KR20200016567A - A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient - Google Patents

Abstract

The present invention relates to a substituted N-heteroaryl derivative, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active component. The derivative has excellent inhibitory activity on various protein kinases including WEE1, so the pharmaceutical composition containing the same as the active component can be usefully used for treating or preventing kinase-related diseases, especially cancer, and has an excellent cancer cell proliferation effect on liver cancer, lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia and ovarian cancer, thereby being able to be usefully used for treating especially, liver cancer, lung cancer, epithelial cell cancer, colon cancer, breast cancer, leukemia or ovarian cancer.

Description

Substituted N-heteroaryl derivatives, preparation methods thereof, and pharmaceutical compositions for the prevention or treatment of cancer comprising the same as active ingredients {A substituted heteroaryl derivatives, preparation method, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient}

Substituted N-heteroaryl derivatives, methods for their preparation and pharmaceutical compositions for the prevention or treatment of cancer comprising the same as an active ingredient.

Human hepatocellular carcinoma (HCC) is a disease caused by long term liver inflammation. Although surgical and percutaneous radiofrequency ablation improves patient survival, new methods of obtaining effective treatment for advanced human hepatocellular carcinoma (HCC) are needed. Treatment alternatives are needed. Thus, induction of apoptosis by chemotherapy and transport of low molecular weight substances is an emerging alternative.

Transforming growth factor beta-1 (TGF-β1) strongly inhibits human hepatocellular carcinoma (HCC) cell growth. In particular, it promotes cell growth in non-epithelial cells, such as fibroblasts and stellate cells, while in rodents and by cell death or cell cycle arrest. It inhibits cell growth in both human hepatocellular carcinoma (HCC) cells.

Induction of apoptosis by TGF-β1 in human hepatocellular carcinoma (HCC) cells is mediated by dephosphorylation of cdc2 Tyr15 (the active form of cdc2), ie reduction in cdc2 phosphorylation. The cdc2 activity is induced by Wee1 kinase downregulation, and cdc2 activity by decreasing Tyr15 phosphorylation is very important for TGF-β1-induced apoptosis in human hepatocellular carcinoma (HCC) cells. A decrease in Wee1 kinase expression is observed after TGF-β1 treatment, and cdc2 phosphorylation is regulated by Wee1 kinase. From this, it can be said that TGF-β1 mediated apoptosis is induced in the Wee1 / cdc2 axis.

In surgically excised samples, Wee1 kinase is overexpressed in human hepatocellular carcinoma (HCC), but kinase expression is not observed in non-cancerous tissues including cirrhotic tissue. Overexpression of Wee1 kinase has been reported in other tumor types, including brain tumors and leukemia (Non-Patent Document 1). In brain tumors, Wee1 kinase expression is upregulated only in tumor cells, and elevated kinases play an important role in cancer cell survival.

Wee1 kinase is a negative regulator of cdc2. Since TGF-β1 is a multifunctional cytokine, it is not a practical therapeutic alternative. Wee1 kinase negatively regulates the G2 / M phase by inhibiting the early stages of mitosis before DNA damage is repaired, thereby preventing premature mitotic entry and subsequent cell death. It is considered. Certain inhibitors or siRNAs can be used to inhibit Wee1 kinase to induce apoptosis in human hepatocellular carcinoma (HCC) cells. Thus, Wee1 kinase inhibitors may be new therapeutic strategies and alternatives emerging in Wee1 kinase-overexpressing carcinomas such as human hepatocellular carcinoma (HCC), and these types of inhibitors may present a realistic therapeutic alternative to advanced solid cancers. Can be.

Harris PS et al., (2014) Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma. Mol Cancer 13: 72

One object of the present invention is to provide a substituted N-heteroaryl derivative.

Another object of the present invention is to provide a method for preparing the substituted N-heteroaryl derivative.

Another object of the present invention to provide a pharmaceutical composition for the prophylaxis or treatment of protein kinase-related diseases.

In order to achieve the above object,

According to one aspect of the invention,

There is provided a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In the above formula 1,

A is CH or N;

L is NH or absent;

R ¹ and R ² are independently unsubstituted or substituted of 3 to 8 atoms comprising one or more heteroatoms selected from the group consisting of hydrogen, halogen, straight or branched C _1-6 alkoxy or N, O and S Heterocycloalkyl, or R ¹ and R ² together with 3 to 8 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atom to which they are attached; Can form

Wherein the substituted heterocycloalkyl is selected from the group consisting of N, O and S and at least one substituted with straight or branched C _1-6 alkyl, unsubstituted or straight or branched C _1-6 alkyl One or more substituents selected from the group consisting of 3 to 8 membered heterocycloalkyl, which is one or more substituted with unsubstituted or straight or branched C _1-6 alkyl containing one or more heteroatoms;

R ³ is a group consisting of-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted C _6-10 aryl and N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one hetero atom selected from

In this case, the substituted aryl and heteroaryl are straight chain or branched C _1-6 alkyl substituted with one or more substituted with halogen, unsubstituted or halogen and straight chained or branched C _1- substituted with one or more substituted with halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₆ alkoxy,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-6 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-6 alkyl and straight or branched C _1-6 alkoxy,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen or straight or branched C _1-6 alkyl).

According to another aspect of the invention,

As shown in Scheme 1 below,

Reacting the compound represented by Formula 4 with the compound represented by Formula 5 (step 1); And

There is provided a process for preparing a compound represented by Formula 1 comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 (step 2):

Scheme 1

(In Scheme 1, A, L, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1;

X ¹ and X ² are each halogen; And

또는

다).L ¹ is

or

All).

According to another aspect of the invention,

Provided is a pharmaceutical composition for preventing or treating a protein kinase related disease containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the invention, there is provided a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Methods of preventing or treating a disease are provided.

According to another aspect of the present invention, there is provided a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a protein kinase related disease. do.

Since the compound represented by the formula (1), the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has excellent inhibitory activity against various protein kinases including WEE1, the pharmaceutical composition containing the same as an active ingredient is a protein It can be usefully used for the treatment or prevention of kinase-related diseases, especially cancer, and has an excellent effect on inhibiting cancer cell proliferation against liver cancer, lung cancer, epithelial cell cancer, colon cancer, breast cancer, leukemia and ovarian cancer, in particular, liver cancer, lung cancer, It can be usefully used for the treatment of epithelial cell cancer, colon cancer, breast cancer, leukemia or ovarian cancer.

Hereinafter, the present invention will be described in detail.

One aspect of the invention,

It provides a compound represented by the following formula (1), optical isomers thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

A is CH or N;

L is NH or absent;

R ¹ and R ² are independently unsubstituted or substituted of 3 to 8 atoms comprising one or more heteroatoms selected from the group consisting of hydrogen, halogen, straight or branched C _1-6 alkoxy or N, O and S Heterocycloalkyl, or R ¹ and R ² together with 3 to 8 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atom to which they are attached; Can form

Wherein the substituted heterocycloalkyl is selected from the group consisting of N, O and S and at least one substituted with straight or branched C _1-6 alkyl, unsubstituted or straight or branched C _1-6 alkyl One or more substituents selected from the group consisting of 3 to 8 membered heterocycloalkyl, which is one or more substituted with unsubstituted or straight or branched C _1-6 alkyl containing one or more heteroatoms;

R ³ is a group consisting of-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted C _6-10 aryl and N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from

In this case, the substituted aryl and heteroaryl are straight chain or branched C _1-6 alkyl substituted with one or more substituted with halogen, unsubstituted or halogen and straight chained or branched C _1- substituted with one or more substituted with halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₆ alkoxy,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-6 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-6 alkyl and straight or branched C _1-6 alkoxy,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen or straight or branched C _1-6 alkyl.

In addition, in Chemical Formula 1,

A is CH or N;

L is NH or absent;

R ¹ and R ² are independently unsubstituted or substituted of 5 to 7 atoms comprising one or more heteroatoms selected from the group consisting of hydrogen, halogen, straight or branched C _1-4 alkoxy or N, O and S Heterocycloalkyl, or R ¹ and R ² together with the carbon atom to which they are attached, an unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing one or more heteroatoms selected from the group consisting of N, O and S Can form

Wherein the substituted heterocycloalkyl is selected from the group consisting of N, O and S and at least one substituted with straight or branched C _1-4 alkyl, unsubstituted or straight or branched C _1-4 alkyl One or more substituents selected from the group consisting of 5 to 7 membered heterocycloalkyl substituted with one or more unsubstituted or straight or branched C _1-4 alkyl containing one or more heteroatoms;

R ³ is-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted C _6-10 aryl and N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one hetero atom selected from

In this case, the substituted aryl and heteroaryl are straight chain or branched C _1-4 alkyl substituted with one or more halogen, unsubstituted or halogen, and straight chain or branched C _1- substituted with one or more substituted or halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₄ alkoxy,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-4 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 9 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-4 alkyl and straight or branched C _1-4 alkoxy,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ may each be hydrogen or straight or branched C _1-4 alkyl.

In addition, in Chemical Formula 1,

A is CH or N;

L is NH or absent;

R ¹ and R ² are independently 6-membered unsubstituted or substituted heterocycloalkyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen, C _1-2 alkoxy or N, O and S, or R ¹ and R ² together with the carbon atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 6 or 7 atoms comprising one or more heteroatoms selected from the group consisting of N, O and S,

In this case, the substituted heterocycloalkyl is a hetero atom selected from the group consisting of N, O and S, and an amine substituted with at least one of straight or branched C _1-4 alkyl, unsubstituted or C _1-2 alkyl. One or more substituents selected from the group consisting of 6-membered heterocycloalkyl unsubstituted or substituted with one or more C _1-2 alkyl;

R ³ is-(C═O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted phenyl and hetero selected from the group consisting of N, O and S 6 to 9 membered unsubstituted or substituted heteroaryl containing one or more atoms,

In this case, the substituted phenyl and heteroaryl are linear, branched C _1-4 alkyl substituted with one or more substituted by halogen, unsubstituted or halogen, and linear or branched C _1- substituted with one or more substituted by unsubstituted or halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₄ alkoxy,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-4 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 9 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-4 alkyl and straight or branched C _1-2 alkoxy,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ may each be hydrogen or straight or branched C _1-2 alkyl.

In addition, in Chemical Formula 1,

A is CH or N;

L is NH or absent;

R ¹ and R ² are independently hydrogen, F, methoxy or unsubstituted or substituted piperidine, or piperazine, or R ¹ and R ² are unsubstituted or substituted piperidine together with the carbon atom to which they are attached Or azepanes,

In this case, the substituted piperidine, piperazine and azepan may be substituted with one or more substituents selected from the group consisting of methyl, -N (CH ₃ ) ₂ and piperazine unsubstituted or substituted with one or more methyl, respectively. There is;

R ³ is — (C═O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, Isoxoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolinyl or quinolinyl,

Wherein the substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolyl and quinolinyl are each F, methyl , May be substituted with one or more substituents selected from the group consisting of CF ₃ and methoxy,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or methyl;

R ⁴ is unsubstituted or substituted pyridinyl or indolyl,

At this time, the substituted pyridinyl and indolyl are NO ₂ , NH ₂ , -NH (C = O) CH ₃ ,-(C = O) NH ₂ , -NHSO ₂ CH ₃ , F, -C (CH ₂ One or more substituents selected from the group consisting of ₂ OH, methyl and methoxy.

In addition, in Chemical Formula 1,

A is CH or N;

,

,

,

또는

이거나, R¹ 및 R²는 이들이 결합된 탄소원자와 함께

,

또는

을 형성할 수 있고;R ¹ and R ² are independently hydrogen, F, methoxy,

,

,

,

or

Or R ¹ and R ² together with the carbon atom to which they are attached

,

or

Can form;

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

이고;R ³ is-(C = O) NHCH ₃ ,-(C = O) N (CH ₃ ) ₂ ,-(P = O) (CH ₃ ) ₂ , -SO ₂ CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

ego;

,

,

,

,

,

,

,

,

,

,

또는

일 수 있다.LR ⁴ is

,

,

,

,

,

,

,

,

,

,

or

Can be.

Examples of the compound represented by Formula 1 according to the present invention include the following compounds:

<1> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrazole-4- Yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<2> 2- (6-((2- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H-pyrazole- 4-yl) pyrimidin-4-amino) pyridin-2-yl) propan-2-ol;

<3> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1H-pyrazol-4-yl) Pyridin-4-ylamino) pyridin-2-yl) propan-2-ol;

<4> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H- Pyrazol-4-yl) pyridin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<5> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridine-3 -Yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<6> 2- (6-((5- (benzofuran-2-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<7> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-indole-5 -Yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

<8> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (furan-3-yl) pyrid Midin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<9> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazole- 4-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

<10> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazole- 3-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

<11> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-3-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<12> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (pyridin-3-yl) pyrid Midin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<13> 2- (6-((5- (benzofuran-3-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;

<14> 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (quinoline- 6-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

<15> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1- Methyl-1H-pyrrole-3-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<16> 2- (6-((5- (benzofuran-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;

<17> 2- (6-((2-((4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-phenylpyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;

<18> 2- (6-((5- (benzo [b] thiophen-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<19> 2- (6-((5- (1H- indol-3-yl) -2-((3-methoxy-4- (4- methylpiperazin-1-yl) piperidine-1- 1) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<20> 2- (6-((5- (benzo [b] thiophen-2-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<21> 2- (6-((5- (5-fluoropyridin-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<22> 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (thiophene -2-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

<23> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H- Pyrrole-3-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<24> 2- (6-((5- (furan-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1 -Yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (benzofuran-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;

<26> 2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (benzofuran-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;

<28> 2- (6-((5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-propan-2-ol;

2- (6-((5- (1-methyl-1H-pyrazol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (thiophen-2-yl) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (benzo [b] thiophen-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (2-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (3-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-2-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<35> 2- (6- (5- (benzo [b] thiophen-2-yl) -2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl Amino) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (benzofuran-3-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrrole-3-yl ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (1H-pyrrol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) pyrimidine-4- I) amino) pyridin-2-propan-2-ol;

2- (6- (5- (benzo [b] thiophen-2-yl) -2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino) pyri) Midin-4-ylamino) pyridin-2-yl) propan-2-ol;

2- (6- (5- (benzo [b] thiophen-2-yl) -2- (1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4- Monoamino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (benzo [b] thiophen-2-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)) Amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<42> 2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;

<45> 2- (6-((5- (6-fluoropyridin-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiazol-5-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (1H-pyrazol-3-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

<48> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (1-methyl-1H- Indol-3-yl) 2-amine;

N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;

<50> N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methyl-1,2,3,4 Tetrahydroisoquinolin-6-amine;

<51> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Thiophen-2-yl) 2-amine;

<52> N- (4- (1-methyl-1H-indol-3-yl) -5- (thiophen-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;

N- (5- (isooxazol-4-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;

<54> N- (4- (1-methyl-1H-indol-3-yl) -5- (1H-pyrazol-4-yl) pyrimidin-2-yl) -1,2,3,4- Tetrahydroisoquinolin-6-amine;

N- (5- (furan-3-yl) -4- (1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline-6- Amines;

N- (5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4 Tetrahydroisoquinolin-6-amine;

N- (5- (5-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4 Tetrahydroisoquinolin-6-amine;

<58> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Thiophen-3-yl) pyrimidin-2-amine;

N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra hydroiso Quinolin-7-amine;

<60> N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2,3,4,5-tetrahydro- 1H-benzo [d] azepin-7-amine;

5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine- 2-amine;

5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indole-3- Yl) pyrimidin-2-amine;

<63> (S) -5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl ) Pyrimidin-2-amine;

<64> (S) -5- (furan-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;

N- (5- (furan-3-yl) -4- (4-nitro-1H-indol-1-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;

<66> N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl)- 1H-indol-4-yl) methanesulfonamide;

N- (4- (4-amino-1 H-indol-1-yl) -5- (furan-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;

N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydro isoquinolin-6-yl) amino) pyrimidin-4-yl)- 1H-indol-4-yl) acetamide;

5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indole-1- Yl) pyrimidin-2-amine;

<70> 1- (5- (furan-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl)- 1H-indol-4-amine;

5- (furan-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indol-1-yl) pyrimidine- 2-amine;

1- (5- (furan-3-yl) -2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -1H-indole-4 Amines;

5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl ) Pyrimidin-2-amine;

N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;

5- (6-Fluoropyridin-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;

(76) (S) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1 -Yl) phenyl) pyrimidin-2-amine;

<77> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoro pyridin-3-yl) -4- (1- Methyl-1H-indol-3-yl) pyrimidin-2-amine;

N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (furan-3-yl) -4- (1-methyl-1H-indole-3- Yl) pyrimidin-2-amine;

N- (5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;

<80> N- (5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetra hydroisoquinolin-6-amine;

N- (4- (1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1,2 , 3,4-tetrahydroisoquinolin-4-yl) 6-amine;

<82> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-methoxy-1-methyl-1H-indol-3-yl ) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

<84> N- (4- (6-methoxy-1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl ) 4-tetrahydroisoquinolin-6-amine;

N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoropyridin-3-yl) -4- (6- Methoxy-1-methyl-1H-indol-3-yl) pyrimidin-3-yl) pyrimidin-2-amine;

5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4 -Methylpiperazin-1-yl) phenyl) pyrimidin-2- amine;

N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;

N- (4- (6-methoxy-1H-indol-3-yl) -5 (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;

N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetra hydroisoquinolin-6-amine;

<90> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -4- (6-methoxy-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

4- (6-methoxy-1 H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- ( Trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -5- (6-fluoropyridin-3-yl) -4- (6- Methoxy-1H-indol-3-yl) pyrimidin-2-amine;

5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin -1-yl) phenyl) pyrimidin-2-amine;

N- (4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine;

N- (4- (6-fluoro-1-methyl-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;

<96> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1H -Indol-3-yl) pyrimidin-2-amine;

5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4-((S) -3-methylpiperazin-1-yl) Phenyl) pyrimidin-2-amine;

(98) (S) -5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3-methylpiperazin -1-yl) phenyl) pyrimidin-2-amine;

N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1H-indol-3-yl) -5- (6- (tri Fluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

<100> (S) -4- (1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoromethyl) pyridine 3-yl) pyrimidin-2-amine;

<101> (S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4- (3-methylpiperazin- 1-yl) phenyl) 2-pyrimidin-amine;

(S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3 Methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

<103> N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indol-3-yl) -5- (6- (tri Fluoromethyl) pyridin-3-yl) pyrimidin-2-amine;

N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4 (1-methyl-1H-indol-3-yl) -5- (6 (Trifluoromethyl) pyridine-3-pyrimidin-2-amine;

<105> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1 Methyl-1H-indol-3-yl) pyrimidin-2-amine;

5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazine -1-yl) phenyl) pyrimidin-2-amine;

(S) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5 (6- (trifluoro Rhomethyl) pyridin-3-yl) pyrimidin-2-amine;

4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (4-((S) -3-methylpiperazin- 1-yl) phenyl) pyrimidin-2-amine;

(S) -4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3) -Methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

<110> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-amine;

<111> N- (4- (6-fluoro-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydro isoquinolin-6-amine;

<112> (S) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1- Methyl-1H-indol-3-yl) pyrimidin-2-amine;

5- (6-Fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidin-4-yl) phenyl) -4- (1-methyl-1H-indole- 3-yl) pyrimidin-2-amine;

5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (piperidin-4-yl) phenyl) pyrid Midin-2-amine;

5- (6-Fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (pi Ferridin-4-yl) phenyl) pyrimidin-2-amine;

4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidine-4) -Yl) phenyl) pyrimidin-2-amine;

3- (5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) -1H-indole-1-carboxamide;

3- (5- (6-fluoropyridin-3-yl) -2-((3-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl ) -1H-indole-1-carboxamide;

3- (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridin-3-yl) Pyrimidin-4-yl) -1-carboxamide;

<120> (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropane-2- 1) pyridin-2-yl) amino) pyrimidin-5-yl) dimethylphosphineoxide;

<121> (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((3-methoxy-4- (4- (4-methylpiperazin -1-yl) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphineoxide;

(4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl ) Amino) pyrimidin-5-yl) dimethylphosphine oxide;

2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5 (methylsulfonyl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (methylsul Phonyl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (methylsulfonyl) -2 ((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol;

2- (6-((2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;

2- (6-((5- (methylsulfonyl) -2-((1,2,3,4-tetra hydroisoquinolin-7-yl) amino) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol;

2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) -5- (methylsulfonyl) pyrimidine-4- Yl) amino) pyridin-2-yl) propan-2-ol;

2- (6-((2- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) pyrimidin-4-yl ) (Methyl) amino) -2-yl) propan-2-ol;

<130> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Methylsulfonyl) pyrimidin-2-amine;

<131> 2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -4- (6- (2-hydroxypropan-2-yl) pyridine- 2-ylamino) -N, N-dimethylpyrimidine-5-carboxamide;

4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((1,2,3,4-tetrahydroiso) Quinolin-6-yl) amino) pyrimidine-5-carboxamide;

4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((2-methyl-1,2,3,4 Tetrahydroisoquinolin-6-yl) pyridin-2-yl) amino) pyrimidine-5-carboxamide;

(S) -4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((4- (3-methylpipepe Razin-1-yl) phenyl) amino) pyrimidine-5-carboxamide;

(R) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) -2- (3-methoxy-4- (3-methylpiperazin-1- Yl) phenylamino) -N, N-dimethylpyrimidine-5-carboxamide;

2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropan-2-yl ) Pyridin-2-yl) amino) -N-methylpyrimidine-5-carboxamide;

4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methyl-2-((1,2,3,4-tetra hydroisoquinoline- 6-yl) amino) pyrimidine-5-carboxamide.

The compound represented by Chemical 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, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, Fluoride, Acetate, Propionate, Decanoate, Caprylate, Acrylate, Formate, Isobutyrate, Caprate, Heptanoate, Propiolate, Oxalate, Malonate, Succinate, Sube Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and the excess acid may be distilled under reduced pressure, dried and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are 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 Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

Another aspect of the invention,

As shown in Scheme 1 below,

Reacting the compound represented by Formula 4 with the compound represented by Formula 5 (step 1); And

It provides a method for producing a compound represented by the formula (1) comprising the step (step 2) of reacting a compound represented by the formula (2) with a compound represented by the formula (3).

Scheme 1

(In Scheme 1, A, L, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1;

X ¹ and X ² are each halogen; And

또는

다).L ¹ is

or

All).

Hereinafter, the preparation method of Scheme 1 will be described in detail.

In the above preparation method, step 1 is a step of obtaining a compound represented by the formula (2) by reacting the compound represented by the formula (4) and the compound represented by the formula (5), specifically, the halogen (X ¹ ) And a primary amine of the compound represented by the formula (5) is reacted by the presence of a base to obtain N-arylation to obtain a compound represented by the formula (2).

The base is N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU Or an organic base such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH or potassium carbonate alone or mixed, or equivalent or excess Can be used as

Furthermore, solvents usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc. can be used individually or in mixture.

In the above preparation method, step 2 is a step of obtaining a compound represented by the formula (1) by reacting the compound represented by the formula (2) and the compound represented by the formula (3), specifically, the halogen and the formula (3) of the compound represented by the formula (2) It is a step of obtaining a compound represented by the formula (1) by reacting the boronic acid compound represented by a metal ligand and basic conditions.

In this case, the boronic acid compound may be used commercially available compounds, or may be prepared by using a known method from the corresponding halide compound, the halide compound may be used iodide or bromide.

In addition, as the metal ligand, copper, palladium, nickel, tin, or the like may be used. In the present invention, Pd (PPh ₃ ) ₄ is used as the palladium ligand, but this is merely an example, but is not limited thereto.

The base also contains N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene Organic bases such as (DBU) or inorganic bases such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH, potassium carbonate, or the like Or in excess.

Furthermore, solvents usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc. can be used individually or in mixture.

In this case, in Scheme 1, step 1 and step 2 may proceed sequentially, and after performing step 2, step 1 may be performed.

In addition, Scheme 1 is only an example for preparing the compound represented by Formula 1 of the present invention, it is not limited thereto.

In addition, specific experimental methods are disclosed in the following examples, and the following examples are also merely examples for preparing the compound represented by Chemical Formula 1, but are not limited thereto.

In addition, in the compound represented by Formula 1 according to the present invention, R ³ is not aryl or heteroaryl-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , or -SO ₂ R ^In case of ⁹ , it may be prepared by performing the method disclosed in Examples 120 to 137. This is also only an example, but it is not limited to this.

Another aspect of the invention,

Provided is a pharmaceutical composition for preventing or treating a protein kinase related disease containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The protein kinase is AAK1, ABL1 (E255K) -phosphorylated. ABL1 (F317I) -nonphosphorylated, ABL1 (F317I) -phosphorylated, ABL1 (F317L) -nonphosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) (Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVRA, ACVRA ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF (V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2K, CAMK2D, , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CHEKK, CHEKK2 , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, DRAK1, DRAK2, DYRK1, DYRK2, DYRK2 -A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHB6 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H) D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-c atalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P ), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2 (G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK2 MEK1 MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK, MYLK MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-beta delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFK1IRE, PH1 PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R ), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (E545K), PIK3CA (H1047L), PIK3CA (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CB, PIKCCG, PIKC3G, PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M.tuberculosis), PLK1, PLK2, PLK2, PLK2, PLK2 , PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK2, RIOK3, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4 (Kin.Dom.1-N-terminal), RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.1-N- terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK1 (Kin.Dom.1, N-terminal), RSK1 (Kin.Dom.2-C-terminal), RSK2 (Kin.Dom.1- N-terminal), RSK2 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.2-C-terminal), RSK4 (Kin.Dom. 1-N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, STK39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TRPM6, TSSK1B TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, NKNK, YANK1, YANK1 It may be at least one selected from the group consisting of YES, YSK1, YSK4, ZAK, and ZAP70.

In addition, in the pharmaceutical composition, the compound is AAK1, ABL1 (E255K) -phosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) -phosphorylated, ABL1 ( Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPKalpha, AMPK-alpha -alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DK2, DK2, DK2 , DLK, DYRK1B, DYRK2, EGFR, EGFR (E746-A750del), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR ( L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FLT3, FLT3 , FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663 Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT ( L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2 (G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4 , MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7G, PDGFRA , PIK3CB, PIP5K1A, PIP5K2B, PKNB (M.tuberculosis), PLK1, PLK2, PYK2, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK3, RIPK1, RPS6KA4 (Kin.Dom. -N-terminal), RSK1 (Kin.Dom.1-N-terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom .1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, Inhibitory activity against one or more kinases selected from the group consisting of TRKC, TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4 Can be represented.

The protein kinase related disease may be cancer.

Specifically, the cancer may include leukemia, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial carcinoma, epithelial cell tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal / sinus sinus Cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, lung cancer, epithelial cancer, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, stomach cancer, Liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penis cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterus Sarcoma, vaginal cancer, female external genital cancer, female urethral cancer or skin cancer.

The compound represented by the formula (1) according to the present invention exhibits excellent inhibitory activity against Wee1 kinase (see Experimental Example 1), and shows inhibitory activity against various kinases (see Experimental Example 4), and therefore, diseases associated with various kinases, in particular, It can be usefully used as a pharmaceutical composition for the treatment or prevention of diseases related to Wee1 kinase.

In addition, the compound represented by the formula (1) according to the present invention exhibits the ability to inhibit liver cancer cell proliferation (see Experimental Example 2), and shows the ability to inhibit cancer cell proliferation of epithelial cell cancer, lung cancer, colon cancer, breast cancer, leukemia, ovarian cancer (experimental) Example 3), it can be usefully used as a pharmaceutical composition for the treatment or prevention of cancer, in particular, liver cancer, epithelial cell cancer, lung cancer, colon cancer, breast cancer, leukemia, ovarian cancer.

When used in the treatment of cancer, the pharmaceutical composition of the present invention may be administered as a separate therapeutic agent or in combination with other anticancer agents in use.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form preparations include at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

Pharmaceutical compositions comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampule or vial unit dosage form. It can be prepared by. The composition may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, etc. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

According to another aspect of the invention, there is provided a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by Chemical Formula 1 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). Generally, the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control purposes, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the compound represented by the formula (1) of the present invention may contain a fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.

According to another aspect of the present invention, a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Methods of preventing or treating a disease are provided.

According to another aspect of the present invention, there is provided a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a protein kinase related disease. do.

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

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

Example 1 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrazole- Preparation of 4-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol

Step 1: Preparation of 2- (6-((2-chloro-5-iodopyridin-4-yl) amino) pyridin-2-yl) propan-2-ol

2,4-Dichloro-5-iodopyrimidine (1.0 equiv) was added to 1,4-dioxane (0.1 M) and dissolved, followed by 2- (6-aminopyridin-2-yl) propan-2-ol (1.0 equiv) and DIPEA (1.0 equiv) were added at room temperature and reacted at 100 ^° C. for 72 hours. The reaction mixture was cooled to rt, poured with water and extracted with EtOAc. (x3) The combined organic layers were washed with brine and then water was removed with MgSO ₄ . After filtration, it was concentrated and the compound was purified using MPLC (MeOH / DCM). After concentration, the desired compound was obtained as a yellow solid. (Yield 99%)

Step 2: 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5-iodopyrimidin-4-yl Preparation of Amino) pyridin-2-yl) propan-2-ol

Compound (1.0 equiv), 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in Step 1; ) Was added to sec-BuOH (0.1 M) to dissolve and sonicated for 1 minute to remove the gas. Pd ₂ (dba) ₃ (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 80 ^° C., followed by reaction for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The filtrate obtained was concentrated and then purified by MPLC (DCM: MeOH with 10% NH ₄ OH) to obtain a target compound as a dark brown solid. (Yield 97%)

Step 3: 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrazole-4- I) Preparation of pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol

Compound prepared in step 2 (1.0 equiv), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.0 equiv) And 1M Na ₂ CO ₃ (aq, 3.0 equivalents) were added to 1,4-dioxane (0.05 M) to dissolve and sonicated for 1 minute to remove the gas. Pd (PPh ₃ ) ₄ (0.1 equivalent) was added to the reaction mixture at 100 ^° C., and reacted for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The obtained filtrate was concentrated and purified by prep-HPLC to give the title compound as a yellow solid. (Yield 38%)

Examples 2 to 47 were prepared in a similar manner to Example 1, and the chemical structures of Examples 1 to 47 are shown in Tables 1 and 2, the compound name and ¹ H NMR, mass, yield and HPLC analysis results Table 3 In summary, it is shown.

Example Chemical structure Example Chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

Example Chemical structure Example Chemical structure 25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

-

Example Compound name ¹ H NMR, MS yield
(%) HPLC
rt (min)
Purity One 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrazol-4-yl) pyrid Midin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.07 (s, 1H), 7.93 (brs, 4H), 7.45 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.11 -7.06 (m, 2H), 3.88 (s, 3H), 3.65-3.61 (m, 2H), 2.95 (s, 6H), 2.82-2.76 (m, 2H), 2.22-2.17 (m, 2H), 2.05 -1.96 (m, 3H), 1.60 (s, 6H); 544 [M + H] ⁺ 63 3.89100% 2 2- (6-((2- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H-pyrazol-4-yl A) pyrimidin-4-amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.11 (s, 1H), 8.01 (s, 1H), 7.91 (s, 2H), 7.87 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 3.83-3.80 (m, 4H), 3.07-3.02 (m, 4H), 2.99-2.93 (m, 3H), 2.86 (s, 5H), 2.16-2.13 (m, 2H), 1.61-1.57 (m, 2H), 1.28 (s, 6H); 570 [M + H] ⁺ 23 3.8199% 3 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1H-pyrazol-4-yl) pyridine-4 -Ylamino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.21 (s, 1H), 7.90 (s, 2H), 7.72-7.68 (m, 1H), 7.66 (s, 1H), 7.34 (d, J = 8.32 Hz, 1H), 7.08 (d, J = 8.32 Hz, 1H), 6.96-6.90 (m, 3H), 3.86 (s, 3H), 3.67-3.60 (m, 2H), 3.45-3.35 (m , 1H), 2.93 (s, 6H), 2.79-2.73 (m, 2H), 2.28-2.15 (m, 2H), 1.99-1.93 (m, 2H), 1.28 (s, 6H); 543 [M + H] ⁺ 2 3.8092% 4 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H-pyrazole- 4-yl) pyridin-4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.31 (s, 1H), 7.92 (s, 2H), 7.75-7.73 (m, 2H), 7.43 (d, J = 8.56 Hz, 1H) , 7.36 (d, J = 7.48 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.96 (d, J = 7.96, 1H), 3.98 (s, 3H ), 3.73-3.70 (m, 2H), 3.48-3.42 (m, 3H), 3.30-3.01 (m, 8H), 2.92 (s, 3H), 2.23-2.19 (m, 2H), 2.07-2.01 (m , 2H), 1.31 (s, 6H); 598 [M + H] ⁺ 6 3.6798% 5 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridin-3-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.36 (s, 1H), 8.24 (s, 1H), 8.11-8.07 (m, 2H), 7.70 (d, J = 8.24 Hz, 1H) , 7.55 (s, 1H), 7.49 (d, J = 7.72 Hz, 1H), 7.29-7.26 (m, 1H), 7.21-7.16 (m, 2H), 3.92 (s, 3H), 3.68-3.65 (m , 2H), 3.52-3.39 (m, 1H), 3.04-2.98 (m, 2H), 2.94 (s, 6H), 2.30-2.21 (m, 2H), 2.13-2.02 (m, 2H), 1.67 (s , 6H); 573 [M + H] ⁺ 13 4.4597% 6 2- (6-((5- (benzofuran-2-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.70 (s, 1H), 8.21-8.10 (m, 1H), 7.88 (d, J = 8.44, 1H), 7.71 (d, J = 7.64 , 1H), 7.65 (d, J = 8.12 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 7.72 Hz, 1H), 7.41-7.38 (m, 1H), 7.35-7.31 (m, 1H), 7.28 (s, 1H), 7.23 (s, 2H), 3.94 (s, 3H), 3.71-3.68 (m, 2H), 3.49-3.43 (m, 1H), 3.12-3.06 (m, 2H) , 2.95 (s, 6H), 2.29-2.26 (m, 2H), 2.13-2.08 (m, 2H), 1.69 (s, 6H); 594 [M + H] ⁺ 7 5.02100% 7 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-indol-5-yl) Pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.02 (s, 1H), 7.96 (d, J = 8.28 Hz, 1H), 7.90-7.85 (m, 1H), 7.72 (d, J = 1.04 Hz, 1H), 7.63 (d, J = 8.48 Hz, 1H), 7.43 (d, J = 3.08 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J = 3.08 Hz, 1H), 7.30 -7.27 (m, 1H), 7.18-7.12 (m, 2H), 6.57 (d, J = 3.04 Hz, 1H), 3.90 (s, 6H), 3.70-3.67 (m, 2H), 3.55-3.49 (m , 1H), 2.97-2.91 (m, 8H), 2.25-2.22 (m, 2H), 2.07-1.99 (m, 2H), 1.53 (s, 6H); 607 [M + H] ⁺ 10 4.9299% 8 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (furan-3-yl) pyrimidine-4 -Yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.22 (s, 1H), 8.09-8.04 (m, 1H), 7.90 (s, 1H), 7.86 (d, J = 8.48 Hz, 1H) , 7.77-7.76 (m, 1H), 7.58 (s, 1H), 7.49 (d, J = 7.64 Hz, 1H), 7.33 (d, J = 8.68 Hz, 1H), 7.24-7.21 (m, 1H), 6.72 (d, J = 0.92 Hz, 1H), 3.94 (s, 3H), 3.76-3.73 (m, 2H), 3.56-3.50 (m, 1H), 3.31-3.24 (m, 2H), 2.95 (s, 6H), 2.34-2.30 (m, 2H), 2.19-2.15 (m, 2H), 1.64 (s, 6H); 544 [M + H] ⁺ 28 4.53100% 9 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazol-4-yl Pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.66 (brs, 1H), 9.52 (brs, 1H), 8.19 (brs, 1H), 8.09 (s, 1H), 8.04 (s, 1H) , 7.78-7.75 (m, 1H), 7.71 (s, 1H), 3.45 (d, J = 11.7 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J = 9.5 Hz, 1H), 6.89 ( d, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.47-3.44 (m, 2H), 3.30-3.26 (m, 2H), 2.81 ((d, J = 4.8 Hz, 6H), 2.68-2.66 (m, 1H), 2.07-2.04 (m, 2H), 1.81-1.73 (m, 2H), 1.41 (s, 6H); 558 [M + H] ⁺ 5 4.3096% 10 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazol-3-yl Pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.51 (brs, 2H), 8.64 (s, 1H), 8.39 (brs, 1H), 7.86 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.26 (d. J = 7.9 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.34-3.45 (m, 2H), 3.29-3.24 (m, 2H), 2.66-2.61 (m, 1H), 2.08-2.05 (m, 2H), 1.82 -74 (m, 2H), 1.48 (s, 6H); 558 [M + H] ⁺ 11 4.3897% 11 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-3-yl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.21 (s, 1H), 8.11-8.02 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.72-7.70 (m, 2H), 7.54 (s, 1H), 7.48-7.46 (m, 1H), 7.33-7.31 (m, 1H), 7.28 (d, J = 8.72 Hz, 1H), 7.26-7.19 (m, 1H), 3.93 (s, 3H), 3.74-3.71 (m, 2H), 3.52-3.46 (m, 1H), 3.32-3.30 (m, 2H), 2.95 (s, 6H), 2.31-2.28 (m, 2H), 2.18-2.07 (m, 2 H), 1.63 (s, 6 H); 560 [M + H] ⁺ 12 4.66100% 12 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (pyridin-3-yl) pyrimidine-4 -Yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.83 (s, 1H), 8.77 (d, J = 4.72 Hz, 1H), 8.27 (s, 1H), 8.25 (d J = 8.24 Hz, 1H), 8.11-8.05 (m, 1H), 7.82-7.79 (m, 1H), 7.73 (d, J = 8.56 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.84 Hz, 1H ), 7.22-7.15 (m, 2H), 3.91 (s, 3H), 3.67-3.64 (m, 3H), 2.99-2.94 (m, 2H), 2.94 (s. 6H), 2.26-2.23 (m, 2H) ), 2.07-1.99 (m, 2H), 1.65 (s, 6H); 555 [M + H] ⁺ 3 4.0194% 13 2- (6-((5- (benzofuran-3-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl ) Phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.49 (s, 1H), 8.20-8.16 (m, 1H), 8.09 (s, 1H), 7.92 (s 1H), 7.68 (d, J = 8.44 Hz, 1H), 7.59-7.56 (m, 2H), 7.50-7.40 (m, 3H), 7.35-7.31 (m, 1H), 4.04 (s, 3H), 3.85-3.76 (m, 2H), 3.68-3.52 (m, 2H), 3.50-3.31 (m, 5H), 3.20-2.98 (m. 4H), 2.31-2.13 (m, 4H), 1.69 (s, 6H); 649 [M + H] ⁺ 19 4.8998% 14 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (quinolin-6-yl Pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 9.23-9.21 (m, 1H), 9.07 (d, J = 8.28 Hz, 1H), 8.53 (s, 1H), 8.45 (d, J = 1.68 Hz, 1H), 8.39 (d, J = 8.84 Hz, 1H), 8.25-8.21 (m, 2H), 8.09-8.02 (m, 1H), 7.94 (d, J = 2.08 Hz, 1H), 7.67 ( d, J = 8.56 Hz, 1H), 7.61 (d, J = 8.96 Hz, 1H), 7.53 (d, J = 7.56 Hz, 1H), 7.45-7.42 (m, 1H), 4.04 (s, 3H), 3.85-3.76 (m, 2H), 3.73-3.63 (m, 2H), 3.65-3.55 (m, 1H), 3.54-3.48 (m. 1H), 3.49-3.36 (m, 3H), 3.21-3.01 (m , 4H), 2.93 (s, 3H), 2.27-2.15 (m, 4H), 1.71 (s, 6H); 660 [M + H] ⁺ 13 4.13 100% 15 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1-methyl-1H Pyrrole-3-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.18 (s, 1H), 8.08-8.04 (m, 1H), 7.84 (d, J = 8.36, 1H), 7.73 (s 1H), 7.56 (d, J = 8.92 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.33-7.30 (m, 1H), 7.02-7.01 (m, 1H), 6.90-6.89 (m, 1H), 6.32-6.31 (m, 1H), 3.99 (s, 3H), 3.88-3.75 (m, 2H), 3.78 (s, 3H), 3.68-3.52 (m, 3H), 3.50-3.36 (m, 4H), 3.25-3.02 (m. 4H), 2.93 (s, 3H), 2.31-2.08 (m, 4H), 1.64 (s, 6H); 612 [M + H] ⁺ 8 4.6399% 16 2- (6-((5- (benzofuran-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl ) Phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.80 (s, 1H), 8.24-8.12 (m, 1H), 7.92-7.89 (m, 2H), 7.71 (d, J = 7.48, 1H ), 7.65 (d, J = 8.28 Hz, 1H), 7.58 (d, J = 8.88 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.43-7.37 (m, 2H), 7.34-7.32 (m, 1H), 7.28 (s, 1H), 4.03 (s, 3H), 3.82-3.73 (m, 2H), 3.69-3.57 (m, 3H), 3.50-3.32 (m, 4H), 3.21-2.98 (m. 4H), 2.91 (s, 3H), 2.30-2.09 (m, 4H), 1.70 (s, 6H); 649 [M + H] ⁺ 15 5.0797% 17 2- (6-((2-((4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-phenylpyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.35 (s, 1H), 8.20 (t, J = 8.2 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.4 Hz , 1H), 7.63-7.54 (m, 6H), 7.51 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 4.05 (s, 3H), 3.83-3.80 (m, 2H), 3.71-3.64 (m, 2H), 3.42-3.33 (m, 4H), 3.21-3.02 (m, 5H), 2.95 (s, 3H), 2.29-2.17 (m, 4H), 1.71 (s, 6H); 609 [M + H] ⁺ 32 4.7298% 18 2- (6-((5- (benzo [b] thiophen-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine-1- 1) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.47 (s, 1H), 8.20 (t, J = 8.2 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.98 (s , 1H), 7.88 (s, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.51-7.49 (m, 1H), 7.46-7.43 (m, 2H), 4.07 (s, 3H), 3.84-3.81 (m, 2H), 3.72-3.66 (m, 2H), 3.51-3.39 (m, 4H), 3.09-3.03 (m, 5H), 2.95 (s, 3H), 2.30-2.18 (m, 4H), 1.72 (s, 6H); 665 [M + H] ⁺ 56 4.9899% 19 2- (6-((5- (1H-indol-3-yl) -2)-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl ) Amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.40 (s, 1H), 8.11 (t, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 8.5 Hz , 1H), 7.59-7.55 (m, 3H), 7.53-7.47 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 4.04 (s, 3H), 3.83-3.80 (m, 2H), 3.68-3.63 (m, 2H), 3.52-3.41 (m, 4H), 3.13-3.05 (m, 5H) , 2.95 (s, 3H), 2.30-2.17 (m, 4H), 1.66 (s, 6H); 648 [M + H] ⁺ 44 4.7997% 20 2- (6-((5- (benzo [b] thiophen-2-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine-1- 1) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.54 (s, 1H), 8.21 (t, J = 8.2 Hz, 1H), 7.97-7.92 (m, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.62 (s, 1H), 7.58-7.54 (m, 2H), 7.50-7.40 (m, 3H), 4.04 (s, 3H), 3.80-3.77 (m, 2H), 3.65-3.59 (m, 2H), 2.92 (s, 3H), 2.30-2.03 (m, 6H), 1.69 (s, 6H), 1.65-1.54 (m, 1H), 1.41-1.20 (m, 6 H); 665 [M + H] ⁺ 12 5.10698% 21 2- (6-((5- (5-fluoropyridin-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl ) Phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.58 (s, 1H), 8.94 (s, 1H) 8.59 (d, J = 9.4 Hz, 2H), 8.21 (s, 1H), 7.93- 7.89 (m, 2H), 7.80 (t, J = 4.0 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 7.5 Hz, 2H), 7.21-7.09 (s, 1H), 3.72 (s , 3H), 3.61-3.58 (m, 3H), 3.50-3.48 (m, 2H), 3.16-2.79 (m, 4H), 2.79 (s, 3H), 2.12-2.00 (m, 2H), 1.77-1.73 (m, 2H), 1.44 (s, 6H); 628 [M + H] ⁺ 39 4.0699% 22 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (thiophen-2- Yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.69 (NH, 1H), 8.39 (NH, 1H), 8.24-2.19 (m, 2H), 7.82 (t, J = 7.8 Hz, 1H) , 7.74 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.36-7.32 (m, 3H), 7.27-7.25 (m, 1H), 7.15-7.09 (m, 1H), 3.76 (s , 3H), 3.53-3.49 (m, 3H), 3.48-3.15 (m, 4H), 3.14-2.83 (m, 6H), 2.82 (s, 3H), 2.06-2.04 (m, 2H), 1.95-1.82 (m, 2 H), 1.38 (s, 6 H); 615 [M + H] ⁺ 23 4.249100% 23 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H-pyrrole-3 -Yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 10.83 (s, 1H), 8.07 (s, 1H), 7.95 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 8.4 Hz , 1H), 7.62 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.98 (s , 1H), 6.89 (s, 1H), 6.26 (s, 1H), 3.87 (s, 3H), 3.67-3.64 (m, 2H), 3.49-3.44 (m, 2H), 3.38-3.20 (m, 4H ), 3.05-2.84 (m, 5H), 2.81 (s, 3H), 2.14-2.11 (m, 2H), 2.07-1.98 (m, 2H), 1.51 (s, 6H); 598 [M + H] ⁺ 16 4.05096% 24 2- (6-((5- (furan-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) Phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.80 (s, 1H), 8.64 (s, 1H), 8.04 (d, J = 13.5 Hz, 1H), 7.86 (d, J = 17.9 Hz , 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 13.0 Hz, 2H ), 6.87 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H); 598 [M + H] ⁺ 16 4.27100% 25 2- (6-((5- (benzofuran-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.70 (s, 1H), 8.10-8.06 (m, 1H), 7.98 (d, J = 8.52, 1H), 7.69-7.67 (m, 2H ), 7.63-7.58 (m, 2H), 7.48 (d, J = 8.08 Hz, 1H), 7.40-7.33 (m, 1H), 7.31-7.24 (m, 1H), 7.23-7.22 (m, 2H), 4.36 (s, 2H), 3.55-3.52 (m, 2H), 3.15-3.12 (m, 2H), 1.67 (s, 6H); 493 [M + H] ⁺ 12 4.8699% 26 2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.59 (s, 1H), 9.05 (s, 1H), 8.22-8.19 (m, 2H), 8.06 (s, 1H), 7.92-7.91 ( m, 1H), 7.85-7.81 (m, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.56 Hz, 1H), 7.15 (d, J = 8.52 Hz, 1H), 6.85 (d, J = 0.96 Hz, 1H), 4.23 (s, 2H), 3.48-3.33 (m, 2H), 2.97-2.92 (m, 2H), 1.41 (s, 6H) ; 443 [M + H] ⁺ 9 4.26 100% 27 2- (6-((5- (benzofuran-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.68 (s, 1H), 9.11-9.06 (m, 1H), 8.32 (s, 1H), 8.31 (s, 1H), 8.16-8.09 ( m, 1H), 7.98-7.85 (m, 1H), 7.74 (d, J = 8.28 Hz, 1H), 7.68-7.59 (m, 2H), 7.55 (d, J = 8.04 Hz, 1H), 7.50-7.37 (m, 2H), 7.33-7.29 (m, 1H), 7.18 (d, J = 8.48 Hz, 1H), 4.25 (s, 2H), 3.45-3.32 (m, 2H), 2.97-2.93 (m, 2H ), 1.38 (s, 6 H); 493 [M + H] ⁺ 21 4.66100% 28 2- (6-((5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl Amino) pyridine-2-propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.59 (s, 1H), 9.00 (br, 2H), 8.36 (d, J = 2.08 Hz, 1H), 8.19-8.09 (m, 1H) , 7.98 (d, J = 7.96 Hz, 1H), 7.90-7.86 (m, 1H), 7.60 (s, 1H), 7.53 (d, J = 8.28 Hz, 1H) 7.36-7.32 (m, 2H), 7.15 (d, J = 8.44 Hz, 1H), 4.23 (s, 2H), 3.39-3.32 (m, 2H), 2.97-2.85 (m, 2H), 1.42 (s, 6H); 472 [M + H] ⁺ 18 4.1598% 29 2- (6-((5- (1-methyl-1H-pyrazol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.96 (br, 2H), 8.70 (s, 1H), 8.40 (d, J = 8.16 Hz, 1H), 7.88 (d, J = 2.24 Hz, 1H), 7.79-7.75 (m, 1H), 7.71 (s, 1H), 7.53 (d, J = 8.44 Hz, 1H) 7.35 (d, J = 7.28 Hz, 1H), 7.17 (d, J = 8.36 Hz, 1H), 6.88 (d, J = 2.36 Hz, 1H), 4.25 (s, 2H), 3.96 (s, 3H), 3.47-3.35 (m, 2H), 3.06-2.97 (m, 2 H), 1.47 (s, 6 H); 457 [M + H] ⁺ 4 4.3891% 30 2- (6-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (thiophen-2-yl) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.26 (s, 1H), 8.11 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.61 (d , J = 3.9 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.26 (d, J = 3.5 Hz, 1H), 7.20-7.16 (m , 2H), 4.29 (s, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H), 1.62 (s, 6H); 459 [M + H] ⁺ 59 4.41798% 31 2- (6-((5- (benzo [b] thiophen-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4- 1) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.36 (s, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.88-7.76 (m, 3H), 7.62 (s, 1H) , 7.53-7.51 (m, 2H), 7.40-7.33 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 4.28 (s, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H), 1.57 (s, 6H); 509 [M + H] ⁺ 49 4.871100% 32 2- (6-((5- (2-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.02 (s, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.55 (s , 1H), 7.48-7.43 (m, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 4.28 (s, 2H), 3.75 (s, 3H), 3.45 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 6.3 Hz, 2H), 1.54 (s, 6H); 483 [M + H] ⁺ 90 4.431 100% 33 2- (6-((5- (3-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.12 (s, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (s , 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.01-6.96 (m, 3H), 4.26 (s, 2H), 3.76 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.3 Hz, 2H), 1.54 (s, 6H); 483 [M + H] ⁺ 59 4.480 100% 34 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-2-yl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.14 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (d , J = 5.2 Hz, 1H), 7.39-7.36 (m, 2H), 7.27 (s, 1H), 7.20-7.19 (m, 1H), 7.05-7.04 (m, 2H), 3.82 (s, 3H), 3.58-3.54 (m, 2H), 3.36-3.30 (m, 1H), 2.83 (s, 6H), 2.16-2.09 (m, 2H), 1.98-1.89 (m, 2H), 1.54 (s, 6H), 1.21-1.14 (m, 2 H); 560 [M + H] ⁺ 4 4.35094% 35 2- (6- (5- (benzo [b] thiophen-2-yl) -2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) pyrid Midin-4-ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOH- d ₆ ) δ 8.30 (s, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.87-7.82 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.39-7.32 (m, 3H), 7.11 (s, 2H), 3.88 (s, 3H), 3.60-3.57 (m, 2H ), 3.38-3.34 (m, 2H), 3.03-2.95 (m, 2H), 2.85 (s, 6H), 2.17-2.08 (m, 2H), 1.98-1.93 (m, 2H), 1.55 (s, 6H) ); 610 [M + H] ⁺ 10 4.809100% 36 2- (6-((5- (benzofuran-3-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.39 (s, 1H), 8.13-8.09 (m, 2H), 7.71-7.65 (m, 3H), 7.59 (d, J = 7.64 Hz, 1H), 7.49-7.42 (m, 2H), 7.36-7.28 (m, 3H), 3.98 (s, 3H), 3.77-3.74 (m, 2H), 3.58-3.51 (m, 1H), 3.37-3.26 ( m, 2H), 2.96 (s, 6H), 2.35-2.24 (m, 2H), 2.24-2.15 (m, 2H), 1.65 (s, 6H); 594 [M + H] ⁺ 16 4.5299% 37 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrrole-3-yl) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 7.84 (s, 1H), 7.84-7.69 (m, 1H), 7.43 (d, J = 7.48 Hz, 1H), 7.19 (s, 1H) , 7.10-7.02 (m, 5H), 6.38 (d, J = 1.8 Hz, 1H), 3.90 (s, 3H), 3.86-3.65 (m, 3H), 2.93 (s, 6H), 2.79-2.66 (m , 2H), 2.28-2.25 (m, 2H), 2.20-2.01 (m, 2H), 1.52 (s, 6H); 543 [M + H] ⁺ 2 4.1691% 38 2- (6-((5- (1H-pyrrol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino Pyridin-2-propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 10.86 (NH, 1H), 7.92 (s, 1H), 7.86-7.77 (m, 2H), 7.45 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 6.26 (s, 1H), 4.28 (s, 2H), 3.44 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.3 Hz, 2H), 1.46 (s, 6H); 442 [M + H] ⁺ 12 4.183100% 39 2- (6- (5- (benzo [b] thiophen-2-yl) -2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino) pyrimidine-4 -Ylamino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.28 (s, 1H), 8.03 (t, J = 8.1 Hz, 1H), 7.80-7.72 (m, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.31-7.24 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.21 (s, 2H), 3.37 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H), 1.51 (s, 6H); 509 [M + H] ⁺ 17 4.84998% 40 2- (6- (5- (benzo [b] thiophen-2-yl) -2- (1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4-ylamino) Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.31 (s, 1H), 8.05 (t, J = 8.2 Hz, 1H), 7.81-7.76 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.46-7.43 (m, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 4.43-4.40 (m, 1H), 4.22-4.19 (m, 1H), 3.69-3.59 (m, 1H), 3.33-3.28 (m, 1H), 3.19-3.03 (m, 2H), 2.92 (s, 3 H), 1.53 (s, 6 H); 523 [M + H] ⁺ 19 4.828100% 41 2- (6-((5- (benzo [b] thiophen-2-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyridine Midin-4-yl) amino) pyridin-2-yl) propan-2-ol ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.32 (s, 1H), 8.05 (t, J = 8.1 Hz, 1H), 7.81-7.76 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.49-7.46 (m, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.31-7.26 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 4.43-4.40 (m, 1H), 4.19-4.15 (m, 1H), 3.69-3.59 (m, 1H), 3.33-3.28 (m, 1H), 3.29-3.08 (m, 1H), 3.06-2.92 (m, 1 H), 2.92 (s, 3 H), 1.53 (s, 6 H); 523 [M + H] ⁺ 20 4.90299% 42 2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.26 (s, 1H), 8.15-8.11 (m, 1H), 7.90 (s, 1H), 7.80-7.76 (m, 2H), 7.65 ( s, 1H), 7.59 (d, J = 8.28 Hz, 1H), 7.50 (d, J = 7.64 Hz, 1H), 7.24 (d, J = 8.44 Hz, 1H), 6.72 (d, J = 0.88 Hz, 1H), 4.59-4.56 (m, 1H), 4.34-4.31 (m, 1H), 3.85-3.71 (m, 1H), 3.51-3.21 (m, 2H), 3.20-3.10 (m, 1H), 3.07 ( s, 3 H), 1.66 (s, 6 H); 457 [M + H] ⁺ 42 4.28 100% 43 2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol 443 [M + H] ⁺ 11 4.2796% 44 2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD) δ 8.25 (s, 1H), 8.14 (t, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 7.1 Hz, 1H) , 7.75 (s. 1H), 7.64 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H) , 6.71 (s, 1H), 4.55 (d, J = 41.0 Hz, 1H), 4.34 (d, J = 13.9 Hz, 1H), 3.97 (brs, 1H), 3.77 (brs, 1H), 3.35-3.15 ( m, 2H), 3.07 (s, 3H), 1.66 (s, 6H); 457 [M + H] ⁺ 41 4.3197% 45 2- (6-((5- (6-fluoropyridin-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.25 (s, 1H), 8.14-8.10 (m, 1H), 7.90 (s, 1H), 7.80-7.76 (m, 2H), 7.66 ( s, 1H), 7.59-7.56 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.48 Hz, 1H), 6.72-6.71 (m, 1H), 4.59-4.55 (m, 1H), 4.35-4.31 (m, 1H), 3.82-3.71 (m, 1H), 3.49-3.25 (m, 2H), 3.23-3.15 (m, 1H), 3.07 (s, 3H), 1.66 (s, 6H); 486 [M + H] ⁺ 27 4.1897% 46 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiazol-5-yl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 9.10 (s, 1H), 8.20 (s, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.08-7.02 (m, 2H), 3.78 (s, 3H), 3.54-3.50 ( m, 2H), 3.34-3.20 (m, 1H), 2.89 (t, J = 12.1 Hz, 2H), 2.80 (s, 6H), 2.12-2.02 (m, 2H), 1.95-1.85 (m, 2H) , 1.53 (s, 6 H); 561 [M + H] ⁺ 10 4.06290% 47 2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (1H-pyrazol-3-yl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.89 (s, 1H), 9.79 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 2H), 7.81-7.73 (m, 2H), 7.69 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 6.5 Hz, 1H), 4.44 (d, J = 15.2 Hz, 1H), 4.26-4.20 (m, 1H), 3.20-3.07 (m, 2H), 2.99 (s, 1H), 2.94 (d, J = 4.6 Hz, 4H), 1.42 (s, 6H); 457 [M + H] ⁺ 16 4.00100%

Example 48 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (1-methyl- Preparation of 1H-indol-3-yl) 2-amine

Step 1: Preparation of 3- (2-chloro-5-iodopyrimidin-4-yl) -1H-indole

Indole (2.0 equiv) was added to THF (0.3 M) to dissolve and then slowly added CH ₃ MgBr (2.0 equiv) over 20 minutes while maintaining the temperature at 0 ^° C. under nitrogen. After reacting for 100 minutes at room temperature, 2,4-dichloro-5-iodopyrimidine (1.0 equiv) was added and reacted at 80 ^° C. for 1 hour. The reaction mixture was cooled to room temperature and the metal activity was removed with methanol and then concentrated. The compound was precipitated with CH ₂ Cl ₂ and then the solvent was removed to give the title compound as a pale brown solid. (Yield 95%)

Step 2: Preparation of 3- (2-chloro-5-iodopyrimidin-4-yl) -1-methyl-1H-indole

The compound prepared in Step 1 (1.0 equiv) was added to THF (0.5 M) to dissolve, followed by addition of NaH (1.2 equiv) at 0 ^° C. The reaction mixture was stirred at 0 ^° C. for 30 minutes, then MeI (1.2 equiv) was added and reacted at room temperature for 1 hour. After the reaction, water was added to the reaction mixture, and the formed precipitate was filtered and dried to obtain the target compound as a brown solid. (Yield 95%)

Step 3: Preparation of 3- (2-chloro-5- (furan-3-yl) pyrimidin-4-yl) -1-methyl-1H-indole

The compound prepared in step 2 (1.0 equiv), furan-3-ylboronic acid-pyrazole (1.0 equiv) and 1M Na ₂ CO ₃ (aq, 3.0 equiv) were added to 1,4-dioxane (0.15 M) After melting by dissolving, gas was removed by sonication for 1 minute. Pd (PPh ₃ ) ₄ (0.1 equivalent) was added to the reaction mixture at 100 ^° C., followed by reaction for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, water was added to remove the metal activity, and extracted with EtOAc. The organic layer was removed / filtered with MgSO ₄ , concentrated, and purified by MPLC (EtOAc: Hex) to give the title compound as a yellow solid. (Yield 68%)

Step 4: N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (1-methyl-1H- Preparation of Indol-3-yl) 2-amine

Compound (1.0 equiv), 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in Step 3 above; ) Was added to sec-BuOH (0.1 M) to dissolve and sonicated for 1 minute to remove the gas. Pd ₂ (dba) ₃ (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 80 ^° C., followed by reaction for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The obtained filtrate was concentrated and purified by prep-HPLC to give the title compound as a yellow solid. (Yield 36%)

Examples 49 to 119 were prepared in a similar manner to Example 48, and the chemical structures of Examples 48 to 119 are given in Tables 4 and 5, and the compound names and the results of ¹ H NMR, mass, yield, and HPLC analysis were shown in Table 6 below. In summary, it is shown.

Example Chemical structure Example Chemical structure 48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

Example Chemical structure Example Chemical structure 84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

Example Compound name ¹ H NMR, MS yield
(%) HPLC
rt (min)
Purity 48 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (1-methyl-1H-indole-3 -Yl) 2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.49 (brs, 1H), 8.33-8.27 (m, 2H), 7.84 (s, 1H), 7.78 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29-7.28 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.96- 6.92 (brs, 1H), 6.42 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.49-3.47 (m 2H), 3.33-3.28 (m, 2H), 2.81-2.80 (d , J = 4.4 Hz, 6H), 2.61-2.54 (m, 1H), 2.08-2.05 (m, 2H), 1.80-1.76 (m, 2H); 523 [M + H] ⁺ 36 4.8292% 49 N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline-6 -Amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.37 (d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.44 (s, 1H), 7.28-7.25 (m, 1H), 7.19-7.14 (m, 2H), 6.38 (s, 1H), 4.34 (s, 2 H), 3.75 9 s, 3 H), 3.52-3.49 (m, 2 H), 3.09 (t, J = 6.3 Hz, 2H); 422 [M + H] ⁺ 26 4.86100% 50 N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methyl-1,2,3,4-tetrahydro Isoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.35 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.55-7.52 (m, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.20-7.13 ( m, 2H), 6.40 (s, 1H), 4.55 (d, 16.0 Hz, 1H), 4.32 (d, J = 14.3 Hz), 3. 82-3.74 (m, 1H), 3.74 (s, 3H), 3.41-3.33 (m, 1 H), 3.31-3.24 (m, 1 H), 3.06 (s, 4H); 436 [M + H] ⁺ 9 51 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- (thiophene- 2-yl) 2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.34 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.56 (s , 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.26-7.18 (m, 5H), 7.10 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 3.81 (s, 3H) , 3.75-3.72 (m, 2H), 3.66 (s, 3H), 3.50-3.45 (m, 1H), 3.13-3.11 (m, 2H), 2.94 (s, 6H), 2.30-2.27 (m, 2H) , 2.14-2.06 (m, 2 H); 539 [M + H] ⁺ 29 5.0896% 52 N- (4- (1-methyl-1H-indol-3-yl) -5- (thiophen-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline- 6-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.10 (s, 1H), 7.74 (s, 1H), 7.69-7.50 (m, 4H), 7.46 (d, J = 8.24 Hz, 1H) , 7.38-7.23 (m, 2H), 7.21-7.15 (m, 1H), 7.07 (d, J = 1.32 Hz, 1H), 6.81 (s, 1H). 4.42 (s, 2H), 3.68 (s, 3H), 3.56-3.49 (m, 2H), 3.14-3.12 (m, 2H); 438 [M + H] ⁺ 11 5.0085% 53 N- (5- (isooxazol-4-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline- 6-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.84 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.23 (d, J = 7.96 Hz, 1H), 7.92 (s, 1H), 7.58 (d, J = 8.52 Hz, 1H), 7.47 (d, J = 8.32 Hz, 1H), 7.30-7.26 (m, 1H). 7.18 (s, 1H), 7.18-7.15 (m, 2H), 4.34 (s, 2H), 3.79 (s, 3H), 3.52-3.48 (m, 2H), 3.14-3.07 (m, 2H); 423 [M + H] ⁺ 10 4.8099% 54 N- (4- (1-methyl-1H-indol-3-yl) -5- (1H-pyrazol-4-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.16 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.53 (s, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.04-7.01 (m, 2H), 4.23 (s, 2H), 3.62 (s, 3H), 3.41-3.36 (m, 2H), 2.99-2.96 (m, 2H); 422 [M + H] ⁺ 19 4.24 100% 55 N- (5- (furan-3-yl) -4- (1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.26 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.66-7.64 (m, 2H), 7.57-7.53 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.36 (s, 1H), 4.29 (s, 3H), 3.43-3.40 (m, 2H), 3.02-2.99 (m, 2H ); 408 [M + H] ⁺ 16 4.5498% 56 N- (5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.14 (s, 1H), 8.10-8.07 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H) , 7.47 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.04 -6.98 (m, 2H), 6.78 (s, 1H), 4.23 (s, 2H), 3.58 (s, 3H), 3.40-3.37 (m, 2H), 2.99-2.96 (m, 2H); 451 [M + H] ⁺ 25 4.91100% 57 N- (5- (5-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.37 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 7.3 Hz , 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 4.23 (s, 2H), 3.59 (s, 3H), 3.40 -3.37 (m, 2H), 2.99-2.96 (m, 2H); 451 [M + H] ⁺ 22 4.89100% 58 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- (thiophene- 3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8341 (d, J = 8.0 Hz, 1H), 8.07 (brs, 1H), 7.64 (d, J = 3.0 Hz, 1H), 7.60 (s , 1H), 7.54 (s, 1H), 7.49-7.42 (m, 1H), 7.36-7.29 (m, 2H), 7.23-7.20 (m, 1H), 7.19-7.10 (m, 2H), 6.80 (s , 1H), 3.84 (s, 3H), 3.78-3.75 (m, 2H), 3.69 (s, 3H), 3.49-3.37 (m, 1H), 3.17-3.11 (m, 2H), 2.33-2.30 (m , 2H), 2.17-2.13 (m, 2H); 539 [M + H] ⁺ 14 4.9693% 59 N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra hydroisoquinoline-7 -Amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.20 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.55 (s, 2H), 7.41-7.36 (m, 1H), 7.33-7.30 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.12 (m, 2H), 7.05-7.00 (m, 1H), 6.30 (s, 1H), 4.16 (s, 2H), 3.59 (s, 3H), 3.34-3.32 (m, 2H), 3.02-3.00 (m, 2H); 422 [M + H] ⁺ 31 4.88100% 60 N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine-7-amines ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.18 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.33-7.29 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H) , 6.35 (s, 1H), 3.61 (s, 3H), 3.21 (s, 4H), 3.10-3.07 (m, 2H), 3.02-2.99 (m, 2H); 436 [M + H] ⁺ 25 4.89100% 61 5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.31 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 1.60 Hz, 1H), 7.50 -7.45 (m, 4H), 7.32-7.45 (m, 1H), 7.20 (d, J = 8.92 Hz, 2H), 7.16-7.05 (m, 1H). 6.54 (d, J = 0.92 Hz, 1H), 3.98-3.93 (m, 2H), 3.76 (s, 3H), 3.69-3.66 (m, 2H), 3.48-3.32 (m, 2H), 3.16-3.07 (m, 2 H), 3.01 (s, 3 H); 465 [M + H] ⁺ 18 4.7499% 62 5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indol-3-yl) pyridine Midin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.34 (d, J = 7.76 Hz, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.73-7.72 (m, 1H) , 7.47-7.44 (m, 2H), 7.35 (d, J = 1.88 Hz, 1H), 7.31-7.28 (m, 1H), 7.14-7.08 (m, 3H). 6.51 (d, J = 0.92 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.68-3.61 (m, 4H), 3.48-3.32 (m, 2H), 3.18-3.08 (m, 2H), 2.99 (s, 3H); 495 [M + H] ⁺ 19 4.8396% 63 (S) -5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) pyrimidine 2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.33 (s, 1H), 7.89 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.58-7.42 (m, 4H), 732-7.28 (m, 1H), 7.20 (d, J = 9 Hz.2H), 7.14-7.10 (m, 1H), 6.53 (d, J = 0.88 Hz, 1H), 3.99-3.85 (m , 2H), 3.76 (s, 3H), 3.56 (d, J = 12.16 Hz, 2H), 3.48-3.47 (m, 1H), 3.14-3.10 (m, 1H), 2.90-2.84 (m, 1H), 1.44 (d, J = 6.56 Hz, 3H); 465 [M + H] ⁺ 5 4.8094% 64 (S) -5- (furan-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indole-3 -Yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.35 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.74-7.73 (m, 1H), 7.47-7.45 ( m, 2H), 7.32-7.28 (m, 2H), 7.14-7.09 (m. 3H), 6.52 (d, J = 1.04 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.62 -3.57 (m, 3H), 3.52-3.48 (m, 1H), 3.38-3.32 (m, 1H), 3.05-3.01 (m, 1H), 2.90-2.84 (m, 1H), 1.42 (d, J = 6.44 Hz, 3 H); 495 [M + H] ⁺ 27 4.8797% 65 N- (5- (furan-3-yl) -4- (4-nitro-1H-indol-1-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline-6 -Amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.61 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.67 (s , 1H), 7.51 (d, J = 3.4 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 7.26 (t, J = 8.2 Hz , 1H), 7.21 (d, J = 3.4 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.89 (s, 1H), 4.18 (s, 2H), 3.38 (t, J = 6.2 Hz , 2H), 2.94 (t, J = 6.2 Hz, 2H); 453 [M + H] ⁺ 36 6.27 100% 66 N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) -1H-indole -4-yl) methanesulfonamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.55 (s, 1H), 7.72 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.1 Hz , 1H), 7.38 (s, 1H), 7.33 (s, 1H), 7.17 (s, 1H), 7.11-7.01 (m, 3H), 6.73 (s, 1H), 5.96 (s, 1H), 4.19 ( s, 2H), 3.36 (t, J = 6.2 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H), 2.87 (s, 3H); 501 [M + H] ⁺ 39 5.0597% 67 N- (4- (4-amino-1 H-indol-1-yl) -5- (furan-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline-6 -Amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.60 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.36 (s , 2H), 7.32 (s, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 5.94 (s , 1H), 4.20 (s, 2H), 3.39 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H); 423 [M + H] ⁺ 37 4.3097% 68 N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydro isoquinolin-6-yl) amino) pyrimidin-4-yl) -1H-indole -4-yl) acetamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.55 (s, 1H), 7.76 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.44 (m, 3H), 7.34 (s, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 3.4 Hz , 1H), 5.99 (s, 1H), 4.19 (s, 2H), 3.38 (t, J = 6.2 Hz, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.13 (s, 3H); 465 [M + H] ⁺ 32 4.9595% 69 5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indol-1-yl) pyridine Midin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.70 (s, 1H), 8.17 (d, J = 7.84 Hz, 1H), 8.04 (d, J = 8.24 Hz, 1H), 7.64 (d , J = 3.44 Hz, 1H), 7.59 (d, J = 2.24 Hz, 1H), 7.50 (s, 1H), 7.42-7.41 (m, 1H), 7.33-7.29 (m, 2H), 7.22-7.19 ( m, 1H), 6.94 (d, J = 8.56 Hz, 1H), 5.99 (d, J = 0.96 Hz, 1H), 3.98 (s, 3H), 3.68-3.43 (m, 6H), 3.12-3.00 (m , 2H), 2.96 (s, 3H); 526 [M + H] ⁺ 44 5.71100% 70 1- (5- (furan-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -1H-indole -4-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.70 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 9.88 Hz, 2H), 7.27-7.21 (m, 2H), 7.16 (d, J = 7.56 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H) , 6.04 (s, 1H), 3.73 (s, 3H), 3.57-3.50 (m, 4H), 3.04-2.91 (m, 4H), 2.96 (s, 3H); 496 [M + H] ⁺ 7 4.4391% 71 5- (furan-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indol-1-yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.56 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.56-7.51 (m, 4H), 7.47-7.45 (m, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.23-7.19 (m, 2H), 6.90 (d, J = 7.7 Hz, 1H), 3.67-3.64 (m, 2H), 3.50-3.47 (m, 2H), 2.94-2.81 (m, 5H), 1.96-1.88 (m, 2H); 496 [M + H] ⁺ 67 5.68100% 72 1- (5- (furan-3-yl) -2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -1H-indol-4-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.50 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.29 (s, 3H), 7.21 (s, 1H), 7.01 (t, J = 8.3 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 6.72 (s, 1H), 6.63 (s, 1H), 5.92 (s, 1H), 5.38 (NH, 1H) , 3.44-3.30 (m, 4H), 2.54 (s, 3H), 1.98-1.84 (m, 4H); 466 [M + H] ⁺ 7 4.3790% 73 5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine 2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.12 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.85 (t, J = 8.3 Hz , 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.06-6.95 (m, 4H), 6.76 (s, 1H), 3.78-3.76 (m, 2H), 3.55-3.52 (m, 5H), 3.22-3.20 (m, 2H), 3.01-2.96 (m, 2H), 2.87 (s, 3H); 494 [M + H] ⁺ 21 4.84100% 74 N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indole-3 -Yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.08 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 8.2 Hz , 1H), 7.63 (d, J = 14.0 Hz, 1H), 7.29-7.25 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.01-6.96 (m, 3H), 6.77 (s, 1H), 3.55 (s, 3H), 3.51-3.44 (m, 4H), 3.25-3.22 (m, 2H), 3.04-3.01 (m, 2H), 2.86 (s, 3H); 512 [M + H] ⁺ 20 5.20 100% 75 5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indole-3 -Yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.23-8.14 (m, 3H), 7.96-7.93 (m, 1H), 7.47-7.42 (m, 2H), 7.29-7.25 (m, 1H ), 7.20-7.15 (m, 2H), 7.11-7.04 (m, 2H), 6.92 (s, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.75-3.56 (m, 4H), 3.47-3.32 (m, 2H), 3.20-3.03 (m, 2H), 2.99 (s, 3H); 524 [M + H] ⁺ 69 4.95100% 76 (S) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) Phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.24-8.21 (m, 2H), 8.20 (s, 1H), 8.01-7.93 (m, 1H), 7.55 (d, J = 7.36 Hz, 2H), 7.43 (d, J = 8.24 Hz, 1H), 7.31-7.29 (m, 1H), 7.27-7.09 (m, 4H), 6.87 (s, 1H), 3.88-3.85 (m, 2H), 3.82 (s, 3H), 3.56-3.53 (m, 2H), 3.37-3.34 (m, 1H), 3.20-3.05 (m, 1H), 2.99-2.82 (m, 1H), 1.44 (d, J = 6.56 Hz , 3H); 494 [M + H] ⁺ 49 4.86 100% 77 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H -Indol-3-yl) pyrimidin-2-amine 552 [M + H] ⁺ 37 4.87100% 78 N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyridine Midin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.68 (s, 1H), 8.31 (s, 2H), 7.91 (d, J = 15.4 Hz, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.50-7.45 (m 2H), 7.33 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H), 6.41 (s, 1H), 3.75 (s, 3H), 3.43-3.32 (m, 4H), 3.269-3.20 (m, 2H), 2.99-2.94 (m, 2H), 1.87 ( d, J = 3.5 Hz, 3H); 483 [M + H] ⁺ 26 5.08
100% 79 N- (5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline- 6-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.09 (d, J = 8.9 Hz, 1H), 7.89 (s, 1H), 7.60 (s, 2H), 7.55 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.34 (s, 1H), 4.27 (s, 2H), 3.68 (s, 3H), 3.40 (t, J = 6.2 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H); 438 [M + H] ⁺ 54 4.65
100% 80 N- (5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra Hydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.09 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.59 (d, J = 4.4 Hz, 2H), 7.55 (s , 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.13-7.11 (m, 2H), 6.81 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.31 (s, 1H) , 4.26 (s, 2H), 3.72 (s, 3H), 3.54 (s, 3H), 3.39 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H); 452 [M + H] ⁺ 75 4.89100% 81 N- (4- (1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-4-yl) 6-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.82 (s, 1H), 8.93 (brs, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 8.06 (t, J = 7.9 Hz, 2H), 7.90 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (s, 1H), 4.23 (brs, 2H), 3.69 (s, 3H), 3.40 (brs, 2H), 2.5 ( t, J = 5.9 Hz, 2H); 501 [M + H] ⁺ 5.47100% 82 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -5 -(6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.57 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.8 Hz , 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.19 (s, 2H), 6.80 (s, 1H), 6.67 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.66-3.62 (m, 2H), 3.52 (s, 3H), 3.43 (t, J = 12.0 Hz, 1H), 3.19- 3.09 (m, 2H), 2.83 (s, 6H), 2.23-2.20 (m, 2H), 2.08-2.00 (m, 2H); 632 [M + H] ⁺ 57 5.16 100% 83 4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- (Trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.59 (s, 1H), 8.05 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.7 Hz , 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.80 (s , 1H), 6.65 (s, 1H), 6.59 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 3H), 3.58-3.40 (m, 7H), 3.26-3.20 ( m, 2H), 3.01-2.97 (m, 2H), 2.86 (s, 3H); 604 [M + H] ⁺ 64 5.36100% 84 N- (4- (6-methoxy-1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) 4- Tetrahydroisoquinolin-6-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.55 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.8 Hz , 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.73 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.81 (s , 1H), 6.67-6.64 (m, 2H), 4.24 (s, 2H), 3.74 (s, 3H), 3.52 (s, 3H), 3.41 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.2 Hz, 2H); 531 [M + H] ⁺ 54 5.38 100% 85 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoro pyridin-3-yl) -4- (6-methoxy- 1-methyl-1H-indol-3-yl) pyrimidin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.85 (t, J = 8.2 Hz , 1H), 7.52 (s, 1H), 7.23-7.14 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.65 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.66-3.63 (m, 2H), 3.54 (s, 3H), 3.43 (t, J = 12.0 Hz, 1H), 3.19-3.09 (m, 2H), 2.83 (s, 6H), 2.28-2.16 (m, 2H), 2.12-1.98 (m, 2H); 582 [M + H] ⁺ 68 4.87100% 86 5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpipepe Razin-1-yl) phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.14 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.2 Hz , 1H), 7.26 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.82 (s , 1H), 6.66 (s, 1H), 6.59 (d, J = 7.2 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.55-3.48 (m, 7H), 3.25 (t, J = 11.8 Hz, 2H), 2.99 (t, J = 11.8 Hz, 2H), 2.87 (s, 3H); 554 [M + H] ⁺ 73 4.92100% 87 N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3 , 4-tetrahydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.11 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.83 (t, J = 8.2 Hz , 1H), 7.76 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.80 (s , 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.63 (s, 1H), 4.24 (s, 2H), 3.75 (s, 3H), 3.54 (s, 3H), 3.42 (t, J = 6.2 Hz, 2H), 3.00 (t, J = 6.2 Hz, 2H); 481 [M + H] ⁺ 53 4.9397% 88 N- (4- (6-methoxy-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1,2,3 , 4-tetrahydroisoquinolin-6-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.68 (s, 1H), 8.32 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J = 8.12 Hz, 1H), 7.59-7.57 (m, 1H), 7.21 (d, J = 8.48 Hz, 1H), 6.92 (d, J = 2.04 Hz, 1H), 6.77-6.75 (m, 2H), 4.36 (s, 2H), 3.82 (s, 3H), 3.53-3.50 (m, 2H), 313-3.09 (m, 2H); 517 [M + H] ⁺ 63 5.21 100% 89 N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra Hydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.22-8.21 (m, 2H), 8.14 (d, J = 8.84 Hz, 1H), 7.97-7.91 (m, 1H), 7.89 (d, 1.52 Hz, 1H), 7.57-7.55 (m, 1H), 7.23 (d, J = 8.44 Hz, 1H), 7.16-7.14 (m, 1H), 6.92 (d, J = 2.24 Hz, 1H), 6.77- 6.75 (m, 2H), 4.37 (s, 2H), 3.82 (s, 3H), 3.54-3.50 (m, 2H), 3.13-3.10 (m, 2H); 467 [M + H] ⁺ 40 4.72 100% 90 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -4- (6-methoxy-1H-indol-3-yl) -5- (6- (Trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.70 (s, 1H), 8.27 (s, 1H), 8.09 (d, J = 7.92 Hz, 1H), 8.02 (d, J = 8.6 Hz , 1H), 7.91 (d, J = 8.12 Hz, 1H), 7.72 (s, 1H), 7.32-7.25 (m, 2H), 6.92 (d, J = 1.6 Hz, 1H), 6.78 (s, 1H) , 6.72 (d, J = 8.96 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.75-3.72 (m, 2H), 3.67-3.45 (m, 1H), 3.30-3.19 (m , 2H), 2.96 (s, 6H), 2.35-2.25 (m, 2H), 2.21-2.05 (m, 2H)); 618 [M + H] ⁺ 35 5.0499% 91 4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoro Methyl) pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.71 (d, J = 1.72 Hz, 1H), 8.22 (s, 1H), 8.10-8.07 (m, 1H), 8.00 (d, J = 8.84 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.23-7.20 (m, 1H), 7.05 (d, J = 8.48 Hz, 1H) , 6.91 (d, J = 2.2 Hz, 1H), 6.78 (s, 1H), 6.69-6.67 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.70-3.55 (m, 4H ), 3.45-3.32 (m, 2H), 3.19-3.02 (m, 2H), 2.99 (s, 3H); 590 [M + H] ⁺ 56 5.18 100% 92 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy- 1H-indol-3-yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.25 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.99-7.94 (m, 1H), 7.59 (s, 1H), 7.28-7.17 (m, 3H), 6.92 (d, J = 2.12 Hz, 1H), 6.80 (s, 1H), 6.72-6.69 (m 1H), 3.98 (s, 3H), 3.83 (s, 3H), 3.69-3.74 (m, 2H), 3.61-3.51 (m, 1H), 3.23-3.12 (m, 2H), 2.95 (s, 3H), 2.38-2.24 (m, 2H), 2.22-2.03 (m, 2H); 568 [M + H] ⁺ 42 4.68100% 93 5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1- I) phenyl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.22 (d, J = 2.32 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 8.96 Hz, 1H), 7.96-7.92 (m, 1H), 7.51 (d, J = 2.12 Hz, 1H), 7.22-7.15 (m, 2H), 7.04 (d, J = 8.52 Hz, 1H), 6.91 (d, J = 2.16 Hz, 1H) , 6.78 (s, 1H), 6.79-6.67 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.61-3.58 (m, 4H), 3.45-3.32 (m, 2H), 3.13 -3.03 (m, 2H), 2.99 (s, 3H); 540 [M + H] ⁺ 26 4.71100% 94 N- (4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra Hydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.14-8.09 (m, 3H), 7.83 (t, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.80-6.75 (m, 2H) , 4.25 (s, 2H), 3.40 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H); 455 [M + H] ⁺ 78 4.88100% 95 N- (4- (6-fluoro-1-methyl-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1,2,3 , 4-tetrahydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.14-8.09 (m, 3H), 7.82 (t, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.11-7.01 (m, 3H), 6.85 (t, J = 9.2 Hz, 1H), 6.75 (s, 1H), 4.25 (s, 2H), 3.54 (s, 3H), 3.42 ( t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.2 Hz, 2H); 469 [M + H] ⁺ 32 5.15 100%
96 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1H-indole- 3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.06 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.29 (s, 2H), 7.12 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), (d, J = 8.9 Hz, 1H), 6.41 ( s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.63-3.60 (m, 2H), 3.34 (t, J = 7.9 Hz, 1H), 2.95 (t, J = 11.3 Hz, 2H ), 2.83 (s, 6H), 2.17-2.14 (m, 2H), 2.00-1.87 (m, 2H); 539 [M + H] ⁺ 35 4.61100% 97 5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4-((S) -3-methylpiperazin-1-yl) phenyl) pyri Midin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.01 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.38 (d, J = 7.7 Hz, 2H), 7.30 (s, 1H), 7.09 (d, J = 12.1 Hz, 1H), 6.81 (s, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.42 (s, 1H) , 3.81 (t, Hz, 2H), 3.70 (s, 3H), 3.45 (d, J = 9.8 Hz, 1H), 3.28-3.23 (m, 1H), 3.02 (t, J = 13.3 Hz, 1H), 2.79 (t, J = 13.2 Hz, 1 H), 1.32 (d, J = 6.4 Hz, 3H); 481 [M + H] ⁺ 41 4.60 100% 98 (S) -5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1- (L) phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.01 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.27 (s, 1H) , 7.14 (s, 1H), 6.96 (s, 2H), 6.79 (s, 1H), 6.53 (d, J = 8.2 Hz, 1H), 6.39 (s, 1H), 3.67 (s, 3H), 3.66 ( s, 3H), 3.46-3.35 (m, 4H), 3.27-3.21 (m, 1H), 2.93 (t, J = 10.8 Hz, 1H), 2.76 (t, J = 12.8 Hz, 1H), 1.28 (d , J = 6.4 Hz, 3H); 511 [M + H] ⁺ 53 4.65100% 99 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1H-indol-3-yl) -5- (6- (trifluoromethyl Pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.69 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 8.11-8.06 (m, 2H), 7.88 (d, J = 8 Hz, 1H), 7.79 (s, 1H), 7.42 (d, J = 8.16 Hz, 1H), 7.34-7.32 (m, 1H), 7.27 (d, J = 8.72 Hz, 1H), 7.22-7.18 ( m, 1H), 7.08-7.05 (m, 1H), 6.95 (s, 1H), 3.82 (s, 3H), 3.78-3.69 (m, 2H), 3.57-3.45 (m, 1H), 3.26-3.15 ( m, 2H), 2.96 (s, 6H), 2.35-2.27 (m, 2H), 2.20-2..08 (m, 2H); 588 [M + H] ⁺ 22 5.0597% 100 (S) -4- (1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoromethyl) pyridine-3- (I) pyrimidine-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.71 (s, 1H), 8.22 (s, 1H), 8.12-8.07 (m, 2H), 7.90 (d, J = 8.2 Hz, 1H) , 7.65 (d, J = 8.88 Hz, 2H), 7.40 (d, J = 8.08 Hz, 1H), 7.21-7.18 (m, 1H), 7.13-7.06 (m, 3H), 6.93 (s, 1H), 3.89-3.75 (m, 2H), 3.62-3.46 (m, 2H), 3.42-3.32 (m, 1H), 3.11-2.99 (m, 1H), 2.90-2.79 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H); 530 [M + H] ⁺ 26 5.08 100% 101 (S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl ) Phenyl) 2-pyrimidin-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.26 (d, J = 1.88 Hz, 1H), 8.16-8.04 (m, 2H), 8.00-7.96 (m, 1H), 757 (d, J = 8.88 Hz, 2H), 7.21-7.14 (m, 3H), 6.91 (d, J = 2.16 Hz, 1H), 6.78 (s, 1H), 6.70-6.68 (m, 1H), 3.90-3.85 (m , 2H), 3.84 (s, 3H), 3.63-3.51 (m, 3H), 3.45-3.32 (m, 1H), 3.19-3.03 (m, 1H), 2.87-2.81 (m, 1H), 1.43 (d , J = 6.6 Hz, 3H); 510 [M + H] ⁺ 36 4.63100% 102 (S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3-methylpipepe Razin-1-yl) phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.26 (d, J = 2.44 Hz, 1H), 8.09-8.07 (m, 2H), 8.00-7.95 (m, 1H), 7.42 (d, J = 2.24 Hz, 1H), 7.21-7.16 (m, 2H), 7.08 (d, J = 8.48 Hz, 1H), 6.91 (d, J = 2.24 Hz, 1H), 6.80 (s, 1H), 6.70- 6.67 (m, 1H), 3.98 (s, 3H), 3.80 (s, 3H), 3.68-3.55 (m, 3H), 3.54-3.43 (m, 1H), 3.47-3.38 (m, 1H), 3.11- 2.99 (m, 1 H), 2.92-2.81 (m, 1 H), 1.41 (d, J = 6.44 Hz, 3H); 540 [M + H] ⁺ 20 4.71100% 103 N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl Pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.68 (s, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.93 -7.87 (m, 2H), 7.62 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.21 (t, J = 7.1 Hz, 1H) , 7.15 (s, 1H), 7.04 (t, J = 7.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.71 (s, 6H), 3.35-3.14 (m, 4H), 2.89- 2.88 (m, 7 H); 574 [M + H] ⁺ 16 5.42 100% 104 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4 (1-methyl-1H-indol-3-yl) -5- (6- (tri Fluoromethyl) pyridine-3-pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.66 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.41-7.36 (m, 1H), 7.22-7.14 ( m, 1H), 7.09 (s, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 14.7 Hz, 1H), 3.70 (s, 6H), 3.26-3.20 (m, 4H ), 2.79 (d, J = 4.9 Hz, 6H), 2.65-2.61 (m, 1H), 2.07-2.04 (m, 2H), 1.78-1.76 (m, 2H); 602 [M + H] ⁺ 22 5.24 100% 105 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1-methyl- 1H-indol-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.79 (s, 1H), 9.59 (s, 1H), 8.23 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 6.71 (d, J = 6.6 Hz, 1H), 6.45 (s, 1H), 3.82 (s, 6H), 3.70 (s, 3H), 3.64 (s, 2H), 3.52-3.49 (m, 2H), 3.40-3.30 (m , 2H), 2.80 (d, J = 4.5 Hz, 6H), 2.12-2.09 (m, 2H), 1.91-1.85 (m, 2H); 553 [M + H] ⁺ 43 4.8496% 106 5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1- Yl) phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.53 (s, 1H), 9.42 (s, 1H), 8.21 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 6.99 (s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.41 (s, 1H), 3.80 (s, 3H), 3.68 (s, 6H), 3.52-3.40 (m, 4H), 3.22-3.14 (m, 4H), 2.88-2.82 (m, 5H); 525 [M + H] ⁺ 16 4.85100% 107 (S) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5 (6- (trifluoromethyl) Pyridin-3-yl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.59 (s, 1H), 8.91 (d, J = 9.9 Hz, 1H), 8.70 (s, 1H), 855-8.52 (m, 1H) , 8.39 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 6.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.309 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 3.72-3.63 (m, 5H), 3.21-3.12 (m, 2H), 2.86 (t, J = 12.2 Hz, 1H), 2.68-2.62 (m, 2H), 1.26 (d, J = 6.5 Hz, 3H); 544 [M + H] ⁺ 16 5.3199% 108 4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (4-((S) -3-methylpiperazin-1-yl ) Phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.13 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.40 (s, 2H), 7.09-6.96 (m, 4H), 6.77 (s, 1H), 6.72 (t, J = 8.6 Hz, 1H), 3.81-3.60 (m, 2H), 3.48-3.34 (m, 2H ), 3.28-3.24 (m, 1 H), 3.06-2.89 (m, 1 H), 2.83-2.64 (m, 1 H), 1.31 (d, J = 6.6 Hz, 3 H); 498 [M + H] ⁺ 40 4.76100% 109  (S) -4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3-methylpipe Razin-1-yl) phenyl) pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.12-8.08 (m, 2H), 8.05 (s, 1H), 7.86 (t, J = 8.3 Hz, 1H), 7.34 (s, 1H) , 7.10 (t, J = 8.6 Hz, 2H), 7.01 (d, J = 9.4 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.79 (s, 1H), 6.74 (t, J = 8.3 Hz, 1H), 3.67 (s, 3H), 3.47-3.35 (m, 4H), 3.28-3.24 (m, 1H), 2.93 (t, J = 12.9 Hz, 1H), 2.76 (t, J = 13.1 Hz, 1H), 1.29 (d, J = 6.5 Hz, 3H); 528 [M + H] ⁺ 60 6.03 100% 110 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-fluoro-1H-indol-3-yl) -5- (6- Fluoropyridin-3-yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.24-8.19 (m, 3H), 7.99-7.92 (m, 1H), 7.66 (s, 1H), 7.30 (d, J = 8.76 Hz, 1H), 7.21-7.10 (m, 4H), 6.90-6.82 (m, 2H), 3.98 (s, 3H), 3.82-3.69 (m, 2H), 3.48-3.43 (m, 1H), 3.10-3.07 ( m, 2H), 2.95 (s, 6H), 2.36-2.22 (m, 2H), 2.20-2.02 (m, 2H); 556 [M + H] ⁺ 26
4.79
99% 111 N- (4- (6-fluoro-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1,2,3 , 4-tetrahydroisoquinolin-6-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.67 (s, 1H), 8.37 (s, 1H), 8.22-8.18 (m, 1H), 8.06 (d, J = 7.92 Hz, 1H) , 7.93 (s, 1H), 7.87 (d, J = 8.04 Hz, 1H), 7.62-7.59 (m, 1H), 7.20 (d, J = 8.44 Hz, 1H), 7.12-7.10 (m, 1H), 6.93-6.86 (m, 2H), 4.35 (s, 2H), 3.53-3.48 (m, 2H), 3.13-2.93 (m, 2H); 505 [M + H] ⁺ 34 5.35
99%
112  (S) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H -Indol-3-yl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.25 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.08 Hz, 1H), 8.13 (s, 1H), 7.98-7.94 (m, 1H), 7.45-7.42 (m, 2H), 7.30-7.26 (m, 1H), 7.20-7.16 (m, 2H), 7.12-7.05 (m, 2H), 6.93 (s, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.76-3.55 (m, 3H), 3.52-3.48 (m, 1H), 3.47-3.32 (m, 1H), 3.18-3.08 (m, 1H), 3.02 -2.92 (m, 1 H), 1.41 (d, J = 6,48 Hz, 3H); 524 [M + H] ⁺ 77 4.94100% 113 5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidin-4-yl) phenyl) -4- (1-methyl-1H-indol-3-yl Pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.22 (s, 2H), 8.15 (d, J = 7.72 Hz, 1H), 7.93-7.90 (m, 1H), 7.54 (s, 1H) , 7.43 (d, J = 8.12 Hz, 1H), 7.27-7.22 (m, 2H), 7.18-7.06 (m, 3H), 6.93 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H ), 3.61-3.52 (m, 2H), 3.30-3.02 (m, 3H), 2.19-2.10 (m, 2H), 2.10-1.91 (m, 2H); 509 [M + H] ⁺ 56 5.10 100% 114 5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (piperidin-4-yl) phenyl) pyrimidine-2 -Amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.22 (s, 2H), 8.16-8.14 (m, 1H), 7.95-7.90 (m, 1H), 7.69 (d, J = 8.32 Hz, 2H), 7.42 (d, J = 8.28 Hz, 1H), 7.33 (d, J = 8.32 Hz, 2H), 7.28-7.24 (m, 1H), 7.15-7.07 (m, 2H), 6.91 (s, 1H ), 3.69 (s, 3H), 3.68-3.51 (m, 2H), 3.27-3.12 (m, 2H), 3.11-2.93 (m, 1H), 2.20-2.13 (m, 2H), 2.11-1.92 (m , 2H); 479 [M + H] ⁺ 29 4.96100% 115 5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (piperidine- 4-yl) phenyl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.23 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.97-7.93 (m, 1H) , 7.45 (s, 1H), 7.21-7.16 (m, 3H), 6.93 (d, J = 1.8 Hz, 1H), 6.78 (s, 1H), 6.72-6.70 (m, 1H), 3.86 (s, 3H ), 3.76 (s, 3H), 3.65 (s, 3H), 3.62-3.52 (m, 2H), 3.30-3.29 (m, 1H), 3.27-3.14 (m, 2H), 2.19-2.12 (m, 2H) ), 2.11-1.93 (m, 2H); 539 [M + H] ⁺ 41 5.0599% 116 4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidin-4-yl) Phenyl) pyrimidin-2-amine ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.22-8.20 (m, 2H), 7.96-7.92 (m, 1H), 7.48 (s, 1H), 7.25-7.09 (m, 4H), 6.91 (s, 1H), 6.84-6.80 (m, 1H), 3.76 (s, 3H), 3.58-3.51 (m, 2H), 3.22-3.09 (m, 3H), 2.17-1.92 (m, 4H); 513 [M + H] ⁺ 29 5.0499% 117 3- (5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) -1H- Indole-1-carboxamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.43 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 7.85-7.75 (m, 3H) , 7.55 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.14-7.07 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 3.43 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H); 480 [M + H] ⁺ 29
4.89
100% 118 3- (5- (6-fluoropyridin-3-yl) -2-((3-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -1H Indole-1-carboxamide ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.41 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.76-7.71 (m, 2H) , 7.63 (s, 1H), 7.50 (s, 1H), 7.22-71.6 (m, 2H), 7.09-6.95 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 3.63 (s, 3H ), 3.42-3.39 (m, 2H), 3.13-3.03 (m, 3H), 1.98-1.84 (m, 4H); 538 [M + H] ⁺ 34 5.14100% 119 3- (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridin-3-yl) pyrimidine- 4-yl) -1-carboxamide ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 9.81-9.66 (m, 1H), 8.56 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H) , 7.87 (t, J = 8.1 Hz, 1H), 7.76-7.62 (m, 4H), 7.39 (s, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 2H), 6.98 (NH, 2H), 5.76 (s, 1H), 3.70 (s, 3H), 3.49-3.46 (m, 2H), 3.39-3.24 (m, 1H), 2.80 (s, 6H), 2.78 -2.64 (m, 2H), 2.13-2.02 (m, 2H), 1.93-1.76 (m, 2H); 581 [M + H] ⁺ 36 4.63100%

Example 120 (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropane- 2-yl) pyridin-2-yl) amino) pyrimidin-5-yl) dimethylphosphineoxide

Compound (1.0 equivalent), dimethylphosphine oxite (1.0 equivalent), K ₃ PO ₄ (1.1 equivalent), Pd (OAc) ₂ (0.05 equivalent) and Xantphos (0.05 equivalent) prepared in Step 2 of Example 1 Was dissolved in DMF (0.05 M) and then reacted at 150 ^° C. for 1 hour using microwave. After the reaction, the reaction mixture was purified by prep-HPLC as it is to obtain the title compound as a red liquid. (Yield 11%)

Example 121 (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((3-methoxy-4- (4- (4-methyl Piperazin-1-yl) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphineoxide

(4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((3-methoxy-4- (4 -(4-methylpiperazin-1-yl) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphineoxide was prepared.

Example 122 (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((1,2,3,4-tetrahydroisoquinoline-6 -Yl) amino) pyrimidin-5-yl) dimethylphosphineoxide

(4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((1,2,3,4-tetra) Hydroisoquinolin-6-yl) amino) pyrimidin-5-yl) dimethylphosphineoxide was prepared.

Example 123 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) pyri Preparation of midin-4-yl) amino) pyridin-2-yl) propan-2-ol

The compound prepared in Step 2 of Example 1 (1.0 equiv), methanesulfinic acid (1.2 equiv), N, N'-dimethylethylenediamine (0.2 equiv) and Cu (CF ₃ SO ₃ ) ₂ (0.1 equiv) After dissolving in DMSO (0.33 M), the mixture was reacted at 110 ^° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and the mixture was filtered through celite. The filtered solution was washed sequentially with water and brine, and then water was removed with MgSO ₄ . After filtration, it was concentrated and the compound was purified using prep-HPLC. After concentration, the desired compound in violet liquid was obtained. (Yield 16%)

Example 124 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- ( Preparation of methylsulfonyl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol

2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino by following the same method as in Example 123 above ) -5- (methylsulfonyl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol was prepared.

Example 125 2- (6-((5- (methylsulfonyl) -2 ((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino Preparation of Pyridin-2-yl) propan-2-ol

2- (6-((5- (methylsulfonyl) -2 ((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol was prepared.

Example 126 2- (6-((2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (methylsulfonyl) pyrimidine-4 Preparation of -yl) amino) pyridin-2-yl) propan-2-ol

2- (6-((2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (methylsulfonyl ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol.

Example 127 2- (6-((5- (methylsulfonyl) -2-((1,2,3,4-tetra hydroisoquinolin-7-yl) amino) pyrimidin-4-yl) Preparation of Amino) pyridin-2-yl) propan-2-ol

2- (6-((5- (methylsulfonyl) -2-((1,2,3,4-tetra hydroisoquinolin-7-yl) amino) pyrimidine was carried out in the same manner as in Example 123. -4-yl) amino) pyridin-2-yl) propan-2-ol was prepared.

Example 128 2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) -5- (methylsulfonyl) pyrimidine- Preparation of 4-yl) amino) pyridin-2-yl) propan-2-ol

2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) -5- (methylsul Phonyl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol.

Example 129 2- (6-((2- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) pyrimidine-4 Preparation of -yl) (methyl) amino) -2-yl) propan-2-ol

2- (6-((2- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) by following the same method as in Example 123, ) Pyrimidin-4-yl) (methyl) amino) -2-yl) propan-2-ol.

Example 130 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5 Preparation of-(methylsulfonyl) pyrimidin-2-amine

N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indole-3 was carried out in the same manner as in Example 123. -Yl) -5- (methylsulfonyl) pyrimidin-2-amine was prepared.

Example 131 2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -4- (6- (2-hydroxypropan-2-yl) Preparation of Pyridin-2-ylamino) -N, N-dimethylpyrimidine-5-carboxamide

Step 1: Preparation of 2,4-dichloro-N, N-dimethylpyrimidine-5-carboxamide

2,4-dichloropyrimidine-5-carbonylchloride (1.0 equiv) was added to CH ₂ Cl ₂ (0.1 M) to dissolve, followed by addition of dimethylamine (0.8 equiv) and TEA (0.8 equiv) at 0 ^° C. After that, the reaction was performed at room temperature for 3 hours. Water was poured into the reaction mixture, followed by extraction with CH ₂ Cl _2. (X3) The combined organic layers were removed with MgSO ₄ . After filtration, it was concentrated and the compound was purified by MPLC (EtOAc: Hex). After concentration, the desired compound was obtained as a light yellow liquid. (Yield 77%)

Step 2: Preparation of 2-chloro-4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethylpyrimidine-5-carboxamide

The compound prepared in Step 1 (1.0 equiv) was dissolved in 1,4-dioxane (0.1 M), followed by 2- (6-aminopyridin-2-yl) propan-2-ol (1.0 equiv) DIPEA (1.0 equiv) was added at room temperature and reacted at 110 ^° C. for 18 hours. The reaction mixture was cooled to room temperature, poured with water and extracted with EtOAc (x3). The combined organic layers were brine and then water was removed with MgSO ₄ . After filtration, it was concentrated and the compound was purified using MPLC (ETOAC: Hex). After concentration, the desired compound was obtained as a yellow solid. (Yield 52%)

Step 3: 2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -4- (6- (2-hydroxypropan-2-yl) pyridine- Preparation of 2-ylamino) -N, N-dimethylpyrimidine-5-carboxamide

Compound (1.0 equiv), 1- (4-amino-2-methoxyphenyl) -N, N-dimethylpiperidin-4-amine (1.0 equiv) and K ₂ CO ₃ (5.0 equiv) prepared in Step 2; ) Was added to sec-BuOH (0.3 M) to dissolve and sonicated for 1 minute to remove the gas. Pd ₂ (dba) ₃ (0.1 equiv) and Xphos (0.1 equiv) were added to the reaction mixture at 100 ^° C., followed by reaction for 2 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The obtained filtrate was concentrated and then purified by prep-HPLC to obtain the target compound as a violet liquid. (Yield 22%)

Example 132 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((1,2,3,4-tetra Preparation of Hydroisoquinolin-6-yl) amino) pyrimidine-5-carboxamide

In the same manner as in Example 131, 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((1,2, 3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine-5-carboxamide was prepared.

Example 133 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((2-methyl-1,2,3 Preparation of, 4-tetrahydroisoquinolin-6-yl) pyridin-2-yl) amino) pyrimidine-5-carboxamide

In the same manner as in Example 131, 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl) pyridin-2-yl) amino) pyrimidine-5-carboxamide was prepared.

Example 134 (S) -4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((4- (3- Preparation of Methylpiperazin-1-yl) phenyl) amino) pyrimidine-5-carboxamide

In the same manner as in Example 131, (S) -4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-(( 4- (3-methylpiperazin-1-yl) phenyl) amino) pyrimidine-5-carboxamide was prepared.

Example 135 (R) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) -2- (3-methoxy-4- (3-methylpiperazin- Preparation of 1-yl) phenylamino) -N, N-dimethylpyrimidine-5-carboxamide

In the same manner as in Example 131, (R) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) -2- (3-methoxy-4- (3 -Methylpiperazin-1-yl) phenylamino) -N, N-dimethylpyrimidine-5-carboxamide was prepared.

Example 136 2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropane-2) Preparation of -yl) pyridin-2-yl) amino) -N-methylpyrimidine-5-carboxamide

In the same manner as in Example 131, 2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2- Hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methylpyrimidine-5-carboxamide was prepared.

Example 137 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methyl-2-((1,2,3,4-tetra hydroiso) Preparation of Quinolin-6-yl) amino) pyrimidine-5-carboxamide

In the same manner as in Example 131, 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methyl-2-((1,2,3, 4-tetra hydroisoquinolin-6-yl) amino) pyrimidine-5-carboxamide was prepared.

The chemical structures of the compounds prepared in Examples 120 to 137 are shown in Table 7 below, and the compound names, ¹ H NMR, mass, yield, and HPLC analysis results are summarized in Table 8 below.

Example Chemical structure Example Chemical structure 120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

Example Compound name ¹ H NMR, MS yield
(%) HPLC
rt (min)
Purity 120  (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropan-2-yl) pyridine -2-yl) amino) pyrimidin-5-yl) dimethylphosphineoxide 554 [M + H] ⁺ 11 4.22100% 121  (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((3-methoxy-4- (4- (4-methylpiperazin-1- 1) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphineoxide ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 11.13 (s, 1H), 9.70 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.27 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.09-7.07 (m, 1H), 3.84 (s, 3H), 3.51- 3.49 (m, 3H), 3.39-3.37 (m, 2H), 3.16 (brs, 4H), 2.74 (s, 7H), 2.12 (brs, 2H), 1.86 (d, J = 14.0 Hz, 8H), 1.41 (s, 6 H); 609 [M + H] ⁺ 26 4.17100% 122  (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) Pyrimidin-5-yl) dimethylphosphineoxide 453 [M + H] ⁺ 23 3.89100% 123 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5 (methylsulfonyl) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.02 (s, 1H), 9.53 (s, 1H), 9.39 (s, 1H), 8.53 (s, 1H), 7.95-7.90 (m, 1H), 7.22 (d, J = 12.2 Hz, 1H), 7.10 (brs, 2H), 6.92 (d, J = 8.6 Hz, 1H), 3.77 (s, 3H), 3.50-3.47 (m, 2H), 3.33 (s, 3H), 3.30-3.26 (m, 2H), 2.80 (d, J = 5.0 Hz, 6H), 2.63 (t, J = 10.3 Hz, 1H), 2.08-2.05 (m, 2H), 1.80 -1.75 (m, 2H), 1.43 (s, 6H); 556 [M + H] ⁺ 16 4.37100% 124 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (methylsulfonyl) pyri Midin-4-yl) amino) pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.73 (s, 1H), 8.21-8.03 (m, 1H), 8.01-7.88 (m, 1H), 7.83-7.80 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.48-7.41 (m, 2H), 3.96 (s, 3H), 3.86-3.75 (m, 2H), 3.73-3.63 (m, 2H), 3.61-3.35 ( m, 5H), 3.41 (s, 3H), 3.22-3.02 (m. 4H), 2.30-2.09 (m, 4H), 1.60 (s, 6H); 611 [M + H] ⁺ 32 4.38 100% 125 2- (6-((5- (methylsulfonyl) -2 ((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine-2- (1) propan-2-ol 455 [M + H] ⁺ 16 4.2793% 126 2- (6-((2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, DMSO- d ₆ ) δ 10.24 (s, 1H), 9.90 (s, 1H), 9.43 (s, 1H), 8.55 (s, 1H), 7.77 (s, 1H) , 7.58 (s, 1H), 7.57-7.41 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 4.28-4.22 (m, 1H), 3.14-3.08 (m, 2H), 3.08-2.93 (m, 5H), 1.41 (s, 6H); 469 [M + H] ⁺ 78 4.35 100% 127 2- (6-((5- (methylsulfonyl) -2-((1,2,3,4-tetra hydroisoquinolin-7-yl) amino) pyrimidin-4-yl) amino) pyridine-2 -Yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.62 (s, 1H), 8.29-8.17 (m, 1H), 7.98-7.82 (m, 1H), 7.73-7.51 (m, 2H), 7.45 (d, J = 7.68 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.54-3.51 (m, 2H), 3.25 (s, 3H), 3.14-3.10 (m, 2 H), 1.58 (s, 6 H); 455 [M + H] ⁺ 21 4.32 100% 128 2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) amino Pyridin-2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.66 (s, 1H), 8.11 (s, 1H), 8.02-7.86 (m, 1H), 7.78-7.57 (m, 2H), 7.48 ( d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.48 Hz, 1H), 4.65-4.47 (m, 1H), .4.45-4.31 (m, 1H), 3.92-3.84 (m, 1H), 3.59-3.43 (m, 2H), 3.27 (s, 3H), 3.25-3.19 (m, 1H), 3.07 (s, 3H), 1.60 (s, 6H); 469 [M + H] ⁺ 37 4.34
100% 129 2- (6-((2- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) pyrimidin-4-yl) (methyl ) Amino) -2-yl) propan-2-ol ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.71 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.50 (s, 1H), 7.14 (d, J = 7.5 Hz , 1H), 7.00 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 3.51-3.48 (m, 3H), 3.34 (s, 3H), 2.95-2.89 (m, 2H), 2.79 ( s, 6H), 2.12-2.09 (m, 2H), 1.93-1.89 (m, 2H), 1.29 (s, 6H); 570 [M + H] ⁺ 6 4.2494% 130 N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- (methylsulfonyl Pyrimidin-2-amine ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.97 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.32-7.29 (m, 1H), 7.24 (s, 1H), 7.14-7.10 (m, 2H), 3.94 (s, 3H), 3.64-3.62 (m, 4H), 3.46-3.41 (m, 2H), 3.13-3.12 (m, 2H), 2.93 (s, 9H), 2.25-2.22 (m, 2H), 2.07-2.02 (m, 2H); 535 [M + H] ⁺ 18 4.67100% 131 2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-yl Amino) -N, N-dimethylpyrimidine-5-carboxamide ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.42 (s, 1H), 8.19-8.07 (m, 1H), 7.80 (d, J = 8.16 Hz, 1H), 7.56 (s, 1H) , 7.51 (d, J = 7.68 Hz, 1H), 7.25-7.16 (m, 2H), 3.93 (s, 3H), 3.71-3.68 (m, 2H), 3.48-3.43 (m, 1H), 3.18 (s , 6H), 3.14-3.05 (m, 2H), 2.29-2.26 (m, 2H), 2.94 (s, 6H), 2.14-2.06 (m, 2H), 1.69 (s, 6H); 549 [M + H] ⁺ 22 3.9199% 132 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((1,2,3,4-tetrahydroisoquinoline-6 -Yl) amino) pyrimidine-5-carboxamide ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.46 (s, 1H), 8.23-8.19 (m, 1H), 7.73 (d, J = 8.52, 1H), 7.68 (s, 1H), 7.61 (d, J = 8.36 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.44 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 2H ), 3.18-3.13 (m, 8 H), 1.69 (s, 6 H); 448 [M + H] ⁺ 47 3.9996% 133 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((2-methyl-1,2,3,4-tetrahydro Isoquinolin-6-yl) pyridin-2-yl) amino) pyrimidine-5-carboxamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.46 (s, 1H), 8.25-8.12 (m, 1H), 7.77-7.73 (m, 2H), 7.62 (d, J = 8.44 Hz, 1H), 7.52 (d, J = 7.88 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.58-4.55 (m, 1H), 4.34-4.31 (m, 1H), 3.85-.374 ( m, 2H), 3.18 (s, 6H), 3.07 (s, 3H), 2.21-2.16 (m, 1H), 2.13-2.01 (m, 1H), 1.60 (s, 6H); 462 [M + H] ⁺ 11 4.02.99% 134 (S) -4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((4- (3-methylpiperazin-1 -Yl) phenyl) amino) pyrimidine-5-carboxamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.34 (s, 1H), 8.29-8.02 (m, 1H), 7.77 (d, J = 8.32 Hz, 1H), 7.56 (d, J = 7.88 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 9 Hz, 2H), 3.84-3.77 (m, 2H), 3.53-3.50 (m, 3H), 3.17 ( s, 6H), 3.07-3.00 (m, 1H), 2.84-2.78 (m, 1H), 1.65 (s, 6H), 1.43 (d, J = 6.6 Hz, 3H); 491 [M + H] ⁺ 2 4.0998% 135 (R) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) -2- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl Amino) -N, N-dimethylpyrimidine-5-carboxamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.39 (s, 1H), 8.21-7.95 (m, 1H), 7.79 (d, J = 8.28, 1H), 7.50 (d, J = 7.68 Hz, 1H), 7.42 (s, 1H), 7.17-7.04 (m, 1H), 7.04 (d, J = 8.52 Hz, 1H), 3.98 (s, 3H), 3.68-3.52 (m, 4H), 3.18 (s, 6H), 3.03-2.96 (m, 1H), 2.85-2.79 (m, 1H), 1.66 (s, 6H), 1,40 (d, J = 6.52 Hz, 3H); 521 [M + H] ⁺ 10 4.15 100% 136 2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropan-2-yl) pyridine- 2-yl) amino) -N-methylpyrimidine-5-carboxamide ^{1 H NMR (400 MHz, TFA} salt, MeOD- d 4) δ 8.78 (s, 1H), 8.25-8.09 (m, 1H), 7.77 (d, J = 8.2, 1H), 7.54 (s, 1H), 7.51 (d, J = 7.72 Hz, 1H), 7.37-7.19 (m, 2H), 3.94 (s, 3H), 3.72-3.69 (m, 2H), 3.50-3.47 (m, 1H), 3.18-3.12 ( m, 2H), 2.95 (s, 9H), 2.31-2.28 (m, 2H), 2.14-2.11 (m, 2H), 1.68 (s, 6H); 535 [M + H] ⁺ 8 4.0399% 137 4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methyl-2-((1,2,3,4-tetra hydroisoquinolin-6-yl ) Amino) pyrimidine-5-carboxamide ¹ H NMR (400 MHz, TFA salt, MeOD- d ₄ ) δ 8.76 (s, 1H), 8.18-8.07 (m, 1H), 7.81 (d, J = 7.68 Hz, 1H), 7.64 (s, 1H) , 7.61 (d, J = 8.32 Hz, 1H), 7.49 (d, J = 7.72 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.32 (s, 2H), 3.55-3.51 (m, 2H), 3.16-3.13 (m, 2H), 2.94 (s, 3H), 1.67 (s, 6H); 434 [M + H] ⁺ 13 4.0999%

Experimental Example 1 Evaluation of Wee1 Kinase Inhibitory Activity

In order to evaluate the inhibitory activity of Wee1 kinase of the compound represented by Formula 1 according to the present invention, the following experiment was performed.

Recombinant Wee1 kinase (Invitrogen, Carlsbad, CA), 3.4umol / l poly G: T (4: 1) (Signal Chem, Richmond, BC, Canada), 20 μmol / L ATP (Invitrogen, Carlsbad, CA) in 384-well plates ) Was added to the kinase reaction buffer (40 mmol / L TrisHCl, 10 mmol / L MgCl 2 and 0.1 μg / μL bovine serum albumin (BSA)) and mixed. Examples 1-21 compounds according to the present invention were added at concentrations of 1 μM or less, more than 1 μM to 10 μM, more than 10 μM to 100 μM and more than 100 μM, respectively, and then reacted in a 30 ° C. incubator for 1 hour. After the reaction was completed, the same amount of Kinase-Glo (Promega, Madison, WI) solution was added for 1 hour and the detection solution was added for 10 minutes at room temperature. microplate reader enzyme linked immunosorbent assay (ELISA microplate reader;, Bio-Tek) by measuring the amount of luciferase (luciferase) was calculated by using the IC ₅₀ values for kinase. The results are shown in Table 9 below.

IC ₅₀ values of the measured kinases are classified as Class A when less than 10 nM, Class C when 10 to 100 nM, and Class B when greater than 100 nM.

Example Enzyme activity
Wee1 Example Enzyme activity
Wee1 One B 70 C 2 B 71 C 3 C 72 C 4 C 73 C 5 B 74 B 6 C 75 A 7 C 76 C 8 B 77 B 9 B 78 B 10 B 79 B 11 C 80 C 12 B 81 B 13 C 82 C 14 C 83 C 15 C 84 C 16 C 85 B 17 C 86 B 18 C 87 B 19 C 88 C 20 C 89 A 21 C 90 C 22 C 91 C 23 B 92 A 24 C 93 B 25 C 94 B 26 B 95 B 27 C 96 B 28 B 97 B 29 C 98 B 30 C 99 C 31 B 100 C 32 C 101 B 33 C 102 B 34 A 103 C 35 C 104 C 36 B 105 B 37 B 106 B 38 C 107 C 39 C 108 A 40 C 109 A 41 C 110 A 42 C 111 C 43 B 112 B 44 A 113 A 45 B 114 B 46 A 115 A 47 C 116 C 48 A 117 A 49 A 118 B 50 A 119 B 51 B 120 C 52 - 121 C 53 - 122 C 54 B 123 B 55 C 124 C 56 B 125 B 57 B 126 C 58 B 127 A 59 B 128 A 60 - 129 B 61 B 130 B 62 B 131 C 63 - 132 C 64 B 133 C 65 C 134 C 66 B 135 C 67 B 136 - 68 B 137 - 69 C

As shown in Table 9 above,

Example compounds of the present invention was confirmed to exhibit excellent inhibitory activity against Wee1 kinase.

Therefore, the compound represented by Formula 1 according to the present invention can be usefully used for the treatment of diseases related to Wee1 kinase activity.

Experimental Example 2 Evaluation of Cell Proliferation Inhibitory Activity of Liver Cancer Cell Lines

In order to evaluate the cell proliferation inhibitory activity of the liver cancer cell line of the compound represented by the formula (1) according to the present invention was carried out the following experiment.

Huh7 cells (manufacturer: Rinken cell bank), a liver cancer cell line, were placed in 96-well plates at a concentration of 3000 cells / well, and cultured for 24 hours to attach the cells to the culture vessel. In the medium, 1-14 compounds were dissolved in concentrations of 1 μM or less, 1 μM or more and 10 μM or less, 10 μM to 100 μM and 100 μM or more, and then replaced with well plates containing cells and incubated for 72 hours. Then MTS (3,-(4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium salt, Promega) solution One hour after 20 μl was added to each well, EC ₅₀ was calculated by measuring absorbance at a wavelength of 490 nm using a microplate ELISA reader (Bio-Tek). The results are shown in Table 10 below.

In Table 10, A is 0.1 μM or less, B is greater than 0.1 μM to 1 μM or less, and C is greater than 1 μM to 100 μM or less.

Example Cellular activity
Huh7 Example Cellular activity
Hep7 One C 70 C 2 C 71 C 3 C 72 C 4 C 73 B 5 C 74 B 6 A 75 B 7 C 76 B 8 C 77 B 9 C 78 B 10 B 79 A 11 B 80 A 12 C 81 B 13 B 82 B 14 C 83 C 15 C 84 B 16 B 85 B 17 C 86 C 18 B 87 B 19 C 88 C 20 A 89 B 21 B 90 C 22 B 91 C 23 B 92 B 24 C 93 B 25 C 94 B 26 B 95 B 27 C 96 A 28 C 97 C 29 C 98 B 30 B 99 B 31 B 100 B 32 C 101 C 33 C 102 C 34 B 103 C 35 A 104 C 36 B 105 C 37 C 106 B 38 C 107 B 39 B 108 B 40 B 109 B 41 B 110 B 42 B 111 C 43 C 112 C 44 B 113 C 45 C 114 C 46 C 115 C 47 C 116 C 48 B 117 C 49 A 118 C 50 B 119 C 51 B 120 C 52 B 121 C 53 C 122 C 54 B 123 C 55 B 124 C 56 B 125 C 57 B 126 C 58 B 127 C 59 B 128 C 60 C 129 C 61 B 130 C 62 B 131 C 63 C 132 C 64 B 133 C 65 B 134 C 66 C 135 C 67 C 136 C 68 C 137 C 69 C

As shown in Table 10 above,

Example compounds according to the present invention can be seen that exhibits the ability to inhibit liver cancer cell proliferation.

Therefore, the compound represented by the formula (1) according to the present invention can be usefully used for the treatment of cancer, in particular for the treatment of liver cancer.

Experimental Example 3 Evaluation of Cell Proliferation Inhibitory Activity in Cancer Cell Lines and Other Cancer Cell Lines

CCK analysis was performed to evaluate the effect of inhibiting cancer cell proliferation (cancer cell death) of the compound represented by Formula 1 according to the present invention. Specifically, cancer cell lines A431 (epithelial carcinoma), NCI-H23 (lung cancer), HT29 (colon cancer), T47D (breast cancer, mammary cancer), KG-1 (leukemia, leukemia ) And UWB1.289 (ovarian cancer) cell lines were analyzed and cultured using media appropriate for each cell.

More specifically, A431 (KCLB), NCI-H23 (ATCC), HT29 (ATCC), T47D (ATCC), KG-1 (ATCC) and UWB1.289 (ATCC) are each well of a 96-well plate (Corning). on each ^{5 x 10 3/100 ㎕,} 5 x 10 3/100 ㎕, 3 x 10 3/100 ㎕, 5 x 10 3/100 ㎕, 2 x 10 4/100 ㎕, 3 x 10 3/100 ㎕ Plated and attached for 1 day. After the culture was removed, the mixture was replaced with a culture medium containing nine concentrations (0.0015-10 μM) of serial dilutions and DMSO control, which were serially diluted in multiples of 3, and then incubated for 72 hours in a 37 ℃ CO ₂ incubator. After 72 hours, the plate treated with the compound is taken out and the Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution is mixed well after 10 μl / well treatment. Incubate for 2 hours in a 37 ° C. CO ₂ incubator and measure the absorbance at 450 nm with a microplate reader. Data are expressed as percentages relative to vehicle reference treated cells and GI ₅₀ values were calculated using GraphPad Prism 5.0 (GraphPad software Inc., San Diego).

In Table 11, A is 1 μM or less, B is greater than 1 μM to 10 μM or less, and C is greater than 10 μM to 100 μM.

Example Cellular activity (GI ₅₀ ) A431 NCI-H23 HT29 T47D KG-1 UWB1.289 68 B B B B A B 117 B C B A A A 77 B B B A A B 89 A B A A A A

As shown in Table 11 above,

Example compounds of the present invention are A431 (epithelial carcinoma), NCI-H23 (lung cancer), HT29 (colon cancer), T47D (breast cancer, mammary cancer), KG-1 (leukemia, leukemia) and UWB1.289 (ovarian cancer) cell lines.

Therefore, the compound represented by the formula (1) according to the present invention can be usefully used for the treatment of cancer, in particular, epithelial cell cancer, lung cancer, colon cancer, breast cancer, leukemia, ovarian cancer.

Experimental Example 4 Kinase Inhibitory Activity Evaluation Experiment

In order to evaluate the inhibitory activity of more compounds of the compound represented by Formula 1 according to the present invention, the following experiment was performed.

Specifically, in Examples 8, 49, and 120 selected among the compound compounds of the present nickname, the enzyme (kinase) selectivity was determined by requesting DiscoverX, and a panel for the scanMAX ^TM Kinase assay was prepared. The experiment was conducted using.

At this time, the concentration of the drug to be treated in the enzyme was set to 1 uM in DMSO, and the percentage control (% control) was determined in the same manner as in the following formula 1, the results are shown in Table 12-16.

[Equation 1]

(Example Compound-Positive Control) / (Negative Control-Positive Control) × 100

Herein, the positive control refers to a compound exhibiting a control percentage of 0%, and the negative control indicates a control percentage of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for that enzyme if the percentage control for each enzyme was <35% (ie less than 35%).

Kinase Example 8 Example 49 Example 120 AAK1 84.0 55.0 28.0 ABL1 (E255K) -phosphorylated 4.2 5.8 45.0 ABL1 (F317I) -nonphosphorylated 60.0 63.0 93.0 ABL1 (F317I) -phosphorylated 76.0 65.0 84.0 ABL1 (F317L) -nonphosphorylated 37.0 43.0 97.0 ABL1 (F317L) -phosphorylated 13.0 41.0 78.0 ABL1 (H396P) -nonphosphorylated 2.2 7.0 36.0 ABL1 (H396P) -phosphorylated 11.0 17.0 67.0 ABL1 (M351T) -phosphorylated 11.0 16.0 69.0 ABL1 (Q252H) -nonphosphorylated 7.7 7.6 48.0 ABL1 (Q252H) -phosphorylated 13.0 7.2 43.0 ABL1 (T315I) -nonphosphorylated 94.0 21.0 91.0 ABL1 (T315I) -phosphorylated 81.0 24.0 51.0 ABL1 (Y253F) -phosphorylated 14.0 21.0 63.0 ABL1-nonphosphorylated 17.0 12.0 80.0 ABL1-phosphorylated 11.0 3.2 54.0 ABL2 53.0 31.0 92.0 ACVR1 90.0 88.0 78.0 ACVR1B 89.0 93.0 76.0 ACVR2A 100.0 100.0 92.0 ACVR2B 100.0 83.0 100.0 ACVRL1 90.0 100.0 100.0 ADCK3 89.0 83.0 94.0 ADCK4 31.0 88.0 82.0 AKT1 100.0 100.0 100.0 AKT2 89.0 86.0 100.0 AKT3 100.0 100.0 100.0 ALK 50.0 66.0 43.0 ALK (C1156Y) 45.0 85.0 44.0 ALK (L1196M) 40.0 68.0 55.0 AMPK-alpha1 80.0 19.0 82.0 AMPK-alpha2 74.0 29.0 96.0 ANKK1 94.0 89.0 80.0 ARK5 72.0 2.4 6.8 ASK1 100.0 100.0 100.0 ASK2 85.0 90.0 88.0 AURKA 97.0 51.0 71.0 AURKB 90.0 20.0 87.0 AURKC 83.0 100.0 98.0 AXL 36.0 68.0 77.0 BIKE 85.0 6.7 83.0 BLK 3.6 18.0 100.0 BMPR1A 98.0 79.0 95.0 BMPR1B 86.0 74.0 39.0 BMPR2 22.0 93.0 34.0 BMX 87.0 74.0 100.0 BRAF 96.0 100.0 100.0 BRAF (V600E) 100.0 100.0 98.0 BRK 68.0 92.0 100.0 BRSK1 100.0 100.0 100.0 BRSK2 99.0 96.0 100.0 BTK 39.0 56.0 66.0 BUB1 36.0 54.0 94.0 CAMK1 93.0 78.0 54.0 CAMK1B 73.0 75.0 100.0 CAMK1D 86.0 85.0 63.0 CAMK1G 96.0 85.0 78.0 CAMK2A 100.0 88.0 76.0 CAMK2B 100.0 98.0 82.0 CAMK2D 94.0 96.0 86.0 CAMK2G 100.0 100.0 87.0 CAMK4 81.0 100.0 100.0 CAMKK1 98.0 96.0 78.0 CAMKK2 100.0 100.0 86.0 CASK 78.0 80.0 84.0 CDC2L1 100.0 99.0 100.0 CDC2L2 95.0 80.0 97.0 CDC2L5 100.0 67.0 74.0 CDK11 93.0 100.0 84.0 CDK2 100.0 97.0 100.0 CDK3 97.0 96.0 100.0 CDK4 71.0 55.0 100.0 CDK4-cyclinD1 65.0 24.0 99.0 CDK4-cyclinD3 99.0 100.0 72.0 CDK5 98.0 85.0 91.0 CDK7 4.5 6.9 14.0 CDK8 100.0 80.0 91.0 CDK9 95.0 84.0 92.0 CDKL1 87.0 22.0 77.0 CDKL2 98.0 0.0 85.0 CDKL3 98.0 8.3 86.0 CDKL5 100.0 96.0 94.0 CHEK1 64.0 95.0 66.0 CHEK2 84.0 100.0 66.0 CIT 75.0 89.0 100.0 CLK1 6.1 19.0 90.0 CLK2 11.0 27.0 56.0 CLK3 76.0 81.0 94.0 CLK4 12.0 11.0 82.0 CSF1R 20.0 0.3 66.0 CSF1R-autoinhibited 37.0 0.2 100.0 CSK 40.0 80.0 93.0 CSNK1A1 27.0 42.0 72.0 CSNK1A1L 45.0 82.0 98.0 CSNK1D 87.0 49.0 91.0 CSNK1E 92.0 59.0 97.0 CSNK1G1 100.0 91.0 95.0 CSNK1G2 99.0 47.0 96.0 CSNK1G3 98.0 72.0 100.0 CSNK2A1 4.5 22.0 2.2 CSNK2A2 1.6 1.2 0.4 CTK 96.0 100.0 51.0

Kinase Example 8 Example 49 Example 120 DAPK1 34.0 79.0 23.0 DAPK2 61.0 91.0 58.0 DAPK3 57.0 87.0 30.0 DCAMKL1 43.0 64.0 21.0 DCAMKL2 90.0 67.0 85.0 DCAMKL3 92.0 65.0 100.0 DDR1 3.0 5.3 79.0 DDR2 27.0 18.0 90.0 DLK 79.0 15.0 16.0 DMPK 100.0 100.0 100.0 DMPK2 100.0 60.0 95.0 DRAK1 92.0 94.0 35.0 DRAK2 86.0 87.0 75.0 DYRK1A 47.0 9.6 70.0 DYRK1B 79.0 0.0 99.0 DYRK2 73.0 28.0 62.0 EGFR 7.1 35.0 93.0 EGFR (E746-A750del) 3.0 18.0 62.0 EGFR (G719C) 39.0 82.0 94.0 EGFR (G719S) 27.0 89.0 72.0 EGFR (L747-E749del, A750P) 0.1 7.6 96.0 EGFR (L747-S752del, P753S) 0.0 14.0 52.0 EGFR (L747-T751del, Sins) 0.9 7.1 97.0 EGFR (L858R) 3.4 36.0 95.0 EGFR (L858R, T790M) 20.0 21.0 23.0 EGFR (L861Q) 4.3 15.0 95.0 EGFR (S752-I759del) 1.9 23.0 71.0 EGFR (T790M) 24.0 34.0 27.0 EIF2AK1 76.0 67.0 75.0 EPHA1 18.0 63.0 69.0 EPHA2 47.0 63.0 91.0 EPHA3 91.0 52.0 86.0 EPHA4 55.0 70.0 100.0 EPHA5 58.0 84.0 100.0 EPHA6 45.0 48.0 100.0 EPHA7 75.0 90.0 100.0 EPHA8 78.0 91.0 95.0 EPHB1 5.0 41.0 98.0 EPHB2 57.0 68.0 100.0 EPHB3 92.0 73.0 99.0 EPHB4 16.0 56.0 96.0 EPHB6 100.0 13.0 81.0 ERBB2 34.0 57.0 100.0 ERBB3 85.0 15.0 100.0 ERBB4 46.0 88.0 93.0 ERK1 100.0 97.0 100.0 ERK2 100.0 90.0 98.0 ERK3 87.0 49.0 87.0 ERK4 100.0 95.0 100.0 ERK5 95.0 100.0 100.0 ERK8 90.0 44.0 100.0 ERN1 17.0 72.0 39.0 FAK 34.0 86.0 81.0 FER 90.0 95.0 98.0 FES 93.0 70.0 100.0 FGFR1 40.0 19.0 90.0 FGFR2 71.0 35.0 88.0 FGFR3 67.0 47.0 100.0 FGFR3 (G697C) 87.0 63.0 92.0 FGFR4 86.0 93.0 99.0 FGR 23.0 36.0 90.0 FLT1 66.0 23.0 94.0 FLT3 0.1 1.0 27.0 FLT3 (D835H) 2.5 6.8 39.0 FLT3 (D835V) 0.0 0.0 3.6 FLT3 (D835Y) 0.5 0.2 15.0 FLT3 (ITD) 0.2 1.2 21.0 FLT3 (ITD, D835V) 0.0 0.0 0.4 FLT3 (ITD, F691L) 0.8 25.0 2.4 FLT3 (K663Q) 0.3 0.1 33.0 FLT3 (N841I) 0.0 0.0 0.0 FLT3 (R834Q) 0.0 0.0 16.0 FLT3-autoinhibited 11.0 2.5 45.0 FLT4 78.0 71.0 100.0 FRK 33.0 64.0 100.0 FYN 12.0 43.0 100.0 GAK 1.1 8.3 41.0 GCN2 (Kin.Dom.2, S808G) 0.0 11.0 2.0 GRK1 84.0 69.0 73.0 GRK2 96.0 80.0 100.0 GRK3 73.0 83.0 100.0 GRK4 98.0 35.0 88.0 GRK7 100.0 92.0 81.0 GSK3A 99.0 100.0 100.0 GSK3B 98.0 92.0 79.0

Kinase Example 8 Example 49 Example 120 HASPIN 84.0 70.0 88.0 HCK 8.2 35.0 91.0 HIPK1 66.0 4.3 69.0 HIPK2 83.0 3.5 72.0 HIPK3 100.0 33.0 79.0 HIPK4 40.0 4.6 100.0 HPK1 20.0 12.0 60.0 HUNK 100.0 95.0 100.0 ICK 91.0 80.0 74.0 IGF1R 56.0 69.0 97.0 IKK-alpha 100.0 92.0 71.0 IKK-beta 100.0 97.0 67.0 IKK-epsilon 44.0 80.0 17.0 INSR 60.0 46.0 75.0 INSRR 58.0 71.0 100.0 IRAK1 4.6 11.0 17.0 IRAK3 69.0 23.0 82.0 IRAK4 3.6 18.0 33.0 ITK 33.0 13.0 90.0 JAK1 (JH1domain-catalytic) 100.0 98.0 52.0 JAK1 (JH2domain-pseudokinase) 0.2 0.0 22.0 JAK2 (JH1domain-catalytic) 1.7 1.4 0.5 JAK3 (JH1domain-catalytic) 26.0 3.9 0.0 JNK1 85.0 41.0 14.0 JNK2 83.0 49.0 19.0 JNK3 73.0 50.0 19.0 KIT 12.0 0.3 64.0 KIT (A829P) 0.0 0.3 69.0 KIT (D816H) 26.0 64.0 11.0 KIT (D816V) 16.0 12.0 5.4 KIT (L576P) 4.3 0.0 27.0 KIT (V559D) 6.2 0.2 62.0 KIT (V559D, T670I) 84.0 31.0 96.0 KIT (V559D, V654A) 46.0 9.2 100.0 KIT-autoinhibited 49.0 1.0 86.0 LATS1 68.0 34.0 93.0 LATS2 77.0 37.0 37.0 LCK 0.8 2.8 74.0 LIMK1 95.0 77.0 93.0 LIMK2 100.0 66.0 85.0 LKB1 94.0 95.0 44.0 LOK 72.0 14.0 100.0 LRRK2 62.0 87.0 6.0 LRRK2 (G2019S) 33.0 60.0 0.7 LTK 99.0 100.0 78.0 LYN 17.0 38.0 98.0 LZK 49.0 52.0 10.0 MAK 100.0 91.0 100.0 MAP3K1 100.0 90.0 88.0 MAP3K15 67.0 69.0 95.0 MAP3K2 16.0 1.6 4.7 MAP3K3 22.0 4.2 14.0 MAP3K4 57.0 63.0 100.0 MAP4K2 92.0 57.0 49.0 MAP4K3 36.0 1.6 88.0 MAP4K4 91.0 12.0 95.0 MAP4K5 76.0 15.0 100.0 MAPKAPK2 100.0 100.0 100.0 MAPKAPK5 100.0 78.0 84.0 MARK1 91.0 27.0 76.0 MARK2 100.0 24.0 40.0 MARK3 77.0 28.0 81.0 MARK4 91.0 56.0 83.0 MAST1 98.0 84.0 81.0 MEK1 90.0 73.0 84.0 MEK2 72.0 62.0 64.0 MEK3 80.0 83.0 60.0 MEK4 100.0 100.0 81.0 MEK5 10.0 34.0 6.9 MEK6 95.0 99.0 62.0 MELK 56.0 11.0 100.0 MERTK 55.0 28.0 96.0 MET 100.0 100.0 100.0 MET (M1250T) 100.0 67.0 83.0 MET (Y1235D) 100.0 92.0 99.0 MINK 54.0 3.4 70.0 MKK7 96.0 97.0 98.0 MKNK1 76.0 83.0 100.0 MKNK2 21.0 86.0 47.0 MLCK 98.0 100.0 100.0 MLK1 5.2 47.0 69.0 MLK2 52.0 95.0 56.0 MLK3 26.0 40.0 88.0 MRCKA 100.0 37.0 99.0 MRCKB 99.0 88.0 100.0 MST1 100.0 37.0 100.0 MST1R 100.0 100.0 100.0 MST2 68.0 39.0 63.0 MST3 91.0 30.0 93.0 MST4 46.0 6.0 73.0 MTOR 89.0 89.0 100.0 MUSK 64.0 13.0 100.0 MYLK 82.0 100.0 95.0 MYLK2 98.0 60.0 86.0 MYLK4 87.0 1.4 48.0 MYO3A 99.0 83.0 90.0 MYO3B 100.0 100.0 100.0 NDR1 44.0 77.0 71.0 NDR2 98.0 84.0 83.0 NEK1 32.0 64.0 48.0 NEK10 59.0 72.0 87.0 NEK11 19.0 55.0 100.0 NEK2 35.0 80.0 51.0 NEK3 73.0 53.0 6.7 NEK4 84.0 88.0 43.0 NEK5 38.0 41.0 54.0 NEK6 17.0 59.0 86.0 NEK7 23.0 49.0 55.0 NEK9 28.0 46.0 79.0 NIK 100.0 74.0 86.0 NIM1 81.0 77.0 83.0 NLK 100.0 68.0 100.0

Kinase Example 8 Example 49 Example 120 OSR1 74.0 85.0 74.0 p38-alpha 92.0 93.0 100.0 p38-beta 93.0 91.0 97.0 p38-delta 100.0 100.0 100.0 p38-gamma 57.0 52.0 79.0 PAK1 78.0 60.0 59.0 PAK2 80.0 67.0 45.0 PAK3 78.0 51.0 76.0 PAK4 85.0 79.0 32.0 PAK6 80.0 79.0 87.0 PAK7 91.0 74.0 18.0 PCTK1 65.0 63.0 77.0 PCTK2 66.0 69.0 94.0 PCTK3 87.0 72.0 97.0 PDGFRA 25.0 27.0 59.0 PDGFRB 6.4 0.3 41.0 PDPK1 94.0 87.0 93.0 PFCDPK1 (P.falciparum) 92.0 87.0 91.0 PFPK5 (P.falciparum) 79.0 54.0 100.0 PFTAIRE2 89.0 90.0 97.0 PFTK1 98.0 81.0 94.0 PHKG1 50.0 47.0 68.0 PHKG2 80.0 77.0 49.0 PIK3C2B 96.0 70.0 87.0 PIK3C2G 75.0 75.0 86.0 PIK3CA 100.0 88.0 100.0 PIK3CA (C420R) 84.0 100.0 95.0 PIK3CA (E542K) 84.0 67.0 93.0 PIK3CA (E545A) 80.0 80.0 81.0 PIK3CA (E545K) 95.0 68.0 90.0 PIK3CA (H1047L) 69.0 78.0 44.0 PIK3CA (H1047Y) 68.0 83.0 91.0 PIK3CA (I800L) 72.0 90.0 87.0 PIK3CA (M1043I) 77.0 70.0 81.0 PIK3CA (Q546K) 79.0 85.0 94.0 PIK3CB 91.0 93.0 13.0 PIK3CD 74.0 55.0 99.0 PIK3CG 98.0 72.0 100.0 PIK4CB 81.0 99.0 77.0 PIKFYVE 95.0 99.0 81.0 PIM1 97.0 88.0 92.0 PIM2 100.0 100.0 100.0 PIM3 89.0 81.0 74.0 PIP5K1A 99.0 23.0 100.0 PIP5K1C 88.0 88.0 85.0 PIP5K2B 85.0 13.0 81.0 PIP5K2C 76.0 77.0 98.0 PKAC-alpha 77.0 78.0 100.0 PKAC-beta 96.0 93.0 100.0 PKMYT1 100.0 88.0 100.0 PKN1 95.0 42.0 80.0 PKN2 100.0 80.0 100.0 MKtuberculosis (PKNB) 41.0 24.0 2.9 PLK1 68.0 100.0 31.0 PLK2 51.0 68.0 34.0 PLK3 51.0 75.0 36.0 PLK4 83.0 77.0 75.0 PRKCD 95.0 92.0 100.0 PRKCE 97.0 63.0 87.0 PRKCH 100.0 100.0 86.0 PRKCI 79.0 47.0 93.0 PRKCQ 90.0 35.0 100.0 PRKD1 100.0 55.0 98.0 PRKD2 96.0 89.0 98.0 PRKD3 88.0 66.0 78.0 PRKG1 100.0 100.0 100.0 PRKG2 92.0 100.0 100.0 PRKR 56.0 98.0 88.0 PRKX 80.0 82.0 100.0 PRP4 67.0 85.0 83.0 PYK2 33.0 45.0 93.0 QSK 91.0 100.0 66.0 RAF1 100.0 100.0 92.0 RET 0.2 1.6 100.0 RET (M918T) 0.4 2.4 94.0 RET (V804L) 31.0 3.4 97.0 RET (V804M) 4.7 1.2 63.0 RIOK1 100.0 14.0 44.0 RIOK2 100.0 82.0 73.0 RIOK3 61.0 22.0 45.0 RIPK1 99.0 12.0 92.0 RIPK2 77.0 86.0 100.0 RIPK4 90.0 86.0 74.0 RIPK5 58.0 73.0 51.0 ROCK1 57.0 51.0 37.0 ROCK2 45.0 64.0 36.0 ROS1 100.0 100.0 86.0 RPS6KA4 (Kin.Dom.1-N-terminal) 100.0 23.0 100.0 RPS6KA4 (Kin.Dom.2-C-terminal) 100.0 73.0 84.0 RPS6KA5 (Kin.Dom.1-N-terminal) 97.0 40.0 100.0 RPS6KA5 (Kin.Dom.2-C-terminal) 97.0 86.0 79.0 RSK1 (Kin.Dom.1-N-terminal) 39.0 8.2 87.0 RSK1 (Kin.Dom.2-C-terminal) 70.0 74.0 89.0 RSK2 (Kin.Dom.1-N-terminal) 10.0 6.8 27.0 RSK2 (Kin.Dom.2-C-terminal) 59.0 70.0 98.0 RSK3 (Kin.Dom.1-N-terminal) 51.0 12.0 87.0 RSK3 (Kin.Dom.2-C-terminal) 92.0 92.0 84.0 RSK4 (Kin.Dom.1-N-terminal) 53.0 30.0 57.0 RSK4 (Kin.Dom.2-C-terminal) 86.0 98.0 94.0

Kinase Example 8 Example 49 Example 120 S6K1 67.0 41.0 89.0 SBK1 55.0 58.0 11.0 SGK 96.0 72.0 89.0 SgK110 100.0 100.0 94.0 SGK2 97.0 100.0 100.0 SGK3 96.0 57.0 88.0 SIK 18.0 46.0 41.0 SIK2 14.0 23.0 66.0 SLK 57.0 15.0 88.0 SNARK 47.0 3.8 1.9 SNRK 100.0 100.0 95.0 SRC 0.4 2.9 94.0 SRMS 64.0 51.0 83.0 SRPK1 86.0 11.0 59.0 SRPK2 100.0 100.0 79.0 SRPK3 93.0 30.0 89.0 STK16 68.0 37.0 37.0 STK33 25.0 55.0 45.0 STK35 90.0 93.0 100.0 STK36 88.0 43.0 100.0 STK39 71.0 80.0 79.0 SYK 92.0 98.0 90.0 TAK1 52.0 13.0 23.0 TAOK1 87.0 25.0 62.0 TAOK2 82.0 17.0 98.0 TAOK3 79.0 36.0 65.0 TBK1 38.0 16.0 21.0 TEC 100.0 100.0 98.0 TESK1 100.0 100.0 95.0 TGFBR1 98.0 100.0 94.0 TGFBR2 99.0 100.0 96.0 TIE1 69.0 62.0 100.0 TIE2 82.0 58.0 87.0 TLK1 100.0 89.0 97.0 TLK2 100.0 84.0 88.0 TNIK 97.0 9.5 76.0 TNK1 11.0 20.0 37.0 TNK2 5.1 36.0 80.0 TNNI3K 68.0 94.0 100.0 TRKA 0.0 0.2 0.0 TRKB 21.0 0.1 42.0 TRKC 27.0 3.0 53.0 TRPM6 75.0 93.0 99.0 TSSK1B 66.0 87.0 59.0 TSSK3 90.0 89.0 87.0 TTK 38.0 29.0 32.0 TXK 39.0 27.0 99.0 TYK2 (JH1domain-catalytic) 29.0 37.0 4.8 TYK2 (JH2domain-pseudokinase) 33.0 0.0 100.0 TYRO3 96.0 64.0 100.0 ULK1 4.9 24.0 0.5 ULK2 3.5 12.0 0.5 ULK3 21.0 60.0 4.9 VEGFR2 62.0 14.0 75.0 VPS34 90.0 77.0 77.0 VRK2 96.0 100.0 100.0 WEE1 6.6 70.0 91.0 WEE2 17.0 53.0 94.0 WNK1 96.0 100.0 99.0 WNK2 87.0 84.0 100.0 WNK3 83.0 98.0 100.0 WNK4 86.0 52.0 100.0 YANK1 40.0 79.0 100.0 YANK2 55.0 100.0 95.0 YANK3 83.0 78.0 100.0 YES 3.4 23.0 92.0 YSK1 92.0 66.0 97.0 YSK4 38.0 8.8 1.2 ZAK 100.0 84.0 100.0 ZAP70 94.0 100.0 89.0

AAK1, ABL1 (E255K) -phosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) -phosphorylated, ABL1 (Q252H) -nonphosphorylated, ABL1 (Q252H) , ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB, BIKE, BLK BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL1, DDR1, DDRK, DLRK, DLKEG E746-A750del), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 (D835V) FLT3 (D835Y), FLT3 (ITD, FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FRK, FYN, GA K, GCN2 (Kin.Dom.2, S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic) -catalytic, JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A) , KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2 (G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MNKK, MINK MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB (M.tuberculosis), PLK1, PLK1 PL2 , RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK3, RIPK1, RPS6KA4 (Kin.Dom.1-N-terminal), RSK1 (Kin.Dom.1-N-terminal), RSK2 ( Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1 , SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseu dokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4 kinase.

This indicates that the example compounds of the present invention have inhibitory activity against the enzymes listed above, thereby implying a useful effect when used in diseases associated with the enzymes listed above.

Therefore, the compound represented by Formula 1 according to the present invention is AAK1, ABL1 (E255K) -phosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) -phosphorylated, ABL1 (Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, K DK4, ADCK4, ADCK4 , AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DLK1 DAP, DK1 , DDR2, DLK, DYRK1B, DYRK2, EGFR, EGFR (E746-A750del), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGRFR1, FGR , FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD, FLT3 (ITD, D835V), FLT3 (ITD, F691L) , FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK -epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V) , KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2 (G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEKK, 4, PA6 PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB (M.tuberculosis), PLK1, PLK2, PYK2, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK3, RIPK1 (RPS6KA) Dom.1-N-terminal), RSK1 (Kin.Dom.1-N-terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 ( Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, T Pharmaceuticals for the treatment or prophylaxis of RKA, TRKB, TRKC, TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4 kinase-related diseases It can be usefully used as a composition.

Therefore, the compound represented by the formula (1), the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has excellent inhibitory activity against various protein kinases including WEE1, and thus, a pharmaceutical composition containing the same as an active ingredient. May be useful for the treatment or prophylaxis of protein kinase related diseases, especially cancer, and has an excellent effect of inhibiting cancer cell proliferation against liver cancer, lung cancer, epithelial cancer, colon cancer, breast cancer, leukemia and ovarian cancer. It can be usefully used for the treatment of lung cancer, epithelial cell cancer, colon cancer, breast cancer, leukemia or ovarian cancer.

Claims (12)

A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
A is CH or N;

L is NH or absent;

R ¹ and R ² are independently unsubstituted or substituted of 3 to 8 atoms comprising one or more heteroatoms selected from the group consisting of hydrogen, halogen, straight or branched C _1-6 alkoxy or N, O and S Heterocycloalkyl, or R ¹ and R ² together with 3 to 8 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atom to which they are attached; Can form
Wherein the substituted heterocycloalkyl is selected from the group consisting of N, O and S and at least one substituted with straight or branched C _1-6 alkyl, unsubstituted or straight or branched C _1-6 alkyl One or more substituents selected from the group consisting of 3 to 8 membered heterocycloalkyl, which is one or more substituted with unsubstituted or straight or branched C _1-6 alkyl containing one or more heteroatoms;

R ³ is a group consisting of-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted C _6-10 aryl and N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from
In this case, the substituted aryl and heteroaryl are straight chain or branched C _1-6 alkyl substituted with one or more substituted with halogen, unsubstituted or halogen and straight chained or branched C _1- substituted with one or more substituted with halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₆ alkoxy,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-6 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,
Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-6 alkyl and straight or branched C _1-6 alkoxy,
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen or straight or branched C _1-6 alkyl).
The method of claim 1,
A is CH or N;

L is NH or absent;

R ¹ and R ² are independently unsubstituted or substituted of 5 to 7 atoms comprising one or more heteroatoms selected from the group consisting of hydrogen, halogen, straight or branched C _1-4 alkoxy or N, O and S Heterocycloalkyl, or R ¹ and R ² together with the carbon atom to which they are attached, an unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing one or more heteroatoms selected from the group consisting of N, O and S Can form
Wherein the substituted heterocycloalkyl is selected from the group consisting of N, O and S and at least one substituted with straight or branched C _1-4 alkyl, unsubstituted or straight or branched C _1-4 alkyl One or more substituents selected from the group consisting of 5 to 7 membered heterocycloalkyl substituted with one or more unsubstituted or straight or branched C _1-4 alkyl containing one or more heteroatoms;

R ³ is a group consisting of-(C = O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted C _6-10 aryl and N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing one or more heteroatoms selected from
In this case, the substituted aryl and heteroaryl are straight chain or branched C _1-4 alkyl substituted with one or more halogen, unsubstituted or halogen, and straight chain or branched C _1- substituted with one or more substituted or halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₄ alkoxy,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-4 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 9 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,
Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-4 alkyl and straight or branched C _1-4 alkoxy,
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen or straight or branched C _1-4 alkyl, optical isomers thereof, or pharmaceutically acceptable salts thereof.
The method of claim 1,
A is CH or N;

L is NH or absent;

R ¹ and R ² are independently 6-membered unsubstituted or substituted heterocycloalkyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen, C _1-2 alkoxy or N, O and S, or R ¹ and R ² together with the carbon atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 6 or 7 atoms comprising one or more heteroatoms selected from the group consisting of N, O and S,
In this case, the substituted heterocycloalkyl is a hetero atom selected from the group consisting of N, O and S, and an amine substituted with at least one of straight or branched C _1-4 alkyl, unsubstituted or C _1-2 alkyl. One or more substituents selected from the group consisting of 6-membered heterocycloalkyl unsubstituted or substituted with one or more C _1-2 alkyl;

R ³ is-(C═O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted phenyl and hetero selected from the group consisting of N, O and S 6 to 9 membered unsubstituted or substituted heteroaryl containing one or more atoms,
In this case, the substituted phenyl and heteroaryl are linear, branched C _1-4 alkyl substituted with one or more substituted by halogen, unsubstituted or halogen, and linear or branched C _1- substituted with one or more substituted by unsubstituted or halogen, respectively. _May be substituted with one or more substituents selected from the group consisting of ₄ alkoxy,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or straight or branched C _1-4 alkyl;

R ⁴ is an unsubstituted or substituted heteroaryl of 5 to 9 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,
Wherein, the substituted heteroaryl is one or more of NO ₂ , NH ₂ , -NH (C = O) R ¹⁰ ,-(C = O) NR ¹¹ R ¹² , -NHSO ₂ R ¹³ , halogen, unsubstituted or OH. One or more substituents selected from the group consisting of substituted straight or branched C _1-4 alkyl and straight or branched C _1-2 alkoxy,
R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen or straight or branched C _1-2 alkyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
A is CH or N;

L is NH or absent;

R ¹ and R ² are independently hydrogen, F, methoxy or unsubstituted or substituted piperidine, or piperazine, or R ¹ and R ² are unsubstituted or substituted piperidine together with the carbon atom to which they are attached Or azepanes,
In this case, the substituted piperidine, piperazine and azepan may be substituted with one or more substituents selected from the group consisting of methyl, -N (CH ₃ ) ₂ and piperazine unsubstituted or substituted with one or more methyl, respectively. There is;

R ³ is — (C═O) NR ⁵ R ⁶ ,-(P = O) R ⁷ R ⁸ , -SO ₂ R ⁹ , unsubstituted or substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, Isoxoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolinyl or quinolinyl,
Wherein the substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolyl and quinolinyl are each F, methyl , May be substituted with one or more substituents selected from the group consisting of CF ₃ and methoxy,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen or methyl;

R ⁴ is unsubstituted or substituted pyridinyl or indolyl,
At this time, the substituted pyridinyl and indolyl are NO ₂ , NH ₂ , -NH (C = O) CH ₃ ,-(C = O) NH ₂ , -NHSO ₂ CH ₃ , F, -C (CH ₂ A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents selected from the group consisting of ₂ OH, methyl and methoxy.
The method of claim 1,
A is CH or N;

R ¹ and R ² are independently hydrogen, F, methoxy,

,

,

,

or

Or R ¹ and R ² together with the carbon atom to which they are attached

,

or

Can form;

R ³ is-(C = O) NHCH ₃ ,-(C = O) N (CH ₃ ) ₂ ,-(P = O) (CH ₃ ) ₂ , -SO ₂ CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

ego;

LR ⁴ is

,

,

,

,

,

,

,

,

,

,

or

Compound, optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
Compound represented by the formula (1) is any one selected from the group of compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof:
<1> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrazole-4- Yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<2> 2- (6-((2- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H-pyrazole- 4-yl) pyrimidin-4-amino) pyridin-2-yl) propan-2-ol;
<3> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1H-pyrazol-4-yl) Pyridin-4-ylamino) pyridin-2-yl) propan-2-ol;
<4> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H- Pyrazol-4-yl) pyridin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<5> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridine-3 -Yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<6> 2- (6-((5- (benzofuran-2-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<7> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-indole-5 -Yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
<8> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (furan-3-yl) pyrid Midin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<9> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazole- 4-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
<10> 2- (6- (2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -5- (1-methyl-1H-pyrazole- 3-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
<11> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-3-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<12> 2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (pyridin-3-yl) pyrid Midin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<13> 2- (6-((5- (benzofuran-3-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;
<14> 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (quinoline- 6-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
<15> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1- Methyl-1H-pyrrole-3-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<16> 2- (6-((5- (benzofuran-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;
<17> 2- (6-((2-((4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-phenylpyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;
<18> 2- (6-((5- (benzo [b] thiophen-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<19> 2- (6-((5- (1H- indol-3-yl) -2-((3-methoxy-4- (4- methylpiperazin-1-yl) piperidine-1- 1) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<20> 2- (6-((5- (benzo [b] thiophen-2-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<21> 2- (6-((5- (5-fluoropyridin-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidine- 1-yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<22> 2- (6- (2- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenylamino) -5- (thiophene -2-yl) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
<23> 2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (1H- Pyrrole-3-yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<24> 2- (6-((5- (furan-2-yl) -2-((3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidine-1 -Yl) phenyl) amino) pyrimidin-4-amino) amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (benzofuran-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;
<26> 2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (benzofuran-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;
<28> 2- (6-((5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-propan-2-ol;
2- (6-((5- (1-methyl-1H-pyrazol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (thiophen-2-yl) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (benzo [b] thiophen-2-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine -4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (2-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (3-methoxyphenyl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiophen-2-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<35> 2- (6- (5- (benzo [b] thiophen-2-yl) -2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl Amino) pyrimidin-4-ylamino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (benzofuran-3-yl) -2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (1H-pyrrole-3-yl ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (1H-pyrrol-3-yl) -2-((1,2,3,4-tetra hydroisoquinolin-6-yl) amino) pyrimidine-4- Yl) amino) pyridin-2-propan-2-ol;
2- (6- (5- (benzo [b] thiophen-2-yl) -2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino) pyri) Midin-4-ylamino) pyridin-2-yl) propan-2-ol;
2- (6- (5- (benzo [b] thiophen-2-yl) -2- (1,2,3,4-tetrahydroisoquinolin-7-ylamino) pyrimidin-4- Monoamino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (benzo [b] thiophen-2-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)) Amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<42> 2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (furan-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;
<45> 2- (6-((5- (6-fluoropyridin-3-yl) -2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino ) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (thiazol-5-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (1H-pyrazol-3-yl) Pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<48> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (1-methyl-1H- Indol-3-yl) 2-amine;
N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;
<50> N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2-methyl-1,2,3,4 Tetrahydroisoquinolin-6-amine;
<51> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Thiophen-2-yl) 2-amine;
<52> N- (4- (1-methyl-1H-indol-3-yl) -5- (thiophen-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;
N- (5- (isooxazol-4-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;
<54> N- (4- (1-methyl-1H-indol-3-yl) -5- (1H-pyrazol-4-yl) pyrimidin-2-yl) -1,2,3,4- Tetrahydroisoquinolin-6-amine;
N- (5- (furan-3-yl) -4- (1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinoline-6- Amines;
N- (5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4 Tetrahydroisoquinolin-6-amine;
N- (5- (5-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4 Tetrahydroisoquinolin-6-amine;
<58> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Thiophen-3-yl) pyrimidin-2-amine;
N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetra hydroiso Quinolin-7-amine;
<60> N- (5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -2,3,4,5-tetrahydro- 1H-benzo [d] azepin-7-amine;
5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine- 2-amine;
5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indole-3- Yl) pyrimidin-2-amine;
<63> (S) -5- (furan-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl ) Pyrimidin-2-amine;
<64> (S) -5- (furan-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;
N- (5- (furan-3-yl) -4- (4-nitro-1H-indol-1-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;
<66> N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl)- 1H-indol-4-yl) methanesulfonamide;
N- (4- (4-amino-1 H-indol-1-yl) -5- (furan-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydroiso Quinolin-6-amine;
N- (1- (5- (furan-3-yl) -2-((1,2,3,4-tetrahydro isoquinolin-6-yl) amino) pyrimidin-4-yl)- 1H-indol-4-yl) acetamide;
5- (furan-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indole-1- Yl) pyrimidin-2-amine;
<70> 1- (5- (furan-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl)- 1H-indol-4-amine;
5- (furan-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (4-nitro-1H-indol-1-yl) pyrimidine- 2-amine;
1- (5- (furan-3-yl) -2-((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -1H-indole-4 Amines;
5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl ) Pyrimidin-2-amine;
N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;
5- (6-Fluoropyridin-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H- Indol-3-yl) pyrimidin-2-amine;
(76) (S) -5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1 -Yl) phenyl) pyrimidin-2-amine;
<77> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoro pyridin-3-yl) -4- (1- Methyl-1H-indol-3-yl) pyrimidin-2-amine;
N- (3-fluoro-4- (4-methylpiperazin-1-yl) phenyl) -5- (furan-3-yl) -4- (1-methyl-1H-indole-3- Yl) pyrimidin-2-amine;
N- (5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3,4-tetrahydro Isoquinolin-6-amine;
<80> N- (5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetra hydroisoquinolin-6-amine;
N- (4- (1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1,2 , 3,4-tetrahydroisoquinolin-4-yl) 6-amine;
<82> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-methoxy-1-methyl-1H-indol-3-yl ) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
<84> N- (4- (6-methoxy-1-methyl-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl ) 4-tetrahydroisoquinolin-6-amine;
N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (6-fluoropyridin-3-yl) -4- (6- Methoxy-1-methyl-1H-indol-3-yl) pyrimidin-3-yl) pyrimidin-2-amine;
5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4 -Methylpiperazin-1-yl) phenyl) pyrimidin-2- amine;
N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;
N- (4- (6-methoxy-1H-indol-3-yl) -5 (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;
N- (5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetra hydroisoquinolin-6-amine;
<90> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -4- (6-methoxy-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
4- (6-methoxy-1 H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -5- (6- ( Trifluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxy phenyl) -5- (6-fluoropyridin-3-yl) -4- (6- Methoxy-1H-indol-3-yl) pyrimidin-2-amine;
5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazin -1-yl) phenyl) pyrimidin-2-amine;
N- (4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-6-amine;
N- (4- (6-fluoro-1-methyl-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydroisoquinolin-6-amine;
<96> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1H -Indol-3-yl) pyrimidin-2-amine;
5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4-((S) -3-methylpiperazin-1-yl) Phenyl) pyrimidin-2-amine;
(98) (S) -5- (furan-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3-methylpiperazin -1-yl) phenyl) pyrimidin-2-amine;
N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1H-indol-3-yl) -5- (6- (tri Fluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
<100> (S) -4- (1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5- (6- (trifluoromethyl) pyridine 3-yl) pyrimidin-2-amine;
<101> (S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (4- (3-methylpiperazin- 1-yl) phenyl) 2-pyrimidin-amine;
(S) -5- (6-fluoropyridin-3-yl) -4- (6-methoxy-1H-indol-3-yl) -N- (3-methoxy-4- (3 Methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
<103> N- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -4- (1-methyl-1H-indol-3-yl) -5- (6- (tri Fluoromethyl) pyridin-3-yl) pyrimidin-2-amine;
N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4 (1-methyl-1H-indol-3-yl) -5- (6 (Trifluoromethyl) pyridine-3-pyrimidin-2-amine;
<105> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -5- (furan-3-yl) -4- (6-methoxy-1 Methyl-1H-indol-3-yl) pyrimidin-2-amine;
5- (furan-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (4-methylpiperazine -1-yl) phenyl) pyrimidin-2-amine;
(S) -4- (1-methyl-1H-indol-3-yl) -N- (4- (3-methylpiperazin-1-yl) phenyl) -5 (6- (trifluoro Rhomethyl) pyridin-3-yl) pyrimidin-2-amine;
4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (4-((S) -3-methylpiperazin- 1-yl) phenyl) pyrimidin-2-amine;
(S) -4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3) -Methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
<110> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (6-fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) pyrimidin-2-amine;
<111> N- (4- (6-fluoro-1H-indol-3-yl) -5- (6- (trifluoromethyl) pyridin-3-yl) pyrimidin-2-yl) -1, 2,3,4-tetrahydro isoquinolin-6-amine;
<112> (S) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (3-methylpiperazin-1-yl) phenyl) -4- (1- Methyl-1H-indol-3-yl) pyrimidin-2-amine;
5- (6-Fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidin-4-yl) phenyl) -4- (1-methyl-1H-indole- 3-yl) pyrimidin-2-amine;
5- (6-fluoropyridin-3-yl) -4- (1-methyl-1H-indol-3-yl) -N- (4- (piperidin-4-yl) phenyl) pyrid Midin-2-amine;
5- (6-Fluoropyridin-3-yl) -4- (6-methoxy-1-methyl-1H-indol-3-yl) -N- (3-methoxy-4- (pi Ferridin-4-yl) phenyl) pyrimidin-2-amine;
4- (6-Fluoro-1H-indol-3-yl) -5- (6-fluoropyridin-3-yl) -N- (3-methoxy-4- (piperidine-4) -Yl) phenyl) pyrimidin-2-amine;
3- (5- (6-fluoropyridin-3-yl) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) -1H-indole-1-carboxamide;
3- (5- (6-fluoropyridin-3-yl) -2-((3-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl ) -1H-indole-1-carboxamide;
3- (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (6-fluoropyridin-3-yl) Pyrimidin-4-yl) -1-carboxamide;
<120> (2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropane-2- 1) pyridin-2-yl) amino) pyrimidin-5-yl) dimethylphosphineoxide;
<121> (4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((3-methoxy-4- (4- (4-methylpiperazin -1-yl) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphine oxide;
(4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -2-((1,2,3,4-tetrahydroisoquinolin-6-yl ) Amino) pyrimidin-5-yl) dimethylphosphine oxide;
2- (6-((2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5 (methylsulfonyl) pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2-((3-methoxy-4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (methylsul Phonyl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (methylsulfonyl) -2 ((1,2,3,4-tetrahydroisoquinolin-6-yl) amino) pyrimidin-4-yl) amino) pyridine -2-yl) propan-2-ol;
2- (6-((2- (2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino) -5- (methylsulfonyl) pyrimidin-4-yl ) Amino) pyridin-2-yl) propan-2-ol;
2- (6-((5- (methylsulfonyl) -2-((1,2,3,4-tetra hydroisoquinolin-7-yl) amino) pyrimidin-4-yl) amino) Pyridin-2-yl) propan-2-ol;
2- (6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) -5- (methylsulfonyl) pyrimidine-4- 1) amino) pyridin-2-yl) propan-2-ol;
2- (6-((2- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -5- (methylsulfonyl) pyrimidin-4-yl ) (Methyl) amino) -2-yl) propan-2-ol;
<130> N- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) -4- (1-methyl-1H-indol-3-yl) -5- ( Methylsulfonyl) pyrimidin-2-amine;
<131> 2- (4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenylamino) -4- (6- (2-hydroxypropan-2-yl) pyridine- 2-ylamino) -N, N-dimethylpyrimidine-5-carboxamide;
4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((1,2,3,4-tetrahydroiso) Quinolin-6-yl) amino) pyrimidine-5-carboxamide;
4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((2-methyl-1,2,3,4 Tetrahydroisoquinolin-6-yl) pyridin-2-yl) amino) pyrimidine-5-carboxamide;
(S) -4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-2-((4- (3-methylpipepe Razin-1-yl) phenyl) amino) pyrimidine-5-carboxamide;
(R) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) -2- (3-methoxy-4- (3-methylpiperazin-1- Yl) phenylamino) -N, N-dimethylpyrimidine-5-carboxamide;
2-((4- (4- (dimethylamino) piperidin-1-yl) -3-methoxyphenyl) amino) -4-((6- (2-hydroxypropan-2-yl ) Pyridin-2-yl) amino) -N-methylpyrimidine-5-carboxamide; And
4-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) amino) -N-methyl-2-((1,2,3,4-tetra hydroisoquinoline- 6-yl) amino) pyrimidine-5-carboxamide.
As shown in Scheme 1 below,
Reacting the compound represented by Formula 4 with the compound represented by Formula 5 (step 1); And
A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 (step 2):
Scheme 1

(In Scheme 1, A, L, R ¹ , R ² , R ³ and R ⁴ are as defined in Formula 1 of claim 1;
X ¹ and X ² are each halogen; And
L ¹ is

or

All).
A pharmaceutical composition for the prophylaxis or treatment of a protein kinase-related disease containing the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 8,
The protein kinase is AAK1, ABL1 (E255K) -phosphorylated. ABL1 (F317I) -nonphosphorylated, ABL1 (F317I) -phosphorylated, ABL1 (F317L) -nonphosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) (Q252H) -nonphosphorylated, ABL1 (Q252H) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVRA, ACVRA ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF (V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2K, CAMK2D, , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CHEKK, CHEKK2 , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, DRAK1, DRAK2, DYRK1, DYRK2, DYRK2 -A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHB6 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H) D835V), FLT3 (D835Y), FLT3 (ITD), FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-cat alytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P ), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2 (G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK2 MEK1 MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK, MYLK MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-beta delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFK1IRE, PH1, PFTTAIRE2, KG PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (E545K), PIK3CA (H1047L), PIK3CA (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CB, PIK3C, PIKCCG PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M.tuberculosis), PLK1, PLK2, PLK3, PLKCH, PRKCH , PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK2, RIOK3, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4 (Kin.Dom.1-N-terminal), RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.1-N-terminal) , RPS6KA5 (Kin.Dom.2-C-terminal), RSK1 (Kin.Dom.1, N-terminal), RSK1 (Kin.Dom.2-C-terminal), RSK2 (Kin.Dom.1-N- terminal), RSK2 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.2-C-terminal), RSK4 (Kin.Dom.1- N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, ST K39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TRPM6, TSSK1B TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, NKNK, YANK1, YANK1 Pharmaceutical composition, characterized in that at least one selected from the group consisting of YES, YSK1, YSK4, ZAK and ZAP70.
The method of claim 8,
The compound is AAK1, ABL1 (E255K) -phosphorylated, ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (H396P) -phosphorylated, ABL1 (M351T) -phosphorylated, ABL1 (Q252H) -nonphosphorylated, ABL1 (H) ) -phosphorylated, ABL1 (T315I) -nonphosphorylated, ABL1 (T315I) -phosphorylated, ABL1 (Y253F) -phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB , BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL1, DDRK, DDR2, DDR2 , EGFR (E746-A750del), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M ), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 D835V), FLT3 (D835Y), FLT3 (ITD, FLT3 (ITD, D835V), FLT3 (ITD, F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinh ibited, FRK, FYN, GAK, GCN2 (Kin.Dom.2, S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain- catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2 (G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MK5, MARKK MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB1 (PKNB1) , PLK2, PYK2, RET, RET (M918T), RET (V804L), RET (V804M), RIOK1, RIOK3, RIPK1, RPS6KA4 (Kin.Dom.1-N-terminal), RSK1 (Kin.Dom.1-N -terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK , SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2 (JH1domain-catalytic), A pharmaceutical composition characterized by exhibiting inhibitory activity against at least one kinase selected from the group consisting of TYK2 (JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4.
The method of claim 8,
The protein kinase-related disease is a pharmaceutical composition, characterized in that cancer.
The method of claim 11,
The cancer may include leukemia, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial carcinoma, epithelial cell tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal / sinus cancer, Nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, lung cancer, epithelial cancer, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, stomach cancer, liver cancer, Gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penis cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, Pharmaceutical composition, characterized in that at least one selected from the group consisting of vaginal cancer, female external genital cancer, female urethral cancer and skin cancer.