, N, O, and S 5- to 10-membered ring heteroaryl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of N, O, and S A 5- to 10-membered ring heteroaryl C _1-10 alkyl, or C _6-10 aryl and C _3-10 cycloalkyl or N, O, and S It contains one or more heteroatoms selected from the group consisting of When the 5- to 10-membered heterocycloalkyl is a fused, substituted or unsubstituted fused ring,

wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or substituted fused ring is amino, halogen, hydroxy, cyano , nitro, oxo (=O), substituted or unsubstituted C _1-10 straight or branched chain alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, or substituted or unsubstituted C substituted with one or more substituents selected from the group consisting of _6-10 aryl,

Here again, substituted alkyl, substituted alkoxy, substituted C _6-10 aryl is selected from the group consisting of substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) substituted with one or more substituents,

Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O),

Or, when R ³ and R ⁴ together form a 5- to 10-membered substituted or unsubstituted heterocycloalkyl with the nitrogen atom to which they are connected,

The heterocycloalkyl may be a heterocycloalkyl further comprising at least one hetero atom selected from the group consisting of N, O, and S in addition to the nitrogen atom to which R ³ and R ⁴ are connected,

wherein the substituted heterocycloalkyl is amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted C _{6-10 arylC 1-10 alkyl , or} from the group consisting of N, O, and S Substituted with one or more substituents selected from the group consisting of substituted or unsubstituted 5- to _{10 -} membered heteroarylC _1-10 alkyl containing one or more heteroatoms selected,

Here again, the substituted C _{6-10 arylC 1-10 alkyl} , or a substituted 5- _{to 10- membered heteroaryl} C _1-10 alkyl is _one selected from the group consisting of halogen and oxo (=O) It is substituted with more than one substituent.

Preferably,

,

,

,

,

,

,

,

,

또는

이다.wherein R ¹ is

,

,

,

,

,

,

,

,

or

am.

On the other hand, preferably,

,

,

,

,

,

,

,

,

,

,

또는

이다.wherein R ² is

,

,

,

,

,

,

,

,

,

,

or

am.

On the other hand, preferably,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

,

,

,

,

,

또는

이거나,The R ³ and R ⁴ are each independently -H, -Cl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

,

,

,

,

,

or

this,

을 형성한다.or R ³ and R ⁴ together with the nitrogen atom to which they are connected

to form

Most preferably,

Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.

(1) 5-bromo-N4-cyclohexyl-N2-p-tolylpyrimidine-2,4-diamine;

(2) N4-cyclohexyl-N2,5-di-p-tolylpyrimidine-2,4-diamine;

(3) 5-bromo-N4-cyclohexyl-N2-(3,5-dichlorophenyl)pyrimidine-2,4-diamine;

(4) 2-chloro-N-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine;

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

(6) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-phenylpyrimidine-2,4-diamine;

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

(8) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-(trifluoromethyl)benzyl)pyrimidine-2,4-diamine;

(9) N2-(3-chloro-4-methoxyphenyl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;

(10) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-o-tolylpyrimidine-2,4-diamine;

(11) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(5-methylisoxazol-3-yl)pyrimidine-2,4-diamine;

(12) N2-(5-tert-butylisoxazol-3-yl)-N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;

(13) N4-cyclohexyl-N2-(2-isopropylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;

(14) N4-cyclohexyl-5-(furan-3-yl)-N2-p-tolylpyrimidine-2,4-diamine;

(15) N4-cyclohexyl-N2-(3,5-dichlorophenyl)-5-(furan-3-yl)pyrimidine-2,4-diamine;

(16) N4-cyclohexyl-N2-(2,2-difluoro-2-(4-methoxyphenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine- 2,4-diamine;

(17) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(2-(pyridin-4-yl)ethyl)pyrimidine-2,4-diamine;

(18) (4-(4-(cyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazin-1-yl)(thiophene-2 -il) methanone;

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

(20) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(3-methylisoxazol-5-yl)pyrimidine-2,4-diamine;

(21) N4-cyclohexyl-N2-(5-ethyl-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2 ,4-diamine;

(22) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-(thiazol-2-yl)pyrimidine-2,4-diamine;

(23) N4-cyclohexyl-N2-adamantyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;

(24) N4-cyclohexyl-N2-(2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;

(25) N4-cyclohexyl-5-(1-methyl-1H-pyrazol-4-yl)-N2-m-tolylpyrimidine-2,4-diamine;

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

trifluoroacetamide;

(27) 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1 -yl)-2,2,2-trifluoroethanone;

(28) N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2 ,4-diamine;

(29) N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine ;

(30) N2-(3,5-dichlorophenyl)-N4-((1s,4s)-4-(dimethylamino)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)pyri midine-2,4-diamine;

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

(32) N2- (3,5-dichlorophenyl) -5- (1-methyl-1H-pyrazol-4-yl) -N4- (1-methylpiperidin-4-yl) pyrimidine-2; 4-diamine;

(33) 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1 -il) ethanone;

(34) 2,2,2-trifluoro-1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(phenylamino)pyrimidin-4-ylamino) piperidin-1-yl)ethanone;

(35) 1-(4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl )-2,2,2-trifluoroethanone;

(36) N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(37) 1-(4-(2-(4-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl )-2,2,2-trifluoroethanone;

(38) N4-(1-benzylpiperidin-4-yl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2, 4-diamine;

(39) 2,2,2-trifluoro-1-(4-(2-(3-fluorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)piperidin-1-yl)ethanone;

(40) N2-(4-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(41) N2-(3-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(42) 5-(1-methyl-1H-pyrazol-4-yl)-N2-phenyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(43) 1-(4-(2-(4-chloro-3-methylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidine- 1-day)-2,2,2-

trifluoroethanone;

(44) 2,2,2-trifluoro-1-(4-(2-(4-methoxyphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)piperidin-1-yl)ethanone;

(45) 1- (4- (2- (3-chloro-4-methoxyphenylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-ylamino) piper din-1-yl)-2,2,2-

trifluoroethanone;

(46) N2-(4-chloro-3-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4- diamine;

(47) N2-(4-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(48) N2- (3-chloro-4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -N4- (piperidin-4-yl) pyrimidine-2, 4-diamine;

(49) 1-(4-(2-(p-toluidino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2 -trifluoroethanone;

(50) 1-(4-(2-(m-toluidino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2 -trifluoroethanone;

(51) 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-p-tolylpyrimidine-2,4-diamine;

(52) 5-(furan-3-yl)-N4-(piperidin-4-yl)-N2-m-tolylpyrimidine-2,4-diamine;

(53) 1-(4-(2-(3-chlorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2 -trifluoroethanone;

(54) 2,2,2-trifluoro-1-(4-(2-(3-fluorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidine -1-yl)ethanone;

(55) N2-(3-fluorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(56) N2-(3-chlorophenyl)-5-(furan-3-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(57) 1-(4-(2-(3,5-dichlorophenylamino)-5-phenylpyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoro ethanone;

(58) N2-(3,5-dichlorophenyl)-5-phenyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(59) 1-(4-(2-(3,5-dichlorophenylamino)-5-(3-methoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2 ,2-trifluoroethanone;

(60) N2-(3,5-dichlorophenyl)-5-(3-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(61) 1-(4-(2-(3,5-dichlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2 ,2,2-trifluoroethanone;

(62) N2-(3,5-dichlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(63) 1-(4-(2-(4-chloro-3-methylphenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)- 2,2,2-trifluoroethanone;

(64) 1-(4-(5-(3,4-dimethoxyphenyl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2, 2,2-trifluoroethanone;

(65) 1-(4-(5-(3,4-dimethoxyphenyl)-2-(2-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2, 2,2-trifluoroethanone;

(66) N2-(4-chloro-3-methylphenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(67) 5-(3,4-dimethoxyphenyl)-N2-(4-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(68) 5-(3,4-dimethoxyphenyl)-N2-(2-methoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(69) 1- (4- (2- (3-chlorophenylamino) -5- (3,4-dimethoxyphenyl) pyrimidin-4-ylamino) piperidin-1-yl) -2,2 ,2-trifluoroethanone;

(70) 2,2,2-trifluoro-1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoro) Roacetyl)-1,2,3,4-tetrahydroisoquinoline-7-

ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone;

(71) 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino )piperidin-1-yl)-2,2,2-

trifluoroethanone;

(72) 5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)-N2-(1,2,3,4-tetrahydroisoquinoline-7- yl) pyrimidine-2,4-diamine;

(73) N2- (3,5-dichlorophenyl) -N4- (piperidin-4-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine-2,4-diamine;

(74) N2-(3-chlorophenyl)-5-(3,4-dimethoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine;

(75) 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethanol;

(76) 2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2, 2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-

ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone;

(77) 1-(4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl amino)piperidin-1-yl)-2,2,2-

trifluoroethanone;

(78) 2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenyl) Amino)pyrimidin-4-ylamino)piperidin-1-

yl) ethanone;

(79) 2-(4-(4-(piperidin-4-ylamino)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl) -1H-pyrazol-1-yl)ethanol;

(80) 2-(4-(2-(4-chloro-3-methylphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl )ethanol;

(81) 2-(4-(2-(4-methoxyphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol ;

(82) 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;

(83) 1-(7-(2-(4-chloro-3-methylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4 -dihydroisoquinolin-2(1H)-yl)-

2,2,2-trifluoroethanone;

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

(85) N2-(4-chloro-3-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(1,2,3,4-tetrahydroisoquinoline-7- yl) pyrimidine-2,4-diamine;

(86) 2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2, 2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-

ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide;

(87) 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino )-3,4-dihydroisoquinoline-2(1H)-

yl)-2,2,2-trifluoroethanone;

(88) N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-(1,2,3,4-tetrahydroiso quinolin-7-yl)pyrimidine-2,4-diamine;

(89) 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethanol;

(90) N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclo hexyl)-2,2,2-trifluoroacetamide;

(91) N-((1s,4s)-4-(2-(3-acetylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclo hexyl)-2,2,2-trifluoroacetamide;

(92) N-((1s,4s)-4-(2-(m-toluidino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclo hexyl)-2,2,2-trifluoroacetamide;

(93) 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;

(94) 2,2,2-trifluoro-1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazole-4- yl) pyrimidin-4-ylamino)-3,4-

dihydroisoquinolin-2(1H)-yl)ethanone;

(95) N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri midin-4-ylamino)cyclohexyl)-2,2,2-

trifluoroacetamide;

(96) 2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2- (2-(2,2,2-trifluoroacetyl)-1,2,3,4-

tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide;

(97) N4-((1s,4s)-4-aminocyclohexyl)-N2-(3-chlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4 -diamine;

(98) 1-(3-(4-((1s,4s)-4-aminocyclohexylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino) phenyl) ethanone;

(99) N4-((1s,4s)-4-aminocyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)-N2-m-tolylpyrimidine-2,4-diamine;

(100) N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine- 4-ylamino)cyclohexyl)-2,2,2-

trifluoroacetamide;

(101) 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethanol;

(102) 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -pyrazol-1-yl)ethanol;

(103) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazole- 1-day) ethanol;

(104) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin- 5-yl)-1H-pyrazol-1-yl)ethanol;

(105) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazole-1- 1) ethanol;

(106) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(4-chloro-3-methylphenylamino)pyrimidin-5-yl)-1H-pyrazole -1-yl)ethanol;

(107) N-((1s,4s)-4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl) pyrimidin-4-ylamino)cyclohexyl)-2,2,2-

trifluoroacetamide;

(108) N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidine) -4-yl)-1H-pyrazol-4-yl)pyrimidin-4-

ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;

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

trifluoroacetamide;

(110) N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri midin-4-ylamino)cyclohexyl)-2,2,2-

trifluoroacetamide;

(111) N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyrimidine-2,4-diamine;

(112) N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2 ,4-diamine;

(113) 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazole- 1-day) ethanol;

(114) N-((1r,4r)-4-((2-((3,5-difluorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine- 4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide;

(115) N-((1r,4r)-4-((2-((3,5-difluorophenylamino)amino)-5-(1-(2-hydroxyethyl)-1H-pyrazole- 4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide;

(116) N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-difluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine- 2,4-diamine;

(117) 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-2-((3,5-difluorophenyl)amino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethan-1-ol;

(118) 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazole- 1-day) ethanol;

(119) N-((1r,4r)-4-((2-((3,5-bis(trifluoromethyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl )pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide;

(120) N4-((1r,4r)-4-aminocyclohexyl)-N2-(3,5-bis(trifluoromethyl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl ) pyrimidine-2,4-diamine; and

(121) 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-2-((3,5-bis(trifluoromethyl)phenyl)amino)pyrimidine-5 -yl)-1H-pyrazol-1-yl)ethan-1-ol.

Meanwhile, the compound represented by Formula 1 of the present invention 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, and 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 negative 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, as shown in Scheme 1 below,

reacting the compound represented by Formula 2 with NH ₂ R ² to prepare a compound represented by Formula 3 (step 1);

preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and

It provides a method for preparing a compound represented by Formula 1 of claim 1, comprising a step of preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3).

[Scheme 1]

In Scheme 1,

R ¹ , R ² , R ³ and R ⁴ are 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 according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Formula 1 according to the present invention, step 1 of Scheme 1 is a step of preparing a compound represented by Formula 3 by reacting the compound represented by Formula 2 with NH ₂ R ² .

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 the compound represented by Formula 3 by introducing a -NH-R ² substituent at the X ¹ position of the compound represented by Formula 2 is included in the present invention without limitation, and in one embodiment preferably 1 It can be carried out by reacting DIPEA (N,N-diisopropylethylamine) and a compound represented by Formula 2 with ,4-dioxane.

In this case, as a solvent that can be used for the reaction, any solvent capable of dissolving the compound represented by Formula 2 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), dimethylsulfoxide (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 according to the present invention, step 2 of Scheme 1 is a step of preparing a compound represented by Formula 4 from the compound represented by Formula 3 prepared in Step 1.

In this case, step 2 may be understood as a step of introducing a substituent R ¹ into the compound represented by Formula 3, and selectively introducing R ¹ according to a desired compound to prepare a compound represented by Formula 4 .

로 표시되는 화합물 및 Pd(dppf)₂Cl₂를 반응시켜 수행될 수 있으나, 이와 상등한 당분야 통상의 기술로 사용되는 방법으로 본 발명의 단계 2와 같이 화학식 4로 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 , Na ₂ CO ₃ and a compound represented by Formula 3 in DMF,

Although it may be carried out by reacting the compound represented by and Pd(dppf) ₂ Cl ₂ , the compound represented by Formula 4 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 nate, 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 according to the present invention, step 3 of Scheme 1 is a step of preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in step 2.

In this case, step 3 may be understood as a step of introducing a -NR ³ R ⁴ substituent into the compound represented by Formula 4, and selectively introducing a -NR ³ R ⁴ substituent according to the desired compound represented by Formula 1 It is a step for preparing the compound of the present invention.

Meanwhile, although not limited thereto, as an example, as part of a method for introducing the -NR ³ R ⁴ substituent, the compound represented by Formula 4 and the compound represented by NHR ³ R ⁴ are reacted in acid-treated ethoxyethanol. It is included in the present invention without limitation as long as it can be carried out as a step capable of preparing the compound represented by Formula 1 as in Step 3 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 An ether solvent containing, for example, methanol, ethanol, lower alcohol containing propanol and butanol, and mixtures thereof may be used, and ethoxyethanol 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 100° C. Further, the reaction time is not particularly limited, but, for example, may be set to 10 to 40 hours, and as another example, the reaction may be performed over 10 to 20 hours.

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

[Scheme 2]

In Scheme 2,

R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1 above.

Furthermore, 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

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a TYRO 3 (Tyrosine-protein kinase receptor)-related disease containing the compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

The pharmaceutical composition is a novel TYRO 3 inhibitory compound of the present invention, wherein the compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, targets TYRO 3 (Tyrosine-protein kinase receptor) and its activity It shows the effect of preventing or treating TYRO 3 (Tyrosine-protein kinase receptor) related diseases from inhibition.

Examples of the TYRO 3 related diseases include all kinds of diseases resulting from abnormal TYRO 3 action due to abnormal expression, abnormal activity, etc. of TYRO 3, and also states by inhibiting TYRO 3 activity of diseases such as cancer Without limitation, as long as it is a disease found to be able to alleviate or ameliorate, prevent or treat It should be understood as a TYRO 3 related disease that can be used as a nutraceutical composition to exhibit useful effects such as prevention, improvement, and treatment, and is included within the scope of the present invention.

Also, for example, TYRO 3 related diseases include all known TYRO 3 related diseases such as cancers identified as being related to TYRO 3 described above in the background of the present invention, for example, breast cancer and ovarian cancer.

Specifically, examples of the TYRO 3 related disease include cancer, and in detail, the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, and oral 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 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 , pediatric brain cancer, juvenile lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant, malignant melanoma tumor, 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 cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma It is at least one selected from the group consisting of cancer, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer.

In addition, the present invention is a health functional food composition for preventing or improving TYRO 3 (Tyrosine-protein kinase receptor)-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient provides

Preferably, the TYRO 3 related disease is cancer,

In this case, the compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as an active ingredient, inhibits TYRO 3 to prevent or improve TYRO 3 related diseases, preferably cancer.

Specifically, 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 Cancer, 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, Ample Barter 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 , glioma, neuroblastoma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, primary site unknown Cancer, 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, anus It is at least one selected from the group consisting of cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer.

On the other hand, the compound represented by Formula 1 according to the present invention may be administered in various oral and parenteral formulations during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants It is prepared using a diluent or excipient such as

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention and at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.

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 addition, the effective dose of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally about 0.001-100 mg/kg/day, preferably Usually 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg/day, preferably 0.7-2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited thereto.

< Example 1> 5- Bromo -N4- cyclohexyl -N2-p- tolylpyrimidine -2,4- diamine Produce

step 1: 5 - Bromo -2- Chloro -N- Cyclohexylpyrimidine -4- amine Produce

5-Bromo-2,4-dichloropyrimidine (1 g, 4.41 mmol) was dissolved in 1,4-dioxane (20 mL), and cyclohexylamine (0.50 mL, 4.41 mmol) and diisopropylamine were dissolved therein. (1.2 mL, 6.62 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours, water (10 mL) and dichloromethane (30 mL) were added, and the product was extracted with an organic layer. The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography to obtain the target compound (0.8 g, 62%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.20 (s, 1H), 5.45 (brS, 1H), 4.01 (m, 1H), 2.04 (m, 2H), 1.81-1.59 (m, 3H), 1.58- 1.25 (m, 5H); LC/MS m/z calcd for C ₁₀ H ₁₃ BrClN ₃ (MH ⁺ ) 291.6, found 292.0.

step 2: 5 - Bromo -N ⁴ - cyclohexyl -N ² -(p- Tolyl )pyrimidine-2,4- diamine Produce

5-Bromo-2-chloro-N-cyclohexylpyrimidin-4-amine (200 mg, 0.68 mmol) and p-toluidine (85 mg, 0.68 mmol) were added to ethoxyethanol (2 mL), HCl (0.08 M, 0.2 mL) was added thereto. The reaction was stirred at 100° C. for 13 hours. Upon completion of the reaction, ethyl acetate (20 mL) and water (2 mL) were added to the reaction mixture, and the product was extracted as an organic layer, dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography. , the target compound was obtained (180 mg, 73%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.98 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 6.85 (brS, 1H), 5.16 (m, 1H), 3.98 (m, 1H), 2.34 (s, 3H), 2.13 (m 2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.48 (m, 2H), 1.28 (m , 3H); LC/MS m/z calcd for C ₁₇ H ₂₁ BrN ₄ (MH ⁺ ) 361.3, found 362.1.

< Example 2> N4- cyclohexyl Preparation of -N2,5-di-p-tolylpyrimidine-2,4-diamine

5-Bromo-N ⁴ -cyclohexyl-N ² -(p-tolyl)pyrimidine-2,4-diamine (30 mg, 0.079 mmol), 4-methylboronic acid (12 mg, 0.079 mmol), K ₂ CO ₃ (32 mg, 0.237 mmol) was added to ethyldimethyl ether (2 mL), and Pd(PPh ₃ ) ₄ (3 mg, 0.0026 mmol) was added thereto. The reaction was stirred at 80° C. for 13 hours. Upon completion of the reaction, ethyl acetate (20 mL) and water (2 mL) were added to the reaction mixture, and the product was extracted as an organic layer, dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography. , the target compound was obtained (20 mg, 63%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (m, 2H), 7.51 (m, 6H), 7.21 (d, J = 8.1 Hz, 2H), 4.91 (s, 1H), 4.10 (s, 1H) , 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (m 2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.48 (m, 2H), 1.28 (m, 3H); LC/MS m/z calcd for C ₂₄ H ₂₈ N ₄ (MH ⁺ ) 372.5, found 373.2.

< Example 3> 5- Bromo -N4- cyclohexyl -N2-(3,5- dichlorophenyl ) Preparation of pyrimidine-2,4-diamine

5-Bromo-2-chloro-N-cyclohexylpyrimidin-4-amine (300 mg, 1.02 mmol) and 3,5-dichloroaniline (165 mg, 1.02 mmol) in ethoxyethanol (2 mL) HCl (0.08 M, ethoxyethanol solution, 0.3 mL) was added thereto. The reaction was stirred at 100° C. for 13 hours. Upon completion of the reaction, ethyl acetate (20 mL) and water (2 mL) were added to the reaction mixture, and the product was extracted as an organic layer, dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography. , the target compound was obtained (280 mg, 66%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (s, 2H), 7.61 (s, 2H), 7.00 (s, 2H), 5.25 (s, 1H), 4.10 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (m 2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.48 (m, 2H), 1.28 (m, 3H).

< Example 4> 2- Chloro -N-cyclohexyl-5-(1-methyl-1H-pyrazole-4- One ) Preparation of pyrimidin-4-amine

5-Bromo-2-chloro-N-cyclohexylpyrimidin-4-amine (375 mg, 1.29 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3, 2-dioxabolen-2-yl)-1H-pyrazole (262 mg, 1.27 mmol), K ₂ CO ₃ (534 mg, 3.87 mmol) was added to dimethylformamide (10 mL), and then Pd ( dppf) ₂ Cl ₂ (133 mg, 0.26 mmol) was added. The reaction was stirred at 80° C. for 13 hours. Upon completion of the reaction, ethyl acetate (40 mL) and water (10 mL) were added to the reaction mixture, and the product was extracted as an organic layer, dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography. , the target compound was obtained (280 mg, 74%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.86 (s, 2H), 7.59 (s, 1H), 7.49 (s, 1H), 5.12 (s, 1H), 4.10 (s, 1H), 4.01 (s, 3H), 2.02 (s, 2H), 1.71 (m, 3H), 1.48 (m, 2H), 1.19 (m, 3H); LC/MS m/z calcd for C ₁₄ H ₁₈ ClN ₅ (MH ⁺ ) 291.7, found 292.2.

< Example 5> N4-cyclohexyl-N2- (3,5- dichlorophenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

2-Chloro-N-cyclohexyl-5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-amine (30 mg, 1.02 mol) with 3,5-dichloroaniline (17 mg, 1.02) mmol) was added to ethoxyethanol (2 mL), and HCl (0.08 M, ethoxyethanol solution, 0.3 mL) was added thereto. The reaction was stirred at 100° C. for 13 hours. Upon completion of the reaction, ethyl acetate (20 mL) and water (2 mL) were added to the reaction mixture, and the product was extracted as an organic layer, dried over Na ₂ SO ₄ , filtered, concentrated, and separated by column chromatography. , the target compound was obtained (31 mg, 72%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76 (s, 1H), 7.68 (s, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 5.12 (brs, 1H), 4.10 (s, 1H), 4.01 (s, 3H), 2.02 (m, 2H), 1.71 (m, 3H), 1.48 (m, 2H), 1.19 (m, 3H); LC/MS m/z calcd for C ₂₀ H ₂₂ C ₁₂ N ₆ (MH ⁺ ) 417.4, found 418.2.

< Example 6> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4- One )-N2- Phenylpyrimidine Preparation of -2,4-diamine

The target compound was obtained in the same manner as in Example 5 except that aniline (17 mg, 0.17 mmol) was used instead of 3,5-dichloroaniline of Example 5 (17 mg, 48%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.81 (s, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.32 (m, 2H) , 7.01 (m, 1H), 4.95 (d, J = 6.0 Hz, 1H), 4.01 (m, 1H), 3.99 (s, 3H), 2.11 (m, 2H), 1.75 (m, 3H), 1.45 ( m, 2H), 1.20 (m, 3H); LC/MS m/z calcd for C ₂₀ H ₂₄ N ₆ (MH ⁺ ) 348.20, found 349.1.

< Example 7>N2-(3- chlorophenyl )-N4- cyclohexyl -5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidine-2,4-diamine

The target compound was obtained in the same manner as in Example 5 except that 3-chloroaniline (18 mg, 0.14 mmol) was used instead of 3,5-dichloroaniline of Example 5 (23 mg, 60 %).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.21 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 7.24 (m, 3H), 6.98 (m, 1H), 4.95 (d, J = 6.0 Hz, 1H), 4.01 (m, 1H), 3.99 (s, 3H), 2.11 (m, 2H), 1.75 (m, 3H), 1.45 (m, 2H), 1.20 (m, 3H); LC/MS m/z calcd for C ₂₀ H ₂₃ ClN ₆ (MH ⁺ ) 382.17, found 382.2.

< Example 8> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4-yl)-N2-(3-( trifluoromethyl ) Preparation of benzyl) pyrimidine-2,4-diamine

The target compound was obtained in the same manner as in Example 5 except that 3-trifluoromethyl benzylamine (20 mg, 0.11 mmol) was used instead of 3,5-dichloroaniline of Example 5 ( 11 mg, 23%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.45 (m, 2H), 7.65-7.28 (m, 5H), 5.32 (s, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.72 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H), 3.85 (m, 1H), 1.78 (m, 3H), 1.70 (m, 3H), 1.45-1.10 (m, 5H); LC/MS m/z calcd for C ₂₂ H ₂₅ F ₃ N ₆ (MH ⁺ ) 430.21, found 431.1.

< Example 9> N2-(3- Chloro -4- methoxyphenyl )-N4- cyclohexyl -5-(1- methyl -1H- fira Preparation of zol-4-yl) pyrimidine-2,4-diamine

The target compound was obtained in the same manner as in Example 5, except that 3-chloro-4-methoxyaniline (20 mg, 0.11 mmol) was used instead of 3,5-dichloroaniline of Example 5. (20 mg, 46%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.02 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H),

7.42 (m, 2H), 7.28 (m, 2H), 6.90 (m, 1H), 4.96 (d, J = 9.0Hz, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 3.97 (s) , 3H), 2.06 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.45-1.10 (m, 3H); LC/MS m/z calcd for C ₂₁ H ₂₅ ClN ₆ O (MH ⁺ ) 412.18, found 413.0.

< Example 10> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4-yl)-N2-o- tolylpyrimidine Preparation of -2,4-diamine

The target compound was obtained in the same manner as in Example 5 except that o-toluidine (40 mg, 0.37 mmol) was used instead of 3,5-dichloroaniline of Example 5 (19 mg, 46%). ).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.21 (d, J = 6.0 Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (m, 2H), 7.28 (m, 2H) , 6.98 (m, 1H), 4.93 (d, J = 9.0Hz, 1H), 4.02 (m, 1H), 4.00 (s, 3H), 2.38 (s, 3H), 2.06 (m, 2H), 1.78 ( m, 2H), 1.52 (m, 2H), 1.45-1.10 (m, 3H); LC/MS m/z calcd for C ₂₁ H ₂₆ N ₆ (MH ⁺ ) 362.22, found 363.10.

< Example 11> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4-yl)-N2-(5- methylisoxazole Preparation of -3-yl)pyrimidine-2,4-diamine

The target compound was obtained in the same manner as in Example 5, except that 5-methylisoxazol-3-amine (30 mg, 0.31 mmol) was used instead of 3,5-dichloroaniline of Example 5. (17 mg, 48%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.38 (brs, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 6.74 (s, 1H), 4.93 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.97 (m, 1H), 2.39 (s, 3H), 2.06 (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H), 1.45-1.10 (m, 3H); LC/MS m/z calcd for C ₁₈ H ₂₃ N ₇ O (MH ⁺ ) 353.20, found 354.10.

< Example 12>N2-(5- tert - butyl isoxazole -3-yl)-N4- cyclohexyl -5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidine-2,4-diamine

In the same manner as in Example 5, except that 5-(tert-butyl)isoxazol-3-amine (30 mg, 0.21 mmol) was used instead of 3,5-dichloroaniline of Example 5, the purpose The compound was obtained (20 mg, 49%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.65 (brs, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 6.83 (s, 1H), 4.97 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 4.00 (m, 1H), 2.08 (m, 2H), 1.82-1.60 (m, 3H), 1.47 (s, 3H), 1.49-1.21 (m) , 4H); LC/MS m/z calcd for C ₂₁ H ₂₉ N ₇ O (MH ⁺ ) 395.2, found 397.2.

< Example 13> N4- cyclohexyl -N2-(2- isopropylphenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidine-2,4-diamine

The target compound was obtained in the same manner as in Example 5 except that 2-isopropylaniline (20 mg, 0.15 mmol) was used instead of 3,5-dichloroaniline of Example 5 (18 mg, 46%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.06 (d, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.07 (d, J = 6.0 Hz, 1H), 6.73 (brs, 1H), 4.97 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 4.00 (m, 1H), 3.22 (m, 1H), 2.08 (m, 2H), 1.82-1.60 (m, 3H), 1.47 (s, 3H), 1.29 (d, J = 9.0) Hz, 9H), 1.49-1.21 (m, 4H); LC/MS m/z calcd for C ₂₁ H ₂₉ N ₇ O (MH ⁺ ) 390.3, found 391.2.

< Example 14> N4- cyclohexyl -5-( furan -3-yl)-N2-p- tolylpyrimidine -2,4- diamine Produce

In the same manner as in Example 2, except that 3-furanyl boronic acid (9.2 mg, 0.083 mmol) was used instead of 4-methylboronic acid of Example 2, the target compound was obtained (25 mg, 86%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (s, 1H), 7.56 (m, 4H), 7.15 (d, J = 6.0 Hz, 1H), 6.52 (s, 1H), 4.95 (d, J = 9.0 Hz, 1H), 4.03 (m, 1H), 2.34 (s, 3H), 2.08 (m, 2H), 1.82-1.63 (m, 3H), 1.47 (s, 3H), 1.49-1.21 (m, 3H) ); LC/MS m/z calcd for C ₂₁ H ₂₄ N ₄ O (MH ⁺ ) 348.4, found 349.3.

< Example 15> N4-cyclohexyl-N2- (3,5- dichlorophenyl Preparation of )-5-(furan-3-yl)pyrimidine-2,4-diamine

In the same manner as in Example 2, except that 3-furanyl boronic acid (8.2 mg, 0.072 mmol) was used instead of 4-methylboronic acid of Example 2, the target compound was obtained (20 mg, 69%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (s, 1H), 7.65 (m, 2H), 7.52 (m, 2H), 6.98 (m, 1H), 6.53 (m, 1H), 5.04 (d, J = 9.0 Hz, 1H), 4.03 (m, 1H), 2.09 (m, 2H), 1.82-1.40 (m, 6H), 1.49-1.21 (m, 3H); LC/MS m/z calcd for C ₂₀ H ₂₀ Cl ₂ N ₄ O (MH ⁺ ) 403.1, found 403.9.

< Example 16> N4- cyclohexyl -N2-(2,2- difluoro -2-(4- methoxyphenyl Preparation of )ethyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

In the same manner as in Example 2, except that difluoro(4-methoxyphenyl)methanamine (20 mg, 0.068 mmol) was used instead of 4-methylboronic acid in Example 2, The target compound was obtained (20 mg, 45%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (s, 1H), 7.76 (s, 1H), 7.55-7.42 (m, 2H), 7.34-7.28 (m, 3H), 7.09-6.99 (m, 2H) ), 6.91-6.81 (m, 2H), 4.48 (t, J = 6.0 Hz, 1H), 3.97 (s, 3H), 3.88-3.78 (m, 5H), 3.51 (s, 3H), 3.7 (s, 1H), 2.00-1.98 (m, 3H); LC/MS m/z calcd for C ₂₃ H ₂₈ F ₂ N ₆ O (MH ⁺ ) 442.1, found 443.2.

< Example 17> N4- cyclohexyl -5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N2-(2-(pyridin-4-yl)ethyl)pyrimidine-2,4-diamine

In the same manner as in Example 2, except that 2-(pyridin-4-yl)ethan-1-amine (20 mg, 0.16 mmol) was used instead of 4-methylboronic acid in Example 2 , the target compound was obtained (30 mg, 79%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.57-8.52 (m, 2H), 7.65 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.18-7.15 (m, 2H) , 4.89 (d, J = 6.0 Hz, 1H), 3.98 (s, 4H), 3.63-3.50 (m, 2H), 2.97-2.86 (m, 2H), 2.06-1.97 (m, 2H), 1.76-1.71 (m, 3H), 1.47-1.33 (m, 2H), 1.30-1.11 (m, 4H); LC/MS m/z calcd for C35H45ClN12 (MH+) 377.2, found 378.2.

< Example 18> (4-(4-( cyclohexylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-2-yl)piperazin-1-yl)(thiophen-2-yl)methanone

Except for using pyrezin-1-yl (thiophen-2-yl) methanone (30 mg, 0.15 mmol) in place of 4-methylboronic acid of Example 2, According to the method, the target compound was obtained (33 mg, 70%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89 - 7.70 (m, 1H), 7.59 - 7.45 (m, 2H), 7.45 - 7.32 (m, 2H), 7.19 - 6.91 (m, 1H), 4.84 (d , J = 7.4 Hz, 1H), 4.03 - 3.93 (m, 4H), 3.90-3.79 (m, 4H), 2.17-1.86 (m, 3H), 1.83-1.66 (m, 2H), 1.40 (dd, J) = 24.1, 11.8 Hz, 2H), 1.33-1.08 (m, 4H); LC/MS m/z calcd for C ₃₇ H ₄₇ ClN ₁₂ OS (MH ⁺ ) 451.6, found 452.2.

< Example 19> 4-(4-( cyclohexylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-2-ylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one

Instead of 4-methylboronic acid of Example 2, 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (30 mg, 0.15 mmol) ) was carried out as in Example 2, except that the target compound was obtained (20 mg, 44%).

LC/MS m/z calcd for C ₂₅ H ₃₀ N ₈ O (MH ⁺ ) 458.2, found 459.2.

< Example 20> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4-yl)-N2-(3- methylisoxazole Preparation of 5-yl)pyrimidine-2,4-diamine

In the same manner as in Example 2, except that 3-methylisoxazol-5-amine (30 mg, 0.31 mmol) was used instead of 4-methylboronic acid in Example 2, the target compound was obtained was obtained (17 mg, 48%).

LC/MS m/z calcd for C ₁₈ H ₂₃ N ₇ O (MH ⁺ ) 352.2, found 353.1.

< Example 21> N4- cyclohexyl -N2-(5-ethyl-1,3,4- Thiadiazole -2-yl)-5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidine-2,4-diamine

The method of Example 2, except that 5-ethyl-1,3,4-thiazol-2-amine (20 mg, 0.15 mmol) was used instead of 4-methylboronic acid of Example 2 According to the procedure, the target compound was obtained (15 mg, 39%).

LC/MS m/z calcd for C ₁₈ H ₂₄ N ₈ S (MH ⁺ ) 384.5, found 385.1.

< Example 22> N4- cyclohexyl -5-(1- methyl -1H- pyrazole -4-yl)-N2-( Thiazole Preparation of -2-yl) pyrimidine-2,4-diamine

In the same manner as in Example 2, except that thiazol-2-amine (25 mg, 0.25 mmol) was used instead of 4-methylboronic acid in Example 2, the target compound was obtained ( 20 mg, 56%).

LC/MS m/z calcd for C ₁₇ H ₂₁ N ₇ S (MH ⁺ ) 355.5, found 356.1.

< Example 23> N4- cyclohexyl -N2- adamantyl -5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidine-2,4-diamine

In the same manner as in Example 2, except that 1-adamentylamine (25 mg, 0.18 mmol) was used instead of 4-methylboronic acid in Example 2, the target compound was obtained (15 mg, 37%).

LC/MS m/z calcd for C ₂₄ H ₃₄ N ₆ (MH ⁺ ) 405, found 406.2.

< Example 24> N4-cyclohexyl-N2- (2-methoxy phenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

In the same manner as in Example 2, except that o-anisidine (20 mg, 0.16 mmol) was used instead of 4-methylboronic acid in Example 2, the target compound was obtained (18 mg , 47%).

LC/MS m/z calcd for C ₂₁ H ₂₆ N ₆ O (MH ⁺ ) 378.4, found 379.2.

< Example 25> N4-cyclohexyl-5-(1-methyl-1H-pyrazole-4- One Preparation of )-N2-m-tolylpyrimidine-2,4-diamine

In the same manner as in Example 2, except that m-toluidine (20 mg, 0.18 mmol) was used instead of 4-methylboronic acid in Example 2, the target compound was obtained (21 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.57 (m, 2H), 7.45 (m, 2H), 7.23 (m, 1H), 6.84 (d, J = 6.0 Hz, 1H) , 4.84 (d, J = 7.4 Hz, 1H), 4.03 (m, 1H), 3.98 (s, 3H), 2.38 (s, 3H), 2.18-2.10 (m, 4H), 1.83-1.65 (m, 3H) ), 1.51-1.28 (m, 2H), 1.28-1.08 (m, 3H); LC/MS m/z calcd for C ₂₁ H ₂₆ N ₆ (MH ⁺ ) 362.4, found 363.3.

< Example 26> N-(( 1s, 4s )-4-(2-(3,5- dichlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 1: t-butyl (( 1s, 4s )-4-((5- brolmo -2- Chloropyrimidine -4-yl) amino) cicle Preparation of rohexyl) carbamate

5-bromo-2,4-dichloropyrimidine (1 g, 4.4 mmol) and t-butyl ((1s,4s)-4-(methyl-4-azanyl)cyclohexyl)carbamate (0.6 g, 4.41 mmol) was added to 1,4-dioxane (20 mL), and diisopropylamine (1.2 mL, 6.62 mmol) was added thereto. The reaction was stirred at room temperature for 6 hours, and when the reaction was completed, ethyl acetate (70 mL) was added to the reaction mixture, the product was extracted into an organic layer, the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, and then column After separation by chromatography, the target compound was obtained (1 g, 55%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.12 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 4.57 (s, 1H), 4.25 - 4.08 (m, 1H), 3.68 (d , J = 8.9 Hz, 1H), 1.85 (ddt, J = 12.8, 8.5, 4.0 Hz, 4H), 1.71 - 1.53 (m, 4H), 1.46 (s, 9H).

Step 2: ( 1s, 4s )-N1-(5- Bromo -2- Chloropyrimidine -4-yl) cyclohexane-1,4- diamine Produce

t-Butyl ((1s,4s)-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)carbamate (980 mg, 2.1 mmol) in methanol (20 mL) It was dissolved, and HCl solution (4 N, 1,4-dioxane solution, 1 mL) was added. Upon completion of the reaction, the reaction mass was concentrated and recrystallized to obtain the target compound (650 mg, 98%).

LC/MS m/z calcd for C ₁₀ H ₁₄ BrClN ₄ (MH ⁺ ) 304.01, found 305.1.

Step 3: N-(( 1s, 4s )-4-((5- Bromo -2- Chloropyrimidine -4-yl) amino) cyclohex Thread) Preparation of -2,2,2-trifluoroacetamide

(1s,4s)-N1-(5-bromo-2-chloropyrimidin-4-yl)cyclohexane-1,4-diamine (500 mg, 1.64 mmol) was dissolved in dichloromethane (10 mL), and here To this was added trifluoroacetic anhydride (0.23 mL, 1.64 mmol), followed by triethylamine (0.5 mL, 3.27 mmol). The reaction was stirred at room temperature for 6 hours, and when the reaction was completed, ethyl acetate (70 mL) was added to the reaction mixture, the product was extracted into an organic layer, the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, and then column After separation by chromatography, the target compound was obtained (0.5 g, 76%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.17 (s, 1H), 6.33 (brs, 1H), 5.54 (m, 1H), 4.22 (m, 1H), 4.11 (m, 1H), 2.15-1.82 (m, 4H), 2.80-1.65 (m, 4H).

Step 4: N-(( 1s, 4s )-4-((2- Chloro -5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

N-((1s,4s)-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide (200 mg, 0.49 mmol) and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103 mg, 0.49 mmol), K ₂ CO ₃ (206 mg, 0.26 mmol) was dissolved in dimethylformamide (10 mL), and Pd(dppf) ₂ Cl ₂ (20 mg, 0.048 mmol) was added thereto. The reaction was stirred at 80 °C for 15 hours, and when the reaction was completed, ethyl acetate (70 mL) was added to the reaction mixture, the product was extracted into an organic layer, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated, After separation by column chromatography, the target compound was obtained (140 mg, 71%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.60 (d, J = 0.9 Hz, 1H), 7.56 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 7.3 Hz, 1H), 4.23 (s, 1H), 4.01 (s, 3H), 3.96 (d, J = 7.0 Hz, 1H), 1.94-1.80 (m, 4H), 1.68 (q) , J = 13.8, 10.7 Hz, 4H).

Step 5: N-(( 1s, 4s )-4-((2-((3,5- dichlorophenyl )amino)-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

N-((1s,4s)-4-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2, Except for using 2-trifluoroacetamide (40 mg, 0.09 mmol), the method of Example 5 was followed to obtain the target compound (47 mg, 98%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.42 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 6.95 (s) , 1H), 6.76 (brs, 1H), 5.10 (d, J = 9.0 Hz, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.98 (s, 3H), 2.19-1.62 (m, 4H), 1.61-1.23 (m, 4H); LC/MS m/z calcd for C ₂₂ H ₂₂ Cl ₂ F ₃ N ₇ O (MH ⁺ ) 527.01, found 528.1.

< Example 27> 1-(4-(2-(3,5- dichlorophenylamino Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 1: t-Butyl 4-((5- Bromo -2- Chloropyrimidine -4-yl)amino)piperidin-1- card Preparation of carboxylate

t-Butyl 4-aminopiperidine-1-carboxylate (295 mg, 1.3 mmol) was carried out in the same manner as in Step 1 of Example 1, except that the target compound was obtained (320 mg, 63 %).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 5.88 (d, J = 6.0 Hz, 1H), 4.15 (m, 3H), 2.95 (m, 2H), 2.11 (m, 2H) , 1.49 (s, 9H), 1.47 (m, 4H).

step 2: 5 - Bromo -2- Chloro -N-(piperidin-4-yl)pyrimidin-4- amine production of hydrochloride

Example 26, except that t-butyl 4-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate (420 mg, 1.07 mmol) was used. The target compound was obtained by carrying out according to the method of step 5 (350 mg, 98%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.26 (s, 1H), 6.75 (d J = 9.0 Hz, 1H), 4.10 (m, 1H), 3.85 (m, 1H) ), 1.98-1.56 (m, 6H).

step 3: 1 -(4-((5- Bromo -2- Chloropyrimidine Preparation of -4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one

As in step 6 of Example 26, except that 5-bromo-2-chloro-N-(piperidin-4-yl)pyrimidin-4-amine hydrochloride (351 mg, 1.07 mmol) was used. and the target compound was obtained (390 mg, 99%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 7.56 (s, 1H), 5.42 (m, 1H), 4.65 (m, 1H), 4.31 (m, 1H), 4.10 (m, 1H), 3.28 (m, 1H), 3.09 (m, 1H), 2.24 (m, 2H), 1.55 (m, 2H).

step 4: 1 -(4-((2- Chloro -5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one

1-(4-((5-bromo-2-chloropyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one (200 mg , 0.49 mmol) was carried out in the same manner as in Step 7 of Example 26, except that the target compound was obtained (185 mg, 85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 5.20 (d, J = 9.00 Hz, 1H), 4.51 (m, 1H) , 4.31 (m, 1H), 4.10 (m, 1H), 4.09 (s, 3H), 3.26 (m, 1H), 2.98 (m, 1H), 2.28 (m, 1H), 1.45 (m, 1H).

step 5: 1 -(4-((2-((3,5- dichlorophenyl )amino)-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one

1-(4-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2 - The method of Example 5 was followed, except that trifluoroethan-1-one (40 mg, 0.103 mmol) was used to obtain the target compound (30 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 4.90 (d, J = 9.00 Hz, 1H), 4.51 (m, 1H), 4.31 (m, 1H), 4.10 (m, 1H), 4.09 (s, 3H), 3.26 (m, 1H), 2.98 (m, 1H), 2.28 (m, 1H), 1.45 (m, 1H).

< Example 28> N4-(( 1s, 4s )-4-amino cyclohexyl )-N2-(3,5- dichlorophenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl) Amino) cyclohexyl) -2,2,2-trifluoroacetamide (35 mg, 0.087 mmol) was dissolved in methanol/tetrahydrofuran/water (1:0.5:0.5, 2 mL), followed by LiOH (10 mg, 0.12 mmol) was added. The reaction was stirred at 100° C. for 15 h. Upon completion of the reaction, ethyl acetate (200 mL) was added to the reaction mixture, the product was extracted into an organic layer, and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated, and then separated by column chromatography to obtain the target compound. (21 mg, 56%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.12 (s, 1H), 5.49 (d, J = 7.6 Hz, 1H), 4.57 (s, 1H), 4.25 - 4.08 (m, 1H), 3.68 (d , J = 8.9 Hz, 1H), 1.85 (ddt, J = 12.8, 8.5, 4.0 Hz, 4H), 1.71 - 1.53 (m, 4H), 1.46 (s, 9H); LC/MS m/z calcd for C ₂₀ H ₂₃ Cl ₂ N ₇ (MH ⁺ ) 432.3, found 433.2.

< Example 29> N2-(3,5- dichlorophenyl )-5-(1-methyl-1H-pyrazole-4- One Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-((2-((3,5-dichlorophenyl)amino)-5-( 1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)-2,2,2-trifluoroethan-1-one (27 mg, 0.052 mmol) was used, and in the same manner as in Example 28, the target compound was obtained (18 mg, 82%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.82 (s, 1H), δ 7.72 (m, 3H), 7.61 (s, 1H), 7.48 (s, 1H(, 6.99 (s, 1H), 5.10 ( m, 1H), 4.24 (m, 1H), 3.91 (s, 3H), 3.48 (m, 1H), 3.10 (m, 1H), 2.40-1.75 (m, 4H); LC/MS m/z calcd for C ₁₉ H ₂₁ Cl ₂ N ₇ (MH ⁺ ) 418.2, found 419.3.

< Example 30>N2-(3,5- dichlorophenyl )-N4-(( 1s, 4s )-4-(dimethylamino) cyclo Preparation of hexyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4- Diamine (30 mg, 0.070 mmol) and paraformaldehyde (11 mg, 6.36 mmol) were dissolved in methanol, and acetic acid (10 μL) and sodium cyanoboronate (23 mg, 6.36 mmol) were added thereto. The reaction was stirred at room temperature for 15 hours, and when the reaction was completed, ethyl acetate (70 mL) was added to the reaction mixture, the product was extracted into an organic layer, the organic layer was dried over Na ₂ SO ₄ , filtered, concentrated, and then column After separation by chromatography, the target compound was obtained (14 mg, 43%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.07 (s, 1H) 7.90-7.83 (m, 1H) , 7.66 (d, J = 3 Hz, 2H), 7.58-7.53 (m, 2H), 6.946 (t , J=1.8 Hz, 1H), 5.44 (d, J=6 Hz, 1H), 4.30-4.28 (m, 1H), 4.07 (s, 1H), 2.91-2.85 (m, 1H), 2.79 (s, 6H), 2.28-2.22 (m, 2H), 2.05-2.03 (m, 4H), 1.88-1.80 (m, 3H).

< Example 31> N-(( 1s, 4s )-4-(2-(3,5- dichlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)cyclohexyl)acetamide

N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4- Diamine (20 mg, 50 mmol) was dissolved in ethyl acetate (1 mL), and acetic anhydride (20 μL, 50 mmol) was added thereto. Upon completion of the reaction, ethyl acetate (70 mL) was added to the reaction mixture, the product was extracted into an organic layer, and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated, and then separated by column chromatography to obtain the target compound. (10 mg, 43%).

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

< Example 32> N2-(3,5- dichlorophenyl )-5-(1- methyl -1H- pyrazole -4-yl)-N4-(1- methylpiperidine Preparation of -4-yl) pyrimidine-2,4-diamine

N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 30 In place of -2,4-diamine, N2-(3,5-dichlorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyri The target compound was obtained in the same manner as in Example 30, except that midine-2,4-diamine (20 mg, 47 mmol) was used.

¹ H NMR (300 MHz, Chloroform-d) δ 7.82 - 7.78 (m, 1H), 7.63 (d, J = 1.8 Hz, 2H), 7.52 (s, 1H), 7.44 (s, 1H), 7.21 (dd , J = 2.2, 1.2 Hz, 1H), 6.98 (t, J = 1.8 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.21 - 4.07 (m, 2H), 4.00 (s, 3H), 3.27 - 3.15 (m, 2H), 2.57 (s, 3H), 2.22 - 2.14 (m, 3H), 2.03 (d, J = 5.7 Hz, 3H); LC/MS m/z calcd for C ₂₀ H ₂₃ Cl ₂ N ₇ (MH ⁺ ) 432.1, found 433.0.

< Example 33> 1-(4-(2-(3,5- dichlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

In place of 2-chloro-N-cyclohexyl-5- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-amine of Example 5, N2- (3,5-dichlorophenyl) Except using -5-(1-methyl-1H-pyrazol-4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine (20 mg, 47 mmol) , was carried out according to the method of Example 5 to obtain the target compound (5 mg, 24%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.64 (d, J = 1.8 Hz, 2H), 7.53 (s, 1H), 7.42 (s, 1H), 6.98 (t, J) = 1.8 Hz, 1H), 4.99 (d, J = 7.3 Hz, 1H), 4.61 (d, J = 13.4 Hz, 2H), 4.24 (dd, J = 11.5, 4.0 Hz, 2H), 3.98 (s, 3H) ), 3.84 (d, J = 13.4 Hz, 2H), 3.34 (d, J = 11.5 Hz, 2H), 2.87 (d, J = 13.6 Hz, 2H), 2.11 (s, 3H).

< Example 34> 2,2,2- trifluoro -1-(4-(5-(1- methyl -1H- pyrazole -4-yl)-2-( phenylamino Preparation of ) pyrimidin-4-ylamino) piperidin-1-yl) ethanone

The target compound was obtained in the same manner as in Example 5, except that aniline (25 μL, 0.35 mmol) was used instead of 3,5-dichloroaniline of Example 5 (22 mg, 71). %) .

₁ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (s, 1H), 7.62 - 7.58 (m, 2H), 7.52 (s, 1H), 7.40 (s, 1H), 7.35 - 7.28 (m, 2H), 7.05 - 7.02 (m, 1H), 6.96 - 6.93 (m, 1H), 4.88 - 4.85 (m, 1H), 4.55 - 4.47 (m, 2H), 3.98 (s, 3H), 3.35 - 3.24 (m, 2H) ), 3.05 - 2.95 (m, 2H), 2.27 - 2.19 (m, 3H); LC/MS m/z calcd for C ₂₁ H ₂₂ F ₃ N ₇ O (MH ⁺ ) 445.1, found 446.0.

< Example 35> 1-(4-(2-(3- Chlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone

In the same manner as in Step 5 of Example 27, except that 3-chloroaniline (35 mg, 0.28 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27, The compound was obtained (27 mg, 81%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (t, J=1.9 Hz, 1H) 7.82 (s, 1H) 7.52 (S, 1H) 7.43 (S, 1H) 7.19 (d, J=9 Hz, 1H) ) 4.92 (d, J=7.2 Hz, 1H) 4.59 - 4.57 (m, 1H) 4.54 - 4.53 (m, 1H) 4.08 - 4.02 (m, 1H) 3.98 (s, 3H) 3.42 - 3.33 (m, 1H) 3.10 - 3.01 (m, 1H) 2.33 - 2.20 (m, 2H) 1.47 - 1.42 (m, 2H); LC/MS m/z calcd for C ₂₁ H ₂₁ ClF ₃ N ₇ O (MH ⁺ ) 479.1, found 480.0.

< Example 36> N2-(3- chlorophenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(3-chlorophenylamino)-5-(1-methyl-1H) -Pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone (20 mg, 47 mmol) In the same manner as in Example 28, the target compound was obtained. (16 mg, 100%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.19 (dd, J = 4.9, 1.2 Hz, 3H), 7.00 - 6.91 (m, 1H), 4.97 (d, J = 7.5 Hz, 1H), 4.22 - 4.05 (m, 1H), 3.98 (s, 3H), 3.12 (d, J = 12.8 Hz, 2H) ), 2.85 (dd, J = 17.7, 6.3 Hz, 2H), 2.10 (d, J = 10.2 Hz, 2H), 1.35 (ddd, J = 23.3, 11.4, 3.7 Hz, 3H); LC/MS m/z calcd for C ₁₉ H ₂₂ ClN ₇ (MH ⁺ ) 383.8, found 384.6.

< Example 37> 1-(4-(2-(4- Chlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone

In the same manner as in Step 5 of Example 27, except that 4-chloroaniline (35 mg, 0.28 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27, The compound was obtained (29 mg, 87%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (s, 1H) 7.56 (d, J=3 Hz, 1H) 7.54 (d, J=3 Hz, 1H) 7.51 (d, J=3 Hz, 1H) 7.40 ( s, 1H) 7.27 (s, 1H) 7.24 (d, J=3Hz, 1H) 4.88 (d, J=6 Hz, 1H) 4.50 (d, J= 15Hz, 1H) 4.29 - 4.20 (m, 1H) 4.05 - 4.01 (m, 1H) 3.34 - 3.24 (m, 1H) 3.05 - 2.95 (m, 1H) 2.23 - 2.04 (m, 2H) 1.47 - 1.39 (m, 2H); LC/MS m/z calcd for C ₂₁ H ₂₁ ClF ₃ N ₇ O (MH ⁺ ) 479.1, found 480.0.

< Example 38> N4-(1- benzylpiperidine -4-yl)-N2-(3,5- dichlorophenyl )-5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidine-2,4-diamine

The target compound was prepared in the same manner as in Example 30, except that benzaldehyde (15 mg, 0.14 mmol) was used instead of paraformaldehyde of Example 30 (12 mg, 54%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.83 (s, 1H), 7.56 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 3.0 Hz) , 1H), 7.40 (s, 1H) 7.27 (s, 1H) 7.24 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 6.0 Hz, 1H), 4.50 (d, J = 15.1 Hz, 1H) ), 4.29-4.20 (m, 1H), 4.05-4.01 (m, 1H), 3.34-3.24 (m, 1H), 3.05-2.95 (m, 1H), 2.23-2.04 (m, 2H), 1.47-1.39 (m, 2H); LC/MS m/z calcd for C ₂₆ H ₂₇ Cl ₂ N ₇ (MH ⁺ ) 508.5 found 509.2.

< Example 39> 2,2,2- trifluoro -1-(4-(2-(3- Fluorophenylamino )-5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

In the same manner as in Step 5 of Example 27, except that 4-fluoroaniline (35 μL, 0.39 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27, The compound was obtained (25 mg, 71%).

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

< Example 40> N2-(4- chlorophenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(4-chlorophenylamino)-5-(1-methyl-1H) -Pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone (15 mg, 30 mmol) In the same manner as in Example 28, the target compound was obtained (14 mg, 100%),

¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.25 - 7.19 (m, 2H), 4.94 (d, J = 7.4 Hz, 1H), 4.06 (dtd, J = 11.0, 7.1, 4.0 Hz, 1H), 3.98 (s, 3H), 3.20 - 3.06 (m, 2H), 2.84 - 2.69 (m, 2H), 2.07 (d, J = 12.5 Hz, 2H), 1.48 - 1.27 (m, 3H) ).

< Example 41> N2-(3- Fluorophenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 2,2,2-trifluoro-1-(4-(2-(3-fluorophenyl) Except using amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone (15 mg, 25 mmol) was carried out in the same manner as in Example 28 to obtain the target compound (13 mg, 100%).

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

< Example 42> 5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N2-phenyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 2,2,2-trifluoro-1-(4-(2-(3-fluorophenyl) Except using amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone (15 mg, 25 mmol) was carried out in the same manner as in Example 28 to obtain the target compound (17 mg, 100%).

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

< Example 43> 1-(4-(2-(4- Chloro -3- methylphenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone

In the same manner as in Step 5 of Example 27, except that 4-chloro-4-methylaniline (15 μL, 0.11 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27 , the target compound was obtained (15 mg, 51%).

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

< Example 44> 2,2,2- trifluoro -1-(4-(2-(4-) methoxyphenylamino )-5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

In the same manner as in Step 5 of Example 27, except that 4-anisidine (13 mg, 0.11 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27, The compound was obtained (26 mg, 78%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.54 - 7.43 (m, 3H), 7.39 (s, 1H), 7.00 (s, 1H), 6.90 - 6.83 (m, 2H) , 4.83 (d, J = 7.2 Hz, 1H), 4.49 (d, J = 13.3 Hz, 1H), 4.28 - 4.18 (m, 1H), 3.97 (s, 4H), 3.81 (s, 3H), 3.33 - 3.21 (m, 1H), 2.98 (t, J = 11.7 Hz, 1H), 2.19 (d, J = 13.5 Hz, 2H), 1.56 - 1.35 (m, 2H).

< Example 45> 1-(4-(2-(3- Chloro -4- methoxyphenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl) pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone

In the same manner as in Step 5 of Example 27, except that 3-chloro-p-anisidine (16 mg, 0.11 mmol) was used instead of 3,5-dichloroaniline used in Step 5 of Example 27 , the target compound was obtained (28 mg, 80%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.08 (d, J = 2.6 Hz, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.40 (d, J = 3.7 Hz, 2H), 7.10 (dd, J = 8.8, 2.6 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 4.90 (d, J = 7.4 Hz, 1H), 4.53 (d, J = 13.5 Hz, 1H), 4.29 (dt, J = 7.4, 4.0 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.42 - 3.29 (m, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.23 (t, J = 11.0 Hz, 3H), 1.54 - 1.35 (m, 2H).

< Example 46> N2-(4- Chloro -3- methylphenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(4-chloro-3-methylphenylamino)-5-(1- Using methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone (7 mg, 0.01 mmol) Except that, the same procedure as in Example 28 was carried out to obtain the target compound (6 mg, 100%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.54 (dd, J = 3.2, 1.6 Hz, 2H), 7.45 - 7.39 (m, 2H), 7.24 (d, J = 8.7 Hz) , 1H), 6.90 (s, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.08 (d, J = 7.5 Hz, 1H), 3.98 (s, 3H), 3.12 (d, J = 12.8 Hz) , 2H), 2.76 (t, J = 10.7 Hz, 2H), 2.38 (s, 3H), 2.07 (d, J = 12.8 Hz, 2H), 1.36 (dd, J = 18.0, 5.7 Hz, 3H).

< Example 47> N2-(4- methoxyphenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 2,2,2-trifluoro-1-(4-(2-(4-methoxyphenyl) Except using amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone (10 mg, 0.02 mmol) was carried out in the same manner as in Example 28 to obtain the target compound (9 mg, 100%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.56 - 7.51 (m, 2H), 7.50 (d, J = 2.2 Hz, 1H), 7.40 (s, 1H), 6.88 (d , J = 2.2 Hz, 1H), 6.87 - 6.81 (m, 2H), 4.88 (d, J = 7.5 Hz, 1H), 4.12 - 4.01 (m, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 3.11 (d, J = 12.7 Hz, 2H), 2.81 - 2.69 (m, 2H), 2.07 (d, J = 12.5 Hz, 2H), 1.34 (td, J = 11.9, 3.9 Hz, 3H).

< Example 48> N2-(3- Chloro -4- methoxyphenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(3-chloro-4-methoxyphenylamino)-5-( Using 1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone (10 mg, 0.02 mmol) Except that, the same procedure as in Example 28 was carried out to obtain the target compound. (8 mg, 100%)

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

< Example 49> 1-(4-(2-(p- toluidino )-5-( furan -3-yl)pyrimidin-4- ilamino ) Preparation of piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that p-toluidine (17 mg, 0.16 mmol) was used to obtain the target compound (28 mg, 65%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.55 (t, J = 1.7 Hz, 1H), 7.50 (dd, J = 2.9, 1.6 Hz, 2H), 7.46 (s, 1H) ), 7.12 (d, J = 8.2 Hz, 2H), 7.06 (s, 1H), 6.47 (dd, J = 1.8, 0.8 Hz, 1H), 4.87 (d, J = 7.1 Hz, 1H), 4.51 (d , J = 11.7 Hz, 1H), 4.28 (dt, J = 7.5, 3.9 Hz, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.37 - 3.23 (m, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.33 (s, 3H), 2.22 (d, J = 8.1 Hz, 2H), 1.55 - 1.38 (m, 2H).

< Example 50> 1-(4-(2-(m- toluidino )-5-( furan -3-yl)pyrimidin-4- ilamino ) Preparation of piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except for using m-toluidine (17 μL, 0.16 mmol) to obtain the target compound (24 mg, 56%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.55 (t, J = 1.7 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.45 - 7.40 (m, 2H), 7.23 - 7.16 (m, 1H), 7.04 (s, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.48 (dd, J = 1.8, 0.9 Hz, 1H), 4.88 (d, J = 7.3 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.37 - 4.22 (m, 1H), 4.02 (d, J = 14.4 Hz, 1H), 3.39 - 3.24 (m, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.36 (s, 3H), 2.23 (d, J = 10.3 Hz, 2H), 1.57 - 1.39 (m, 2H).

< Example 51> 5-( furan -3-yl)-N4-(piperidin-4-yl)-N2-p- tolylpyrimidine -2,4- dia manufacturing of min

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(p-toluidino)-5-(furan-3-yl) ) Pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone (14 mg, 0.03 mmol) was carried out in the same manner as in Example 28, except that to obtain the target compound (9 mg, 90%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.60 - 7.45 (m, 4H), 7.11 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 6.50 (s, 1H), 4.91 (d, J = 7.2 Hz, 1H), 4.12 (dd, J = 7.0, 3.7 Hz, 1H), 3.13 (d, J = 12.6 Hz, 2H), 2.78 (t, J = 10.9 Hz, 2H), 2.32 (s, 3H), 2.08 (t, J = 9.7 Hz, 2H), 1.48 - 1.29 (m, 3H).

< Example 52> 5-( furan -3-yl)-N4-(piperidin-4-yl)-N2-m- tolylpyrimidine -2,4- diamine Produce

N-((1s,4s)-4-((2-((3,5-dichlorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine of Example 28 -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide in place of 1-(4-(2-(m-toluidino)-5-(furan-3-yl) ) Pyrimidin-4-ylamino) piperidin-1-yl) -2,2,2-trifluoroethanone (14 mg, 0.03 mmol) was carried out in the same manner as in Example 28, except that to obtain the target compound (11 mg, 90%).

¹ H NMR (300 MHz, MeOH-d ₄ ) δ 7.70 (s, 1H), 7.59 (s, 1H), 7.57 - 7.53 (m, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.49 (d, J = 1.0 Hz, 1H), 4.17 (t, J = 12.9 Hz, 1H), 3.27 ( d, J = 12.9 Hz, 2H), 2.90 (t, J = 11.4 Hz, 2H), 2.24 (s, 4H), 2.13 (d, J = 9.8 Hz, 3H), 1.71-1.41 (m, 3H).

< Example 53> 1-(4-(2-(3- Chlorophenylamino )-5-( furan -3-yl)pyrimidin-4- ilamino ) Preparation of piperidin-1-yl)-2,2,2-trifluoroethanone

In the same manner as in Step 5 of Example 14, except that 3-chloroaniline (17 μL, 0.16 mmol) was used instead of 3,5-dichloroaniline of Example 5, the target compound was obtained (29 mg, 58%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.17 (t, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.57 (t, J = 1.6 Hz, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 0.9 Hz) , 1H), 4.95 (d, J = 7.4 Hz, 1H), 4.55 (d, J = 13.9 Hz, 1H), 4.42 - 4.27 (m, 1H), 4.06 (d, J = 16.9 Hz, 1H), 3.37 (dd, J = 19.1, 7.3 Hz, 1H), 3.07 (t, J = 11.9 Hz, 1H), 2.27 (t, J = 12.5 Hz, 2H), 1.56 - 1.40 (m, 2H).

< Example 54> 2,2,2- trifluoro -1-(4-(2-(3- Fluorophenylamino )-5-( furan Preparation of -3-yl)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

Step 5 of Example 14 was followed except that 3-fluoroaniline (17 μL, 0.16 mmol) was used to obtain the target compound (20 mg, 45%).

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

< Example 55> N2-(3- Fluorophenyl )-5-( furan Preparation of -3-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

2,2,2-trifluoro-1-(4-(2-(3-fluorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1- Day) The target compound was obtained in the same manner as in Example 28 except that ethanone (10 mg, 0.02 mmol) was used (8 mg, 99%).

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

< Example 56> N2-(3- chlorophenyl )-5-( furan Preparation of -3-yl)-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3-chlorophenylamino)-5-(furan-3-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoro The target compound was obtained in the same manner as in Example 28 except that loethanone (10 mg, 0.02 mmol) was used (12 mg, 98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.56 (dd, J = 6.2, 4.5 Hz, 2H), 7.29 (s, 1H) , 7.25 - 7.12 (m, 2H), 6.96 (dt, J = 7.0, 2.0 Hz, 1H), 6.50 (dd, J = 1.7, 0.8 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 4.15 (ddd, J = 13.8, 7.2, 3.1 Hz, 1H), 3.19 (d, J = 12.8 Hz, 2H), 3.00 - 2.80 (m, 2H), 2.15 (d, J = 15.2 Hz, 2H), 1.56 - 1.35 (m, 3H), 0.92 - 0.79 (m, 2H).

< Example 57> 1-(4-(2-(3,5- dichlorophenylamino )-5- Phenylpyrimidine -4- ilamino ) Preparation of piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that 3,5-dichloroaniline (63 mg, 0.39 mmol) was used to obtain the target compound (43 mg, 65%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 1.9 Hz, 2H), 7.51 (d, J = 1.6 Hz, 1H), 7.49 (q, J = 1.4 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.38 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 1.3 Hz, 1H), 7.01 (t, J = 1.8 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H), 4.57 (d, J = 13.7 Hz, 1H), 4.37 (td, J = 7.6, 6.7, 3.1 Hz, 1H), 4.11 - 4.01 (m, 1H), 3.48 - 3.34 (m, 1H), 3.07 (t, J = 12.4 Hz, 1H), 2.27 (t, J = 12.3 Hz, 2H), 1.46 (q, J = 12.1 Hz, 2H) . LC/MS m/z calcd for C ₂₃ H ₂₀ Cl ₂ F ₃ N ₅ O (MH ⁺ ) 508.5 found 509.2.

< Example 58> N2-(3,5- dichlorophenyl Preparation of )-5-phenyl-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3,5-dichlorophenylamino)-5-phenylpyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone ( 10 mg, 0.02 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (15 mg, 94%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.69 (d, J = 1.8 Hz, 2H), 7.62 (d, J = 11.3 Hz, 1H), 7.49 (dd, J = 7.5) , 3.0 Hz, 2H), 7.45 - 7.35 (m, 3H), 6.98 (s, 1H), 5.03 (d, J = 7.6 Hz, 1H), 4.23 - 4.02 (m, 1H), 3.94 - 3.75 (m, 1H), 2.96-2.72 (m, 2H), 2.11 (d, J = 12.8 Hz, 2H), 1.91 (d, J = 11.7 Hz, 2H), 1.43-1.31 (m, 2H). LC/MS m/z calcd for C ₂₁ H ₂₁ Cl ₂ N ₅ (MH ₊ ) 413.9 found 415.0.

< Example 59> 1-(4-(2-(3,5- dichlorophenylamino )-5-(3- methoxyphenyl Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that 3,5-dichloroaniline (63 mg, 0.39 mmol) was used to obtain the target compound (25 mg, 51%).

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

< Example 60> N2-(3,5- dichlorophenyl )-5-(3-methoxy phenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3,5-dichlorophenylamino)-5-(3-methoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2- Except for using trifluoroethanone (15 mg, 0.027 mmol), the same procedure as in Example 28 was carried out to obtain the target compound (10 mg, 90%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.85 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.47 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.96 (q, J = 1.6 Hz, 2H), 6.94 - 6.91 (m, 1H), 6.89 (t, J = 2.0 Hz, 1H), 5.08 (d, J = 7.6 Hz, 1H), 4.23 - 4.07 (m) , 1H), 3.85 (s, 3H), 3.11 (d, J = 12.7 Hz, 2H), 2.85 (td, J = 12.6, 12.1, 2.6 Hz, 2H), 2.10 (d, J = 13.3 Hz, 2H) , 2.05 - 1.95 (m, 1H), 1.37 (td, J = 11.7, 4.0 Hz, 2H).

< Example 61> 1-(4-(2-(3,5- dichlorophenylamino )-5-(3,4- dimethoxyphenyl Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that 3,5-dichloroaniline (63 mg, 0.39 mmol) was used to obtain the target compound (43 mg, 63%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.91 (s, 1H), 7.68 (d, J = 1.8 Hz, 2H), 7.02 - 6.96 (m, 2H), 6.91 (dd , J = 8.2, 1.9 Hz, 1H), 6.84 (d, J = 1.9 Hz, 1H), 5.04 (d, J = 7.5 Hz, 1H), 4.61 - 4.52 (m, 1H), 4.43 - 4.27 (m, 1H), 4.06 (d, J = 14.3 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 4H), 3.63 - 3.53 (m, 1H), 3.46 - 3.33 (m, 1H), 3.07 (t) , J = 12.9 Hz, 1H), 2.27 (t, J = 11.1 Hz, 2H), 1.45 (q, J = 12.3, 11.8 Hz, 2H).

< Example 62> N2-(3,5- dichlorophenyl )-5-(3,4- dimethoxyphenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3,5-dichlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2, Step 5 of Example 14 was followed except that 2-trifluoroethanone (15 mg, 0.026 mmol) was used to obtain the target compound (11 mg, 92%).

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

< Example 63> 1-(4-(2-(4- Chloro -3- methylphenylamino )-5-(3,4- dimethoxyphenyl Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that 4-chloro-3-methylaniline (30 mg, 0.067 mmol) was used to obtain the target compound (32 mg, 86%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.85 (s, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.44 (dd, J = 8.6, 2.7 Hz, 1H), 7.24 (s, 1H) ), 6.97 (d, J = 2.8 Hz, 1H), 6.94 (s, 1H), 6.87 (dd, J = 8.2, 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.90 (d) , J = 7.3 Hz, 1H), 4.47 (d, J = 13.7 Hz, 1H), 4.27 (ddt, J = 15.1, 11.0, 5.6 Hz, 1H), 4.02 (s, 1H), 3.93 (s, 3H) , 3.89 (s, 3H), 3.29 (t, J = 11.8 Hz, 1H), 3.01 (t, J = 12.1 Hz, 1H), 2.38 (s, 3H), 2.20 (d, J = 13.0 Hz, 2H) , 1.70 (s, 1H), 1.47 - 1.37 (m, 2H).

< Example 64> 1-(4-(5-(3,4- dimethoxyphenyl )-2-(4- methoxyphenylamino Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that p-anisidine (25 mg, 0.20 mmol) was used to obtain the target compound (28 mg, 80%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 6.93 (t, J = 7.8) Hz, 2H), 6.90 - 6.87 (m, 2H), 6.85 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.86 (d, J = 7.3 Hz, 1H), 4.46 (d, J = 13.7 Hz, 1H), 4.31 - 4.16 (m, 1H), 3.99 (d, J = 14.5 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.81 (s) , 3H), 3.33 - 3.22 (m, 1H), 2.99 (t, J = 12.4 Hz, 1H), 2.19 (d, J = 13.5 Hz, 2H), 1.75 (s, 1H), 1.42 (q, J = 11.8 Hz, 2H).

< Example 65> 1-(4-(5-(3,4- dimethoxyphenyl )-2-(2- methoxyphenylamino Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

The method of step 5 of Example 14 was followed except that o-anisidine (23 mg, 0.20 mmol) was used to obtain the target compound (18 mg, 51%).

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

< Example 66> N2-(4- Chloro -3- methylphenyl )-5-(3,4- dimethoxyphenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3,5-dichlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2, The target compound was obtained in the same manner as in Example 28 except that 2-trifluoroethanone (15 mg, 25 mmol) was used (20 mg, 80%).

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

< Example 67> 5-(3,4- dimethoxyphenyl )-N2-(4- methoxyphenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(5-(3,4-dimethoxyphenyl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2 - Trifluoroethanone (15 mg, 28 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (12 mg, 100%).

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

< Example 68> 5-(3,4- dimethoxyphenyl )-N2-(2- methoxyphenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(5-(3,4-dimethoxyphenyl)-2-(2-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2 - Trifluoroethanone (15 mg, 28 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (9 mg, 97%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.61 - 8.51 (m, 1H), 7.85 (s, 1H), 7.57 (s, 1H), 6.97 (dd, J = 2.5, 1.7 Hz, 1H), 6.96 - 6.93 (m, 2H), 6.93 - 6.91 (m, 1H), 6.89 (q, J = 2.7 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 4.94 (d, J = 7.4 Hz, 1H), 4.26 - 4.12 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.16 (d, J = 12.5 Hz, 2H), 2.82 (t, J) = 10.9 Hz, 2H), 2.14 (d, J = 13.0 Hz, 2H), 1.46 - 1.31 (m, 2H).

< Example 69> 1-(4-(2-(3- Chlorophenylamino )-5-(3,4- dimethoxyphenyl Preparation of )pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Step 5 of Example 14 was followed except that 3-chloroaniline (21 mg, 0.20 mmol) was used to obtain the target compound (12 mg, 34%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.83 (s, 1H), 7.19 (d, J = 5.8 Hz, 2H), 7.15 (s, 1H), 6.96 (d, J) = 8.1 Hz, 2H), 6.91-6.86 (m, 1H), 6.81 (d, J = 1.9 Hz, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.23 - 4.09 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.15 (d, J = 12.4 Hz, 2H), 2.87 (t, J = 11.7 Hz, 2H), 2.12 (d, J = 12.9 Hz, 2H), 1.46 - 1.34 (m, 2H).

< Example 70> 2,2,2-trifluoro-1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2-trifluoro Preparation of acetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

Except using (7-amino-3,4-dihydroisoquinolin-2(1H)-yl)((difluor μL3-methyl)μL2-floranyl)methanone (30 mg, 0.121 mmol) , was carried out according to the method of step 5 of Example 14, to obtain the target compound (44 mg, 58%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 7.9 Hz, 1H), 7.57 (s, 2H), 7.51 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 9.2, 4.9 Hz, 1H), 6.02 (t, J = 8.8 Hz, 1H), 4.75 (d, J = 8.6 Hz, 2H), 4.63 - 4.51 (m, 1H), 4.30 (s) , 1H), 4.06 (d, J = 15.0 Hz, 1H), 3.99 (s, 3H), 3.89 (q, J = 6.3 Hz, 2H), 3.48 (q, J = 7.0 Hz, 1H), 3.25 (q) , J = 11.8, 11.2 Hz, 1H), 3.00 - 2.89 (m, 3H), 2.36 (s, 1H), 2.17 (d, J = 12.7 Hz, 2H).

< Example 71> 1-(4-(2-(3,5- dichlorophenylamino )-5-(1-(2- hydroxyethyl Preparation of )-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Except for using 3.5-dichloroaniline (13 mg, 0.079 mmol), the method of step 5 of Example 14 was followed to obtain the target compound (20 mg, 71%).

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 (t, J = 1.9 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H), 4.56 (d, J = 13.7 Hz, 1H), 4.37 - 4.28 (m, 3H), 4.11 - 4.03 (m, 3H), 3.75 (s, 1H), 3.38 (t, J = 13.2 Hz, 1H), 3.05 (t, J = 12.8 Hz, 1H), 2.25 (t, J = 12.3 Hz, 3H), 1.46 (q, J = 12.1 Hz, 2H).

< Example 72> 5-(1- methyl -1H- pyrazole -4-yl)-N4-(piperidin-4-yl)-N2-(1,2,3,4- frame Preparation of trihydroisoquinolin-7-yl)pyrimidine-2,4-diamine

1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperi Din-1-yl)-2,2,2-trifluoroethanone (37 mg, 0.062 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (24 mg, 99 %).

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.79 (s, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.51 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.32 (s, 2H), 3.97 (s, 3H), 3.47 (d, J = 5.9 Hz, 3H), 3.12 - 3.03 (m, 3H), 2.25 (d, J = 14.0) Hz, 2H), 1.94 (d, J = 0.7 Hz, 3H), 1.75 (d, J = 13.2 Hz, 2H).

< Example 73> N2-(3,5- dichlorophenyl Preparation of )-N4-(piperidin-4-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

1-(4-(4-(2-((3,5-dichlorophenyl)amino)-4-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino) Pyrimidin-5-yl)-1H-pyrazol-1-yl)pyreridin-1-yl)-2,2,2-trifluoroethan-1-one (13 mg, 0.019 mmol) was used. Except it was carried out in the same manner as in Example 28 to obtain the target compound (7 mg, 78%).

¹ H NMR (300 MHz, Methanol-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 ( d, 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 (dt, J = 22.5, 11.6 Hz, 4H), 2.15 (t, J = 13.1 Hz, 3H), 2.09 - 1.94 (m, 3H), 1.63 - 1.43 (m, 3H).

< Example 74> N2-(3- chlorophenyl )-5-(3,4- dimethoxyphenyl Preparation of )-N4-(piperidin-4-yl)pyrimidine-2,4-diamine

1-(4-(2-(3-chlorophenylamino)-5-(3,4-dimethoxyphenyl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2- The target compound was obtained in the same manner as in Example 28 except that trifluoroethanone (10 mg, 0.019 mmol) was used (8 mg, 98%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.82 (s, 1H), 7.20 (d, J = 5.8 Hz, 2H), 7.16 (s, 1H), 6.97 (d, J) = 8.1 Hz, 2H), 6.92 - 6.88 (m, 1H), 6.84 (d, J = 1.9 Hz, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.23 - 4.09 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.15 (d, J = 12.4 Hz, 2H), 2.87 (t, J = 11.7 Hz, 2H), 2.12 (d, J = 12.9 Hz, 2H), 1.46 - 1.34 (m, 2H).

< Example 75> 2-(4-(2-(3,5- dichlorophenylamino )-4-(piperidine-4- ilamino ) Preparation of pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperi The method of step 5 of Example 14 was followed, except that din-1-yl)-2,2,2-trifluoroethanone (11 mg, 0.021 mmol) was used to obtain the target compound (9 mg). , 85%).

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.81 (t, J = 2.2 Hz, 4H), 7.64 (s, 1H), 6.97 (d, J = 1.8 Hz, 1H), 4.31 (t, J = 5.2 Hz, 2H), 4.19 (d, J = 10.9 Hz, 1H), 3.96 (t, J = 5.2 Hz, 2H), 3.12 (d, J = 12.9 Hz, 2H), 2.84 (dd, J = 13.6, 11.0 Hz, 2H), 2.11 - 1.99 (m, 2H), 1.59 - 1.40 (m, 3H).

< Example 76> 2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2) Preparation of ,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

Except using (7-amino-3,4-dihydroisoquinolin-2(1H)-yl)((difluor μL3-methyl) μL2-floranyl)methanone (22 mg, 0.089 mmol) , the method of step 5 of Example 14 was carried out to obtain the target compound (39 mg, 62%).

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 = 12.4 Hz, 2H), 4.49 (d, J = 13.3 Hz, 1H), 4.31 (t, 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 (t, J = 12.8 Hz, 1H), 3.03 (d, J) = 12.5 Hz, 1H), 2.92 (q, J = 6.3 Hz, 2H), 2.20 (s, 2H), 1.44 (d, J = 21.2 Hz, 3H).

< Example 77> 1-(4-(2-(4- Chloro -3- methylphenylamino )-5-(1-(2- hydroxyethyl Preparation of )-1H-pyrazol-4-yl)pyrimidin-4-ylamino)piperidin-1-yl)-2,2,2-trifluoroethanone

Except for using 3-methyl-4-chloroaniline (20 mg, 0.14 mmol), the method of step 5 of Example 14 was followed to obtain the target compound (38 mg, 79%).

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) = 8.5, 2.7 Hz, 1H), 6.97 (s, 1H), 4.88 (d, J = 7.3 Hz, 1H), 4.49 (d, J = 13.8 Hz, 1H), 4.38 - 4.27 (m, 2H), 4.25 (d, J = 4.1 Hz, 1H), 4.11 - 4.03 (m, 2H), 4.00 (s, 1H), 3.29 (t, J = 13.0 Hz, 1H), 3.00 (t, J = 12.8 Hz, 1H) , 2.37 (s, 3H), 2.19 (s, 2H), 1.56 - 1.35 (m, 2H).

< Example 78> 2,2,2- trifluoro -1-(4-(5-(1-(2-) hydroxyethyl )-1H- pyrazole Preparation of -4-yl)-2-(4-methoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone

Except for using p-anisidine (18 mg, 0.14 mmol), the method of step 5 of Example 14 was followed to obtain the target compound (31 mg, 62%).

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) = 2.1 Hz, 1H), 7.06 (s, 1H), 6.90 - 6.83 (m, 2H), 4.87 (d, J = 7.2 Hz, 1H), 4.49 (dd, J = 11.2, 6.7 Hz, 1H), 4.34 - 4.27 (m, 2H), 4.21 (dq, J = 11.0, 6.8, 5.5 Hz, 1H), 4.09-4.00 (m, 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).

< Example 79> 2-(4-(4-(piperidine-4- ilamino )-2-(1,2,3,4- tetrahydroisoquinoline Preparation of -7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2,2,2) -trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone (34 mg, 0.054 mmol) Except for using, the same procedure as in Example 28 was carried out to obtain the target compound (20 mg, 87%).

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) , 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 4.90 (d, J = 7.7 Hz, 1H), 4.30 (t, J = 4.7 Hz, 3H), 4.10 (d) , J = 7.1 Hz, 1H), 4.05 (t, J = 4.8 Hz, 3H), 4.01 (s, 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).

< Example 80> 2-(4-(2-(4- Chloro -3- methylphenylamino )-4-(piperidine-4- ilamino ) Preparation of pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

1-(4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)p Peridin-1-yl)-2,2,2-trifluoroethanone (31 mg, 0.059 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (26 mg, 98%).

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), 4.30 (dd, J = 5.6, 4.0 Hz) , 2H), 4.09 (q, J = 3.3 Hz, 1H), 4.04 (dd, 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).

< Example 81> 2-(4-(2-(4- methoxyphenylamino )-4-(piperidine-4- ilamino ) Preparation of pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenylamino)pyri The target compound was obtained in the same manner as in Example 28, except that midin-4-ylamino)piperidin-1-yl)ethanone (24 mg, 0.047 mmol) was used (14 mg, 74%). ).

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), 6.88 (d, J = 3.3 Hz, 2H), 6.85 (d, J = 2.2 Hz, 1H), 4.89 (d, J = 7.5 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.09 (s, 1H) ), 4.05 (dd, J = 5.5, 4.0 Hz, 2H), 3.80 (s, 3H), 3.12 (d, J = 12.8 Hz, 2H), 2.76 (t, J = 11.4 Hz, 2H), 2.07 (d) , J = 13.3 Hz, 3H), 1.43 - 1.29 (m, 3H).

< Example 82> 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-di Preparation of hydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Except that 3,5-dichloroaniline (28 mg, 0.13 mmol) was used, the method of step 5 of Example 27 was followed to obtain the target compound (22 mg, 41%).

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).

< Example 83> 1-(7-(2-(4-chloro-3-methylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4- Preparation of dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Except that 4-chloro-3-methyl aniline (30 mg, 0.21 mmol) was used, the method of step 5 of Example 27 was followed to obtain the target compound (58 mg, 78%).

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).

< Example 84> N2-(3,5- dichlorophenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

1-(7-(2-(4-chloro-3-methylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydro The target compound was obtained in the same manner as in Example 28, except that isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (14 mg, 0.021 mmol) was used ( 11 mg, 95%).

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).

< Example 85> N2-(4- Chloro -3- methylphenyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N4-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

1-(7-(2-(4-chloro-3-methylphenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3,4-dihydro The target compound was obtained in the same manner as in Example 28, except that isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (38 mg, 0.070 mmol) was used ( 30 mg, 96%).

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).

< Example 86> 2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2) Preparation of ,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide

Except using (7-amino-3,4-dihydroisoquinolin-2(1H)-yl)((difluor μL3-methyl) μL2-floranyl)methanone (27 mg, 0.11 mmol) , the method of step 5 of Example 14 was carried out to obtain the target compound (44 mg, 58%).

¹ H NMR (500 MHz, Chloroform-d) δ 7.83 (d, J = 2.9 Hz, 1H), 7.57 (s, 1H), 7.56 - 7.54 (m, 1H), 7.47 (s, 1H), 7.37 (ddd , J = 16.1, 8.2, 2.2 Hz, 1H), 7.19 (d, J = 21.2 Hz, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 5.06 (t, J = 7.1 Hz, 1H), 4.75 (d, J = 22.2 Hz, 2H), 4.24-4.14 (m, 1H), 4.02 - 4.00 (m, 1H), 3.99 (s, 4H), 3.89 ( t, J = 6.1 Hz, 1H), 3.85 (t, J = 5.9 Hz, 1H), 2.91 (dt, J = 9.8, 6.0 Hz, 2H), 1.96 - 1.83 (m, 5H), 1.69 (t, J) = 9.7 Hz, 4H).

< Example 87> 1-(7-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino) Preparation of -3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Step 5 of Example 27 was followed except that 3,5-dichloroaniline (23 mg, 0.14 mmol) was used to obtain the target compound (43 mg, 81%).

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).

< Example 88> N4-(( 1s, 4s )-4- aminocyclohexyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N2-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidine-2,4-diamine

2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-methyl-1H-pyrazol-4-yl)-2-(2-(2,2,2) -trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide (29 mg, 0.047 mmol) Then, in the same manner as in Example 28, the target compound was obtained (21 mg, 95%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.79 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.37 (d, J) = 2.2 Hz, 1H), 7.30 (dd, J = 8.2, 2.3 Hz, 1H), 7.03 (d, J = 3.1 Hz, 1H), 7.00 (d, J = 5.3 Hz, 1H), 6.35 (d, J) = 7.6 Hz, 1H), 5.01 (d, J = 6.9 Hz, 1H), 4.19 (s, 1H), 4.01 (s, 2H), 3.98 (d, J = 2.2 Hz, 3H), 3.14 (t, J) = 5.9 Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 1.87 (q, J = 13.0, 9.3 Hz, 3H), 1.78-1.59 (m, 6H), 1.38 (d, J = 5.8 Hz) , 1H).

< Example 89> 2-(4-(2-(3,5- dichlorophenylamino )-4-(1,2,3,4- tetrahydro Preparation of isoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

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 (25 mg, 0.042 mmol) was carried out in the same manner as in Example 28, except that the purpose The compound was obtained (21 mg, 98%).

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).

< Example 90 > N-(( 1s, 4s )-4-(2-(3- Chlorophenylamino Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3-chloroaniline (20 μL, 0.18 mmol) was used to obtain the target compound (32 mg, 53%).

₁ H NMR (300 MHz, Chloroform-d) δ 8.10 (d, J = 2.4 Hz, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.23 (s, 1H) ), 7.20 (d, J = 4.0 Hz, 1H), 7.18 (s, 1H), 6.96 (dt, J = 6.8, 2.2 Hz, 1H), 6.29 (s, 1H), 5.06 (d, J = 7.0 Hz) , 1H), 4.29-4.15 (m, 1H), 4.04 (s, 1H), 4.00 (s, 3H), 1.94 (tt, J = 13.0, 3.9 Hz, 5H), 1.70 (d, J = 14.9 Hz, 4H).

< Example 91> N-(( 1s, 4s )-4-(2-(3- Acetylphenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3-acetylaniline (25 mg, 0.18 mmol) was used to obtain the target compound (58 mg, 93%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.40 (t, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.4 Hz, 1H), 7.50 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.38 (s, 1H), 5.10 (d, J = 7.1 Hz, 1H), 4.32 (s, 1H), 4.03 (s, 1H), 3.99 (s, 4H), 2.61 (s, 3H), 1.93 (q, J = 4.1 Hz, 4H) ), 1.77 - 1.55 (m, 5H).

< Example 92> N-(( 1s, 4s )-4-(2-(m- toluidino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3-methylaniline (20 mg, 0.18 mmol) was used, to obtain the target compound (51 mg, 88%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.57 (s, 1H), 7.46 (d, J = 4.6 Hz, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.30 (s, 1H), 5.02 (d, J = 6.9 Hz, 1H), 4.21 (s, 1H), 3.99 (s, 3H), 2.36 (s, 3H), 1.90 (td, J = 18.2, 15.7, 6.8 Hz, 5H), 1.70 (d, J = 9.1 Hz, 4H).

< Example 93> 1-(7-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)-3 Preparation of ,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Step 5 of Example 27 was followed except that 3-methylaniline (15 mg, 0.14 mmol) was used to obtain the target compound (35 mg, 70%).

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).

< Example 94> 2,2,2-trifluoro-1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl ) Preparation of pyrimidin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone

Except for using 3-fluoroaniline (12 mg, 0.12 mmol), the method of step 5 of Example 27 was followed to obtain the target compound (32 mg, 72%).

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).

< Example 95> N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine Preparation of -4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3,5-dichloroaniline (25 mg, 0.14 mmol) was used to obtain the target compound (33 mg, 61%).

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

< Example 96> 2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-( Preparation of 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide

Except using (7-amino-3,4-dihydroisoquinolin-2(1H)-yl)((difluor μL3-methyl) μL2-floranyl)methanone (21 mg, 0.087 mmol) , was carried out according to the method of step 5 of Example 14 to obtain the target compound. (48 mg, 77%)

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, 1H), 7.09 (t, J = 7.3 Hz, 1H), 6.92 (s, 1H), 5.34-5.22 (m, 1H), 4.74 (d, J = 11.8 Hz, 2H), 4.41-4.29 (m, 2H), 4.24 (s, 1H), 4.05 (d, J = 5.5 Hz, 2H), 3.94 (s, 1H), 3.86 (dt, J = 11.3, 6.1 Hz, 2H), 2.92 (t, J = 5.9 Hz, 2H), 1.80 (s, 6H), 1.61 (d, J = 10.6 Hz, 2H).

< Example 97> N4-(( 1s, 4s )-4- aminocyclohexyl )-N2-(3- chlorophenyl )-5-(1- mail Preparation of tyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (20 mg, 0.041 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (17 mg, 98%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.09 (d, J = 2.5 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.19 (d, J) = 6.4 Hz, 2H), 7.11 (s, 1H), 6.94 (dt, J = 6.2, 2.1 Hz, 1H), 5.14 (d, J = 7.3 Hz, 1H), 4.19 (s, 1H), 3.98 (s) , 3H), 3.02 (s, 1H), 1.80 (t, J = 4.3 Hz, 6H), 1.40 (d, J = 10.3 Hz, 4H).

< Example 98> 1-(3-(4-(( 1s, 4s )-4- aminocyclohexylamino )-5-(1- methyl Preparation of -1H-pyrazol-4-yl)pyrimidin-2-ylamino)phenyl)ethanone

N-((1s,4s)-4-(2-(m-toluidino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)- In the same manner as in Example 28, except that 2,2,2-trifluoroacetamide (52 mg, 0.10 mmol) was used, the target compound was obtained (37 mg, 88%).

¹ H NMR (300 MHz, Chloroform-d) δ 8.33 (t, J = 1.9 Hz, 1H), 7.84 (d, J = 3.1 Hz, 1H), 7.82-7.78 (m, 1H), 7.57 (d, J = 3.0 Hz, 1H), 7.54 (t, J = 1.3 Hz, 1H), 7.46 (s, 2H), 7.38 (t, J = 7.9 Hz, 1H), 5.18 (d, J = 7.4 Hz, 1H), 4.24 (d, J = 14.1 Hz, 1H), 3.99 (s, 3H), 2.98 (d, J = 7.6 Hz, 1H), 2.61 (s, 3H), 1.80 (dt, J = 8.1, 4.6 Hz, 5H) ), 1.73 (d, J = 5.3 Hz, 2H), 1.54 (s, 3H), 1.35 (t, J = 6.9 Hz, 2H).

< Example 99> N4-(( 1s, 4s )-4- aminocyclohexyl )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)-N2-m-tolylpyrimidine-2,4-diamine

N-((1s,4s)-4-(2-(m-toluidino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)- In the same manner as in Example 28, except that 2,2,2-trifluoroacetamide (39 mg, 0.082 mmol) was used, the target compound was obtained (27 mg, 85%).

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

< Example 100> N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 Preparation of -ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3-chloroaniline (15 μL, 0.15 mmol) was used to obtain the target compound (41 mg, 82%).

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

< Example 101> 2-(4-(2-(3- Chlorophenylamino )-4-(1,2,3,4- tetrahydroiso Preparation of quinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl Amino) cyclohexyl) -2,2,2-trifluoroacetamide (29 mg, 0.043 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (17 mg, 85%). ).

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).

< Example 102> 2-(4-(2-(3- Fluorophenylamino )-4-(1,2,3,4- tetrahydro Preparation of soquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

2,2,2-trifluoro-1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri The target compound was carried out in the same manner as in Example 28, except that midin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (21 mg, 0.038 mmol) was used. was obtained (16 mg, 94%).

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).

< Example 103> 2-(4-(4-(( 1s, 4s )-4- aminocyclohexylamino )-2-(3,5- diqlo Preparation of rophenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (21 mg, 0.041 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (10 mg, 52%).

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), 7.31 (s, 1H), 6.94 (t, J = 1.8 Hz, 1H), 5.34 - 5.28 (m, 1H), 4.37 - 4.32 (m, 2H), 4.31 (s, 1H), 4.00 - 3.92 (m, 2H), 2.95 (d, J = 9.6 Hz, 1H), 1.88-1.76 (m, 2H), 1.75-1.62 (m, 4H), 1.26 (s, 2H).

< Example 104> 2-(4-(4-(( 1s, 4s )-4- aminocyclohexylamino )-2-(1,2,3,4- frame Preparation of trihydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide (35 mg, 0.054 mmol ) was carried out in the same manner as in Example 28, except that the target compound was obtained (23 mg, 91%).

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), 7.01 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 5.23 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 4.6 Hz, 3H), 4.00 (s, 2H), 3.98 - 3.91 (m, 2H), 3.13 (t, J = 5.9 Hz, 2H), 2.99-2.88 (m, 1H), 2.74 (t, J = 6.0 Hz, 2H), 1.80 (d, J = 11.4 Hz) , 3H), 1.63 (t, J = 13.2 Hz, 4H), 1.26 (t, J = 11.6 Hz, 3H).

< Example 105> 2-(4-(4-(( 1s, 4s )-4- aminocyclohexylamino )-2-(3- Chlorophe Preparation of nylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl Amino) cyclohexyl) -2,2,2-trifluoroacetamide (30 mg, 0.057 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (21 mg, 57%). ).

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 (d, J = 8.2 Hz, 1H), 4.34 (dd , J = 5.3, 3.9 Hz, 2H), 3.96 (dd, J = 5.3, 3.9 Hz, 2H), 2.96 (dt, J = 9.6, 5.4 Hz, 1H), 2.77 - 2.50 (m, 2H), 1.89 - 1.75 (m, 2H), 1.74 - 1.60 (m, 4H), 1.26 (dd, J = 9.0, 4.6 Hz, 3H).

< Example 106> 2-(4-(4-(( 1s, 4s )-4- aminocyclohexylamino )-2-(4- Chloro Preparation of -3-methylphenylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

Except for using 3-methyl-4-chloroaniline (20 mg, 0.145 mmol), the method of step 5 of Example 27 was followed to obtain the target compound (28 mg, 54%).

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 (d, J = 7.2 Hz, 1H), 4.38 - 4.30 (m, 2H), 4.23 (d, J = 6.6 Hz, 1H), 4.12-4.03 (m, 2H), 3.96 (s, 1H), 2.36 (s, 3H), 1.91-1.79 (m, 4H), 1.76 (d, J = 6.8 Hz, 2H), 1.62 (s, 2H).

< Example 107> N-((1s,4s)-4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri Preparation of midin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(4-chloro-3-methylphenylamino)pyrimidin-5-yl)-1H-pyrazole-1- Day) The target compound was obtained in the same manner as in Example 28 except that ethanol (18 mg, 33 mmol) was used (14 mg, 98%).

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, 2.7 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 5.26 (d, J = 8.3 Hz, 1H), 4.34 (dd, J) = 5.3, 3.9 Hz, 2H), 4.31 (s, 1H), 4.00-3.90 (m, 2H), 2.94 (dt, J = 10.0, 5.7 Hz, 1H), 2.36 (s, 3H), 1.89-1.76 ( m, 3H), 1.64 (t, J = 13.4 Hz, 5H), 1.24 (d, J = 10.9 Hz, 3H).

< Example 108> N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidine- Preparation of 4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Except for using 3,5-dichloroaniline (50 mg, 0.088 mmol), the method of step 5 of Example 27 was followed to obtain the target compound (32 mg, 58%).

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 (m, 2H), 4.22 (s) , 1H), 3.99 (s, 1H), 3.37 (t, J = 13.1 Hz, 1H), 3.07 (t, J = 12.5 Hz, 1H), 2.34 (d, J = 13.0 Hz, 2H), 2.22-2.08 (m, 2H), 2.03-1.86 (m, 5H), 1.82 (s, 2H), 1.67 (s, 2H).

< Example 109> N-(( 1r, 4r )-4-(2-(3,5- dichlorophenylamino )-5-(1- methyl -1H- pyrazole Preparation of -4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Except that 3,5-dichloroaniline (25 mg, 0.015 mmol) was used, the method of step 5 of Example 27 was followed to obtain the target compound (25 mg, 49%).

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

< Example 110> N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine Preparation of -4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide

Except that 3,5-dichloroaniline (19 mg, 0.012 mmol) was used, the method of step 5 of Example 27 was followed to obtain the target compound (32 mg, 76%).

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), 7.18 (s, 1H), 6.98 (t, J = 1.8 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.35 - 4.28 (m, 2H) ), 4.07 (d, J = 4.7 Hz, 2H), 4.05 - 3.94 (m, 1H), 3.83 (s, 1H), 2.24 (d, J = 12.8 Hz, 2H), 2.13 (d, J = 12.6 Hz) , 2H), 1.78 - 1.61 (m, 1H), 1.52 (q, J = 12.4 Hz, 3H), 1.36 (d, J = 12.4 Hz, 2H).

< Example 111>N4-(( 1s, 4s )-4- aminocyclohexyl )-N2-(3,5- dichlorophenyl Preparation of )-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidine-4- yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (22 mg, 0.032 mmol) In the same manner as in Example 28, the target compound was obtained (11 mg, 65%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.66 (d, J = 1.8 Hz, 2H), 7.59 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H) ), 6.94 (t, J = 1.8 Hz, 1H), 5.19 (d, J = 7.3 Hz, 1H), 4.28 (tt, J = 11.8, 4.1 Hz, 1H), 4.17 (s, 1H), 3.27 (d) , J = 12.5 Hz, 2H), 3.03 (s, 1H), 2.86 - 2.74 (m, 2H), 2.22 (d, J = 12.3 Hz, 2H), 1.94 (qd, J = 12.1, 4.2 Hz, 3H) , 1.80 (d, J = 3.6 Hz, 6H), 1.44 (d, J = 16.6 Hz, 5H).

< Example 112> N4-(( 1r, 4r )-4- aminocyclohexyl )-N2-(3,5- dichlorophenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl ) )-2,2,2-trifluoroacetamide (14 mg, 0.026 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (7 mg, 63%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.64 (d, J = 1.8 Hz, 2H), 7.54 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H) ), 6.96 (t, J = 1.8 Hz, 1H), 4.91 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H), 3.94 (dd, J = 7.5, 3.8 Hz, 1H), 2.67 (td) , J = 10.9, 5.4 Hz, 1H), 2.15 (d, J = 12.2 Hz, 2H), 1.93 (d, J = 12.8 Hz, 2H), 1.47 (d, J = 12.0 Hz, 3H), 1.42-1.29 (m, 3H).

< Example 113> 2-(4-(4-(( 1r, 4r )-4- aminocyclohexylamino )-2-(3,5- dichlorophenylamino ) Preparation of pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine-4 -ylamino)cyclohexyl)-2,2,2-trifluoroacetamide (22 mg, 0.039 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (16 mg, 88%).

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

< Example 114> N-((1r,4r)-4-((2-((3,5-difluorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4 Preparation of -yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3,5-difluoroaniline (20 μL, 0.14 mmol) was used to obtain the target compound (38 mg, 77%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.52 (d, J = 0.9 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.27-7.23 (m, 2H), 6.45-6.34 (m, 1H), 4.90 (d, J = 7.5 Hz, 1H), 3.96 (s, 3H), 3.91 (dd, J = 7.4, 3.6 Hz, 1H) , 2.72-2.60 (m, 1H), 2.14 (d, J = 11.9 Hz, 2H), 2.00-1.87 (m, 2H), 1.46-1.13 (m, 6H).

< Example 115> N-((1r,4r)-4-((2-((3,5-difluorophenylamino)amino)-5-(1-(2-hydroxyethyl)-1H-pyrazole-4 Preparation of -yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 3,5-difluoroaniline (15 μL, 0.12 mmol) was used to obtain the target compound (28 mg, 70%).

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), 7.30-7.23 (m, 2H), 6.45-6.35 (m, 1H), 4.91 (d, J = 7.5 Hz, 1H), 3.95 (s, 3H), 3.92 (dd, J = 7.4, 3.6 Hz, 1H) , 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).

< Example 116> N4-(( 1r, 4r )-4- aminocyclohexyl )-N2-(3,5- difluorophenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1r,4r)-4-((2-((3,5-difluorophenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl )Amino)cyclohexyl)-2,2,2-trifluoroacetamide (25 mg, 0.05 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (20 mg, 99). %).

¹ H NMR (300 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.54 (d, J = 0.9 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.29 - 7.25 (m, 2H), 6.47 - 6.36 (m, 1H), 4.92 (d, J = 7.5 Hz, 1H), 3.98 (s, 3H), 3.93 (dd, J = 7.4, 3.6 Hz, 1H) , 2.74 - 2.62 (m, 1H), 2.16 (d, J = 11.9 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.48 - 1.13 (m, 6H).

< Example 117> 2-(4-(4-((( 1r, 4r )-4- aminocyclohexyl )amino)-2-((3,5- difluorophenyl Preparation of )amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethan-1-ol

N-((1r,4r)-4-((2-((3,5-difluorophenylamino)amino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl ) pyrimidin-4-yl) amino) cyclohexyl) -2,2,2-trifluoroacetamide (18 mg, 0.034 mmol) was carried out in the same manner as in Example 28, except that the target compound was prepared was obtained (11 mg, 78%).

¹ H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 1.0 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.31 ( d, J = 2.2 Hz, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 6.46 - 6.36 (m, 1H), 4.91 (d, J = 7.4 Hz, 1H), 4.32 (t, J) = 4.7 Hz, 2H), 4.07 (dd, J = 5.4, 4.0 Hz, 2H), 4.00 - 3.87 (m, 1H), 2.71 - 2.60 (m, 1H), 2.16 (d, J = 12.2 Hz, 2H) , 1.94 (d, J = 12.5 Hz, 3H), 1.40 - 1.13 (m, 6H).

< Example 118> 2-(4-(4-(( 1r, 4r )-4- aminocyclohexylamino )-2-(3,5- dichlorophenylamino ) Preparation of pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol

Step 5 of Example 27 was followed except that 4-bistrifluoromethylaniline (23 μL, 0.14 mmol) was used to obtain the target compound (28 mg, 50%).

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

< Example 119>N-((1r,4r)-4-((2-((3,5-bis(trifluoromethyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl) Preparation of pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide

Step 5 of Example 27 was followed except that 4-bistrifluoromethylaniline (18 μL, 0.11 mmol) was used to obtain the target compound (28 mg, 70%).

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 ( d, J = 6.0 Hz), 4.06 (m, 1H), 4.32 (m, 2H), 4.06 (m, 2H), 4.01 (m, 1H), 2.61 (m, 1H), 2.14 (m, 2H), 1.96 (m, 2H), 1.43 (m, 3H).

< Example 120> N4-(( 1r, 4r )-4- aminocyclohexyl )-N2-(3,5- Bis(trifluoromethyl)phenyl Preparation of )-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

N-((1r,4r)-4-((2-((3,5-bis(trifluoromethyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine -4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide (18 mg, 0.03 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (15 mg, 99%).

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

< Example 121> 2-(4-(4-((( 1r, 4r )-4- aminocyclohexyl )amino)-2-((3,5- bis Preparation of (trifluoromethyl)phenyl)amino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethan-1-ol

N-((1r,4r)-4-((2-((3,5-bis(trifluoromethyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine -4-yl) amino) cyclohexyl) -2,2,2-trifluoroacetamide (19 mg, 0.03 mmol) was carried out in the same manner as in Example 28, except that the target compound was obtained (16 mg, 98%).

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 ( d, J = 6.0 Hz), 4.09 (m, 1H), 4.34 (m, 2H), 4.08 (m, 2H), 4.02 (m, 1H), 2.62 (m, 1H), 2.15 (m, 2H), 1.98 (m, 2H), 1.42 (m, 3H).

The structural formulas of the compounds prepared in Examples 1-121 are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

62

2

63

3

64

4

65

5

66

6

67

7

68

8

69

9

70

10

71

11

72

12

73

13

74

14

75

15

76

16

77

17

78

18

79

19

80

20

81

21

82

22

83

23

84

24

85

25

86

26

87

27

88

28

89

29

90

30

91

31

92

32

93

33

94

34

95

35

96

36

97

37

98

38

99

39

100

40

101

41

102

42

103

43

104

44

105

45

106

46

107

47

108

48

109

49

110

50

111

51

112

52

113

53

114

54

115

55

116

56

117

57

118

58

119

59

120

60

121

61

< Experimental example 1> TYRO 3, AXL , and on MERTK Inhibitory activity evaluation and selectivity evaluation for

TYRO 3 (Tyrosine-protein kinase receptor), AXL (Tyrosine-protein kinase receptor UFO) of the compound according to the present invention. In order to evaluate the inhibitory activity and selectivity for MERTK (Proto-oncogene tyrosine-protein kinase MER), the following experiment was performed.

Specifically, the experimental method was performed according to the method provided by Cisbio. After starting the reaction by adding ATP to a mixture in which Tryo3 or MERTK, or AXL and the substrate peptide, and the compounds of the Examples are present, and after 1 hour, the reaction is stopped by adding a solution containing EDTA, the phosphorylated peptide is europium Samples were obtained using an antibody recognizing a phosphorylated peptide with (Eu) attached thereto. After 1 hour, it was excited with 320 nm or 340 nm light using an Envision Reader, and 665 nm emission light was measured, and the results are shown in the table below. Meanwhile, IC50 was converted using a grippad prism, and the LDC1267 compound was used as a comparative example. When confirming the Tyro3 inhibitory ability of the compounds, first check the inhibition rate of the compound at concentrations of 1uM and 0.2uM, and for the compounds showing inhibition of 90% or more at 0.2uM concentration, various concentration ranges diluted 10 times or more by 1/3 at 1uM IC ₅₀ values were obtained as shown in Table 2 below by testing the inhibition rate in

Example TYRO 3
IC ₅₀
(μM) AXL
IC ₅₀
(μM) MER
IC ₅₀
(μM) Example TYRO 3
IC ₅₀
(μM) AXL
IC ₅₀
(μM) MER
IC ₅₀
(μM) One 0 >10 >10 62 0.0297 2 0 >10 >10 63 0.7783 3 0.427 >10 64 27 4 0 65 2.275 5 0.657 71.46 >2 66 0.3705 6 1.461 67 0.8449 7 0.394 20.8 68 10 8 0.616 69 0.5511 9 0 70 1.731 10 0 71 0.003501 11 0 72 10 12 0 73 0.001806 4.538 0.03151 13 0 74 0.02967 14 >10 75 0.00000006 3.575 0.02975 15 0.628 76 0.04511 16 1.03 77 0.2449 17 1.16 78 0.137 18 1.37 79 10 19 4.59 80 0.05897 20 9.71 81 0.3497 21 >10 82 0.0245 0.06633 0.0124 22 2.23 83 0.1202 23 0.606 84 0.000041 0.06669 0.01178 24 0.573 85 0.002341 25 0.156 86 0.4931 26 0.018 2.382 >2 87 0.01581 0.2148 0.0155 27 0.015 7.946 >4 88 0.8752 28 0.0008991 0.7368 0.043 89 0.000041 0.2072 0.01581 29 0.0001 14.21 0.21 90 0.002518 30 0.00892 38584 >0.2 91 0.003443 31 0.37 92 0.00287 32 0.38 93 0.02833 33 0.002757 7.009 0.2734 94 0.01629 34 0.255 18.58 0.3952 95 0.006547 35 0.284 96 2.517 36 0.298 97 0.0004073 37 0.301 98 0.1157 38 0.421 99 0.006957 0.04523 0.001308 39 0.287 100 0.0008984 0.03243 0.0009116 40 0.354 101 0.00001249 0.7311 0.02592 41 0.278 102 0.0004211 0.03247 0.000355 42 0.454 103 0.0001938 0.6994 0.02528 43 1.787 104 0.184 44 0.574 105 0.002376 45 0.498 106 0.4886 46 0.277 107 0.01338 47 3.544 108 0.008657 48 0.398 109 0.002845 0.04502 0.04457 49 4.512 110 0.0002784 0.917 0.02771 50 5.352 111 0.0004846 0.3784 0.04458 51 1.232 112 0.0001145 0.917 0.02771 52 0.357 113 0.00037 0.2251 0.006883 53 0.288 114 0.028 54 0.323 115 0.052 55 0.251 116 0.0015 0.35 0.009 56 0.275 117 0.0016 0.52 0.001 57 0.0357 118 0.43 58 0.02288 119 0.38 59 0.1061 120 0.021 0.48 0.02 60 0.01329 121 0.003 0.37 0.01 61 0.1673

As can be seen in Table 2, it can be confirmed that the novel compound according to the present invention can selectively inhibit TYRO 3 compared to AXL and MERTK, and also excellently inhibit TYRO 3 at a concentration of nanomolar or less.

Therefore, the novel TYRO 3 inhibitory compound according to the present invention excellently inhibits TYRO 3 at a concentration of nanomolar or less, and shows TYRO 3 selective inhibitory activity compared to AXL and MERTK, TYRO 3 related diseases, preferably prevention of cancer Or it may be usefully used as a therapeutic pharmaceutical composition and a health functional food composition.

Claims (10)

A compound represented by the following formula (1), a stereoisomer or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is substituted pyrazol-4-yl,
wherein the substituted pyrazol-4-yl is substituted with hydroxy C _1-4 alkyl or a substituted or unsubstituted piperidinyl substituent,
again wherein said substituted piperidinyl is substituted with one or more substituents selected from the group consisting of halogen, oxo (=O), hydroxy and trifluoroacetyl;
R ² is a substituted or unsubstituted C _3-10 cycloalkyl, a substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S, or ,
Or C _6-10 aryl and C _3-10 cycloalkyl or 5 to 10-membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of N, O, and S is fused (fused) , a substituted or unsubstituted fused ring,
wherein the substituted cycloalkyl, substituted heterocycloalkyl or substituted fused ring is substituted or unsubstituted amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted C _1-10 straight chain or branched substituted with one or more substituents selected from the group consisting of chain alkyl, substituted or unsubstituted C _1-10 straight-chain or branched alkoxy, or substituted or unsubstituted C _6-10 arylC _1-10 alkyl; ,
Again, wherein said substituted amino, substituted alkyl, substituted alkoxy, substituted C _6-10 arylC _1-10 alkyl is a substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) is substituted with one or more substituents selected from the group consisting of,
Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O); and
R ³ and R ⁴ are each independently —H, halogen, substituted or unsubstituted C _3-10 cycloalkyl, N, O, and a substitution containing one or more heteroatoms selected from the group consisting of S Or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of unsubstituted 5 to 10-membered heterocycloalkyl, substituted or unsubstituted C _6-10 aryl, N, O, and S 5- to 10-membered ring heteroaryl, substituted or unsubstituted C _6-10 aryl C _1-10 alkyl, or substituted or unsubstituted containing one or more heteroatoms selected from the group consisting of N, O, and S A 5- to 10-membered ring heteroaryl C _1-10 alkyl, or C _6-10 aryl and C _3-10 cycloalkyl or N, O, and S It contains one or more heteroatoms selected from the group consisting of When the 5- to 10-membered heterocycloalkyl is a fused, substituted or unsubstituted fused ring,
wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or substituted fused ring is amino, halogen, hydroxy, cyano , nitro, oxo (=O), substituted or unsubstituted C _1-10 straight or branched chain alkyl, substituted or unsubstituted C _1-10 straight or branched chain alkoxy, or substituted or unsubstituted C substituted with one or more substituents selected from the group consisting of _6-10 aryl,
Here again, substituted alkyl, substituted alkoxy, substituted C _6-10 aryl is selected from the group consisting of substituted or unsubstituted C _1-5 straight or branched chain alkyl, halogen, and oxo (=O) substituted with one or more substituents,
Again here, the substituted C _1-5 straight or branched chain alkyl is substituted with one or more substituents selected from the group consisting of halogen, and oxo (=O),
Or, when R ³ and R ⁴ together form a 5- to 10-membered substituted or unsubstituted heterocycloalkyl with the nitrogen atom to which they are connected,
The heterocycloalkyl may be a heterocycloalkyl further comprising at least one hetero atom selected from the group consisting of N, O, and S in addition to the nitrogen atom to which R ³ and R ⁴ are connected,
Here, the substituted heterocycloalkyl is amino, halogen, hydroxy, cyano, nitro, substituted or unsubstituted C _{6-10 arylC 1-10} alkyl, or from the group consisting of N, O, and S Substituted with one or more substituents selected from the group consisting of substituted or unsubstituted 5- to 10-membered heteroaryl C _1-10 alkyl containing one or more selected hetero atoms,
Here again, the substituted C _{6-10 arylC 1-10} alkyl, or a substituted 5- to 10-membered heteroaryl C _1-10 alkyl is one selected from the group consisting of halogen and oxo (=O) substituted with more than one substituent). According to claim 1,
R ¹ is

,

or

A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that According to claim 1,
R ² is

,

,

,

,

,

,

,

,

,

,

or

A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that
According to claim 1,
R ³ and R ⁴ are each independently -H, -Cl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

,

,

,

,

or

this,
or R ³ and R ⁴ together with the nitrogen atom to which they are connected

A compound, characterized in that it forms a stereoisomer or a pharmaceutically acceptable salt thereof. According to claim 1,
The compound represented by Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, is any one selected from the following compound groups, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(71) 1-(4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino )piperidin-1-yl)-2,2,2-trifluoroethanone;
(73) N2- (3,5-dichlorophenyl) -N4- (piperidin-4-yl) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine-2,4-diamine;
(75) 2-(4-(2-(3,5-dichlorophenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl) ethanol;
(76) 2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(2-(2, 2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone;
(77) 1-(4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl amino)piperidin-1-yl)-2,2,2-trifluoroethanone;
(78) 2,2,2-trifluoro-1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-(4-methoxyphenyl) amino)pyrimidin-4-ylamino)piperidin-1-yl)ethanone;
(79) 2-(4-(4-(piperidin-4-ylamino)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl) -1H-pyrazol-1-yl)ethanol;
(80) 2-(4-(2-(4-chloro-3-methylphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl )ethanol;
(81) 2-(4-(2-(4-methoxyphenylamino)-4-(piperidin-4-ylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanol ;
(87) 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;
(89) 2-(4-(2-(3,5-dichlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethanol;
(93) 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;
(94) 2,2,2-trifluoro-1-(7-(2-(3-fluorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazole-4- yl)pyrimidin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;
(95) N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri midin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;
(96) 2,2,2-trifluoro-N-((1s,4s)-4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2- (2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4-ylamino)cyclohexyl)acetamide;
(100) N-((1s,4s)-4-(2-(3-chlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidine- 4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;
(101) 2-(4-(2-(3-chlorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H- pyrazol-1-yl)ethanol;
(102) 2-(4-(2-(3-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-5-yl)-1H -pyrazol-1-yl)ethanol;
(103) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazole- 1-day) ethanol;
(104) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin- 5-yl)-1H-pyrazol-1-yl)ethanol;
(105) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(3-chlorophenylamino)pyrimidin-5-yl)-1H-pyrazole-1- 1) ethanol;
(106) 2-(4-(4-((1s,4s)-4-aminocyclohexylamino)-2-(4-chloro-3-methylphenylamino)pyrimidin-5-yl)-1H-pyrazole -1-yl)ethanol;
(107) N-((1s,4s)-4-(2-(4-chloro-3-methylphenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl) pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;
(108) N-((1s,4s)-4-(2-(3,5-dichlorophenylamino)-5-(1-(1-(2,2,2-trifluoroacetyl)piperidine) -4-yl)-1H-pyrazol-4-yl)pyrimidin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;
(110) N-((1r,4r)-4-(2-(3,5-dichlorophenylamino)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyri midin-4-ylamino)cyclohexyl)-2,2,2-trifluoroacetamide;
(111) N4-((1s,4s)-4-aminocyclohexyl)-N2-(3,5-dichlorophenyl)-5-(1-(piperidin-4-yl)-1H-pyrazole- 4-yl)pyrimidine-2,4-diamine;
(113) 2-(4-(4-((1r,4r)-4-aminocyclohexylamino)-2-(3,5-dichlorophenylamino)pyrimidin-5-yl)-1H-pyrazole- 1-day) ethanol;
(115) N-((1r,4r)-4-((2-((3,5-difluorophenylamino)amino)-5-(1-(2-hydroxyethyl)-1H-pyrazole- 4-yl)pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide;
(117) 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-2-((3,5-difluorophenyl)amino)pyrimidin-5-yl)- 1H-pyrazol-1-yl)ethan-1-ol;
(119) N-((1r,4r)-4-((2-((3,5-bis(trifluoromethyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-4-yl )pyrimidin-4-yl)amino)cyclohexyl)-2,2,2-trifluoroacetamide; and
(121) 2-(4-(4-(((1r,4r)-4-aminocyclohexyl)amino)-2-((3,5-bis(trifluoromethyl)phenyl)amino)pyrimidine-5 -yl)-1H-pyrazol-1-yl)ethan-1-ol.
As shown in Scheme 1 below,
reacting the compound represented by Formula 2 with NH ₂ R ² to prepare a compound represented by Formula 3 (step 1);
preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and
A method for preparing a compound represented by Formula 1 of claim 1, comprising a step of preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3):
[Scheme 1]

(In Scheme 1,
R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1 of claim 1 ;
X ¹ , X ² and X ³ are halogen).
A pharmaceutical composition for the prevention or treatment of TYRO 3 (Tyrosine-protein kinase receptor)-related diseases containing the compound represented by Formula 1 of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and TYRO 3 A pharmaceutical composition, characterized in that the related disease is cancer. delete 8. The method of claim 7,
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 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, A pharmaceutical composition, characterized in that at least one selected from the group consisting of rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer.
A health functional food composition for the prevention or improvement of TYRO 3 (Tyrosine-protein kinase receptor) related diseases containing the compound represented by Formula 1 of claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient, and TYRO 3 The related disease is characterized in that the cancer A health functional food composition.