KR102319676B1 - Pyrrolopyrimidine, pyrrolopyridine, and indazole derivatives as therapeutic agents - Google Patents

Abstract

The present invention provides a compound selected from novel pyrrolopyrimidine, pyrrolopyridine, and indazole derivatives having protein kinase inhibitory activity, and pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and the compounds It relates to a pharmaceutical composition for preventing, alleviating or treating cancer, including.
The compound according to the present invention has excellent ability to inhibit the activity of Bcr-Abl tyrosine kinase and T315I-Bcr-Abl tyrosine kinase, which is a drug-resistant mutant, and has no inhibitory activity against VEGFR2 protein kinase. It can be usefully used for the prevention, alleviation or treatment of cancer, specifically hematological cancer, particularly chronic myelogenous leukemia, while greatly reducing side effects.

Description

Pyrrolopyrimidine, pyrrolopyridine, and indazole compound derivatives and therapeutic pharmaceutical compositions comprising the same

The present invention provides a compound selected from novel pyrrolopyrimidine, pyrrolopyridine, and indazole derivatives having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof, and the compound It relates to a pharmaceutical composition for preventing, alleviating or treating cancer, including.

Chronic myelogenous leukemia (CML) is a type of blood cancer caused by abnormal expansion of a hematopoietic stem cell clone with a Philadelphia chromosome. The Philadelphia chromosome is caused by the formation and sustained activity of the Bcr-Abl fusion protein, which is the causative protein of CML. More than 90% of chronic myelogenous leukemia (CML) patients and about 40% of acute lymphoblastic leukemia (ALL) patients express this abnormal Bcr-Abl protein, and the sustained activity of Bcr-Abl further promotes leukemia. . For this reason, Bcr-Abl tyrosine kinase has been considered as a promising drug target for CML.

Imatinib as a treatment drug for chronic myeloid leukemia is commercialized and sold as Gleevec, but various point mutants resistant to Gleevec have recently been reported. In particular, T315I, known as a gatekeeper mutant, is not treated with Gleevec as well as nilotinib, Dasatinib, and Bosutinib, which are known as second-generation Bcr-Abl inhibitors. have. Many studies have been conducted to overcome these gatekeeper mutants, but so far, only Ponatinib has been reported as the only drug approved for limited clinical use.

Ponatinib has been reported to strongly inhibit wild-type Bcr-Abl and T315I-Bcr-Abl in vitro and in vivo, and a phase 1 clinical trial in patients with chronic myeloid leukemia with T315I ( NCT00660920) and phase 2 clinical trials (NCT01207440) showed excellent efficacy. However, it has been reported that ponatinib simultaneously has activity on various kinases such as VEGFR2, PDGFR, KIT, FLT3, and FGFR, so that the selectivity of the kinase is low, causing side effects such as myelosuppression and pancreatitis. (Cortes JE et al. , N. Engl. J. Med. 367:2075-2088, 2012). In addition, in the recently conducted phase 3 clinical trial (NCT01650805), side effects such as rapid cardiovascular disease caused by the strong VEGFR2 inhibitory ability of ponatinib were observed, and clinical trials and sales were suspended (Senior M., Nat. Biotech. 32(1): 9-11, 2014). Therefore, there is an urgent need to develop a therapeutic agent for CML that inhibits the activity of the T315I-Bcr-Abl gatekeeper mutant and at the same time has excellent selectivity for kinases and does not have inhibitory activity on VEGFR2 in particular.

Korean Patent Registration No. 10-1116756

Cortes JE et al., N. Engl. J. Med. 367:2075-2088, 2012 Senior M., Nat. Biotech. 32(1):9-11, 2014

An object of the present invention is to provide a compound selected from a compound represented by [Formula 1] having inhibitory activity of protein kinase, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof.

Another object of the present invention is a cancer comprising as an active ingredient a compound selected from the compound represented by [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, specifically blood cancer, particularly To provide a pharmaceutical composition for preventing, alleviating or treating chronic myelogenous leukemia.

In order to achieve the above object, the present invention provides a compound selected from a compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

X ₁ , X ₂ and X ₃ are each independently hydrogen or nitrogen,

L is -NR ⁵ -; -NR ⁵ CH ₂ -; -NHR ⁵ -; -NR ⁵ C(O)-; -C(O)NR ⁵ -; -NR ⁵ C(O)NR ⁵ -; -S(O) ₂ -; -NR ⁵ S(O) ₂ -; and -S(O) ₂ NR ⁵ -;

A is a C ₆ -C ₁₀ aryl group; or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;

R ¹ is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ¹ may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{2 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}

R ² is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ² may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{1 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}

R ³ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; or a C ₃ -C ₁₀ cyclyl group;

R ⁴ is hydrogen; hydroxyl group; halogen group; amino group; nitro; cyano group; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;

R ⁵ is hydrogen; C ₁ -C ₆ alkyl group; and an oxazole group; selected from the group consisting of;

m is an integer from 1 to 3,

The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be selected from the group consisting of hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it comprises one or more substituents selected from the group consisting of _{C 3} -C _{10 heterocyclyl group,}

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ⁶ R ⁷ ); _{a C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{a C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ⁶ R ⁷ ); amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

said R ⁶ and R ⁷ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes at least one selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group,}

The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

In addition, the present invention is a pharmaceutical for preventing, alleviating or treating cancer comprising a compound represented by the above [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a compound selected from stereoisomers thereof as an active ingredient. A composition is provided.

The compound according to the present invention has excellent ability to inhibit the activity of Bcr-Abl tyrosine kinase and a drug-resistant mutant T315I-Bcr-Abl tyrosine kinase. Therefore, it can be used for the purpose of treating, preventing and alleviating cancer caused by abnormal cell growth while overcoming drug resistance.

On the other hand, the compound according to the present invention does not have inhibitory activity against VEGFR2 protein kinase. Therefore, by selectively inhibiting the activity of Bcr-Abl tyrosine kinase and T315I mutant Bcr-Abl tyrosine kinase, drug side effects such as induction of cardiovascular disease occurring in patients taking Bcr-Abl or T315I mutant Bcr-Abl tyrosine kinase inhibitory drugs occur has the effect of reducing

Accordingly, the compound according to the present invention can be usefully used as a target therapeutic agent capable of treating hematologic cancer, particularly chronic myelogenous leukemia (CML), while greatly reducing drug resistance and side effects.

Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, a range of "10% to 30%" includes values such as 10%, 11%, 12%, 13%, and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subrange, such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited range, such as 10.5%, 15.5%, 25.5%, and the like.

Hereinafter, the present invention will be described in detail.

In order to solve the above problems, the present inventors have continued research to develop compounds effective for targeted treatment, prevention and alleviation of chronic myelogenous leukemia (CML), which can be said to be fatal among tumor diseases. By selecting a novel compound that has excellent ability to inhibit the activity of tyrosine kinase and a drug-resistant mutant T315I-Bcr-Abl tyrosine kinase and does not have inhibitory activity against VEGFR2 protein kinase, the present invention has been completed.

One aspect of the present invention provides a compound selected from a compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

X ₁ , X ₂ and X ₃ are each independently hydrogen or nitrogen,

L is -NR ⁵ -; -NR ⁵ CH ₂ -; -NHR ⁵ -; -NR ⁵ C(O)-; -C(O)NR ⁵ -; -NR ⁵ C(O)NR ⁵ -; -S(O) ₂ -; -NR ⁵ S(O) ₂ -; and -S(O) ₂ NR ⁵ -;

A is a C ₆ -C ₁₀ aryl group; or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;

R ¹ is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ¹ may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{2 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}

R ² is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ² may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{1 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}

R ³ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; or a C ₃ -C ₁₀ cyclyl group;

R ⁴ is hydrogen; hydroxyl group; halogen group; amino group; nitro; cyano group; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;

R ⁵ is hydrogen; C ₁ -C ₆ alkyl group; and an oxazole group; selected from the group consisting of;

m is an integer from 1 to 3,

The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be selected from the group consisting of hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it comprises one or more substituents selected from the group consisting of _{C 3} -C _{10 heterocyclyl group,}

The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ⁶ R ⁷ ); _{a C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{a C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ⁶ R ⁷ ); amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}

said R ⁶ and R ⁷ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes at least one selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group,}

The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

In one aspect of the present invention, L is -NHC(O)-; -C(O)NH-; and -NHC(O)NH-,

Wherein R ³ is CH _{3 And}

A may be any one of benzene, thiophene, furan, cyazole, oxazole, pyrazole, and pyridine.

In one aspect of the present invention, the compound represented by the [Formula 1] provides a compound selected from the group consisting of the following compound numbers 1 to 66:

(Compound No. 1) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(trifluoromethyl)benzamide;

(Compound No. 2) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -methoxybenzamide;

(Compound No. 3) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(trifluoromethyl)benzamide;

(Compound No. 4) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -cyanobenzamide;

(Compound No. 5) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -chlorobenzamide;

(Compound No. 6) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -chlorobenzamide;

(Compound No. 7) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -chlorobenzamide;

(Compound No. 8) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -nitrobenzamide;

(Compound No. 9) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -nitrobenzamide;

(Compound No. 10) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluorbenzamide;

(Compound No. 11) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methoxybenzamide;

(Compound No. 12) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -(dimethylamino)benzamide;

(Compound No. 13) N-thiophene between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -2-carboxamide;

(Compound No. 14) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,4-dimethoxybenzamide;

(Compound No. 15) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromofuran-2-carboxamide;

(Compound No. 16) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -bromo-5-(trifluoromethyl)benzamide;

(Compound No. 17) N-triazolo between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -4-carboxamide;

(Compound No. 18) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -Meticisoxazole-3-carboxamide;

(Compound No. 19) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -(pyridin-4-yl)cyazole-4-carboxamide;

(Compound No. 20) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-1 -phenyl-5- (tri-fluoro methyl) -1 H-pyrazole-4-carboxamide;

(Compound No. 21) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromothiophene-2-carboxamide;

(Compound No. 22) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 23) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) benzamide ;

(Compound No. 24) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -methylbenzamide;

(Compound No. 25) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -chloro-3-(trifluoromethyl)benzamide;

(Compound No. 26) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-cyanopropen-2-yl)benzamide;

(Compound No. 27) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,5-dimethylfuran-3-carboxamide;

(Compound No. 28) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -morpholino-5-(trifluoromethyl)benzamide;

(Compound No. 29) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 30) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;

(Compound No. 31) (S) - N - (3- (1- (6- aminomethyl-pyridin-4-yl) -1 H - pillow as [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 32) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 33) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 34) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 35) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((2-(dimethylamino)ethyl)(methyl)amino)-3-(trifluoromethyl)benzamide;

(Compound No. 36) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(2,4-dimethyl- 1H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 37) N - (3- (1- (6- amino-pyridin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methyl-phenyl) -4- (4-methyl-1 H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 38) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(dimethylamino)-3-(trifluoromethyl)benzamide;

(Compound No. 39) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide;

(Compound No. 40) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2,4-dimethyl- 1H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 41) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;

(Compound No. 42) tert-butyl-4- (4 - ((3- (1- (6-amino-pyrimidin-4-yl) -1 H-pyrrolo [3,2-c] pyridin-6-yl )-4-methylphenyl)carbamoyl)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate;

(Compound No. 43) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methyl-3-(trifluoromethyl)benzamide;

(Compound No. 44) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluor-3-(trifluoromethyl)benzamide;

(Compound No. 45) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-hydroxypiperidin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 46) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(morpholinomethyl)-3-(trifluoromethyl)benzamide;

(Compound No. 47) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -morpholino-3-(trifluoromethyl)benzamide;

(Compound No. 48) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-methoxyphenyl)urea;

(Compound No. 49) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(3-(trifluoromethyl)phenyl)urea;

(Compound No. 50) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-(trifluoromethyl)benzamide;

(Compound No. 51) 3- (4-methyl -1 H-imidazol -1-) - N - (4-methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) - 1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-5-(trifluoromethyl)benzamide;

(Compound No. 52) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-morpholino-5-(trifluoromethyl)benzamide;

(Compound No. 53) N - (3- (1- (6- ( cyclopropylamine) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 54) N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine -6 -yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 55) N - (3- (1- (7 H - pyrrolo [2,3-d] pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine-6 yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 56) N - (3- (7- (6- amino-pyrimidin-4-yl) -7 H-pyrrolo [2,3-d] pyrimidin-2-yl) -4-methylphenyl) - 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 57) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 58) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (tri-fluoro methyl) benzamide ;

(Compound No. 59) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-4-((4-methylpiperazine) -1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 60) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-3-(dimethylamino)-5 -(trifluoromethyl)benzamide;

(Compound No. 61) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -6- (tri-fluoro methyl) nicotinamide ;

(Compound No. 62) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (2,4-dimethyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 63) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4 yl) -1 H - indazol-6-yl) phenyl) -5- (tri-fluoro methyl) benzamide;

(Compound No. 64) 3- (2,4-dimethyl -1 H-imidazol -1-) - N - (3- ( 1- (6 - ((2- hydroxyethyl) amino) pyrimidin- 4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide;

(Compound No. 65) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidine -4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide; and

(Compound No. 66) N - (3- (2- (6- amino-pyrimidin-4-yl) -2 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide.

As used herein, the term 'substitution' refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and 'substituent' refers to an introduced atomic group.

The substituent is, for example, a halogen atom, a halogen atom, a C ₁ -C ₂₀ alkyl group _{substituted with a halogen atom (eg, CCF 3} , CHCF ₂ , CH ₂ F, CCl _{3 ,} etc.), C ₁ -C ₂₀ alkoxy, C _2- C ₂₀ Alkoxyalkyl, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or its salt, sulfonyl group, sulfamoyl group, sulfonic acid group or its salt, phosphoric acid or its salt salt, or C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ heteroalkyl group, C ₆ -C ₂₀ aryl group, C ₆ -C ₂₀ arylalkyl group, It may be a C ₆ -C ₂₀ heteroaryl group, a C ₇ -C ₂₀ heteroarylalkyl group, a C ₆ -C ₂₀ heteroaryloxy group, and a C ₆ -C ₂₀ heteroaryloxyalkyl group or a C ₆ -C ₂₀ heteroarylalkyl group. .

In the definition of a substituent in the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl can be "saturated alkyl" containing no alkenyl or alkynyl moieties, or "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" means a group comprising at least one carbon-carbon double bond, and "alkynyl" means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may each be cyclic, branched or straight-chain.

The term 'aryl', alone or in combination with other radicals, refers to a carbocyclic containing 6 carbon atoms which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, saturated or unsaturated. aromatic monocyclic group. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, teprahyadronaphthyl, and the like. Aryl may be linked with other groups at appropriate positions on the aromatic ring.

The term 'alkoxy' refers to an alkyl group linked to another group through an oxygen atom (ie, -O-alkyl). Alkoxy groups may be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C ₁ -C ₆ )alkoxy groups such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O -2-Methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl -1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O -3-Methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl -1-butyl, -O-butyl, -O-isobutyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl .

The term 'phenoxy' refers to a phenyl group linked to another group through an oxygen atom (ie, -O-aryl). The phenoxy group is unsubstituted or one or more halogen; an alkyl group; It may be substituted with an aryl group and a hetero aryl group, but is not limited thereto.

The term 'amino group' refers to an alkyl group linked to another group through a nitrogen atom (ie -NH- or -N-alkyl). The amine group may be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6)amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl; -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2 -Dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2 -Ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N, N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, - N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N- propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N- Propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N- Dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl , -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl.

The term 'halogen atom' refers to an atom of group 7 of the periodic table. Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

The term 'carbonyl group' refers to -(C=O)-, and may be substituted with hydrogen, an alkyl group, an alkoxy group, or an amino group, but is not limited thereto.

The term 'heterocycle group' refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise specified. Preferably, the heterocyclyl group may include a pyrrolidine group, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mol It may include a porine group, but is not limited thereto.

The term 'heteroaryl group' refers to a heteroaromatic compound including at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise stated. Preferably, the heteroaryl group is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include, but is not limited to, an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group.

The term 'derivative' refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.

The term 'stereoisomer' refers to a compound having the same molecular formula and the same method for connecting members, but having different spatial arrangement between atoms. The stereoisomer may be a diasteromer or an enantiomer. An enantiomer refers to an isomer that does not overlap the mirror image as in the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are divided into R (Rectus: clockwise) and S (sinister: counterclockwise) when 4 or more substituents differ from each other at the chiral central carbon. Diastereomers refer to stereoisomers that are not in a mirror image relationship, and can be divided into cis-trans isomers due to the spatial arrangement of atoms.

The compound represented by the above [Formula 1] according to the present invention is specifically exemplified as follows:

(Compound No. 1) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(trifluoromethyl)benzamide;

(Compound No. 2) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -methoxybenzamide;

(Compound No. 3) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(trifluoromethyl)benzamide;

(Compound No. 4) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -cyanobenzamide;

(Compound No. 5) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -chlorobenzamide;

(Compound No. 6) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -chlorobenzamide;

(Compound No. 7) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -chlorobenzamide;

(Compound No. 8) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -nitrobenzamide;

(Compound No. 9) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -nitrobenzamide;

(Compound No. 10) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluorbenzamide;

(Compound No. 11) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methoxybenzamide;

(Compound No. 12) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -(dimethylamino)benzamide;

(Compound No. 13) N-thiophene between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -2-carboxamide;

(Compound No. 14) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,4-dimethoxybenzamide;

(Compound No. 15) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromofuran-2-carboxamide;

(Compound No. 16) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -bromo-5-(trifluoromethyl)benzamide;

(Compound No. 17) N-triazolo between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -4-carboxamide;

(Compound No. 18) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -Meticisoxazole-3-carboxamide;

(Compound No. 19) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -(pyridin-4-yl)cyazole-4-carboxamide;

(Compound No. 20) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-1 -phenyl-5- (tri-fluoro methyl) -1 H-pyrazole-4-carboxamide;

(Compound No. 21) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromothiophene-2-carboxamide;

(Compound No. 22) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 23) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) benzamide ;

(Compound No. 24) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -methylbenzamide;

(Compound No. 25) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -chloro-3-(trifluoromethyl)benzamide;

(Compound No. 26) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-cyanopropen-2-yl)benzamide;

(Compound No. 27) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,5-dimethylfuran-3-carboxamide;

(Compound No. 28) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -morpholino-5-(trifluoromethyl)benzamide;

(Compound No. 29) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 30) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;

(Compound No. 31) (S) - N - (3- (1- (6- aminomethyl-pyridin-4-yl) -1 H - pillow as [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 32) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 33) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 34) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 35) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((2-(dimethylamino)ethyl)(methyl)amino)-3-(trifluoromethyl)benzamide;

(Compound No. 36) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(2,4-dimethyl- 1H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 37) N - (3- (1- (6- amino-pyridin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methyl-phenyl) -4- (4-methyl-1 H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;

(Compound No. 38) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(dimethylamino)-3-(trifluoromethyl)benzamide;

(Compound No. 39) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide;

(Compound No. 40) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2,4-dimethyl- 1H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 41) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;

(Compound No. 42) tert-butyl-4- (4 - ((3- (1- (6-amino-pyrimidin-4-yl) -1 H-pyrrolo [3,2-c] pyridin-6-yl )-4-methylphenyl)carbamoyl)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate;

(Compound No. 43) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methyl-3-(trifluoromethyl)benzamide;

(Compound No. 44) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluor-3-(trifluoromethyl)benzamide;

(Compound No. 45) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-hydroxypiperidin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 46) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(morpholinomethyl)-3-(trifluoromethyl)benzamide;

(Compound No. 47) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -morpholino-3-(trifluoromethyl)benzamide;

(Compound No. 48) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-methoxyphenyl)urea;

(Compound No. 49) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(3-(trifluoromethyl)phenyl)urea;

(Compound No. 50) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-(trifluoromethyl)benzamide;

(Compound No. 51) 3- (4-methyl -1 H-imidazol -1-) - N - (4-methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) - 1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-5-(trifluoromethyl)benzamide;

(Compound No. 52) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-morpholino-5-(trifluoromethyl)benzamide;

(Compound No. 53) N - (3- (1- (6- ( cyclopropylamine) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 54) N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine -6 -yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 55) N - (3- (1- (7 H - pyrrolo [2,3-d] pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine-6 yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 56) N - (3- (7- (6- amino-pyrimidin-4-yl) -7 H-pyrrolo [2,3-d] pyrimidin-2-yl) -4-methylphenyl) - 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 57) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 58) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (tri-fluoro methyl) benzamide ;

(Compound No. 59) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-4-((4-methylpiperazine) -1-yl)methyl)-3-(trifluoromethyl)benzamide;

(Compound No. 60) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-3-(dimethylamino)-5 -(trifluoromethyl)benzamide;

(Compound No. 61) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -6- (tri-fluoro methyl) nicotinamide ;

(Compound No. 62) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (2,4-dimethyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

(Compound No. 63) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4 yl) -1 H - indazol-6-yl) phenyl) -5- (tri-fluoro methyl) benzamide;

(Compound No. 64) 3- (2,4-dimethyl -1 H-imidazol -1-) - N - (3- ( 1- (6 - ((2- hydroxyethyl) amino) pyrimidin- 4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide;

(Compound No. 65) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidine -4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide; and

(Compound No. 66) N - (3- (2- (6- amino-pyrimidin-4-yl) -2 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;

.

.

The compound of [Formula 1] according to the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, and preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, and lactic acid. , pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, It may be at least one selected from the group consisting of salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.

The compound of [Formula 1] or a pharmaceutically acceptable salt thereof according to the present invention may include hydrates and solvates. The hydrate may mean that the compound of [Formula 1] is formed by bonding with water molecules.

Another aspect of the present invention is cancer prevention, alleviation, including a compound selected from the compound represented by [Formula 1] according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof according to the present invention as an active ingredient. Or it provides a pharmaceutical composition for treatment.

The pharmaceutical composition according to the present invention has excellent ability to inhibit the activity of protein kinase. The protein kinase is specifically ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PEAK1, PKA, PYK2, RAF1, RET, RIPK3, RIPK4, ROS, RIPK RSK2, SLK, STK21, TAOK1, TAOK2, TAOK3, TESK1, TIE2, TNK1, TYK1, TYRO3, YES, and ZAK.

In one example, the MER kinase whose activity is inhibited by the compound of the present invention is a tyrosine kinase belonging to the TAM (Tyro3, Axl and Mer) family together with TYRO3 and AXL, and is known to be associated with cancer progression, metastasis and drug resistance. In addition, it is known that it can relieve inflammation in immune cells and inhibit the survival of cancer cells. That is, the MER kinase inhibition according to the pharmaceutical composition comprising the compound of the present invention as an active ingredient promotes immune action and suppresses cancer cell survival, as well as promotes sensitivity to anticancer agents and inhibits metastasis of cancer cells.

Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing and alleviating cancer caused by abnormal cell growth. Cancers that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention include blood cancer, lymphoma, bladder cancer, breast cancer, melanoma, endometrial cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer , bone cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, and fibroadenoma. Specifically, the hematologic cancer may be chronic myelogenous leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia.

In particular, the pharmaceutical composition of the present invention inhibits the activity of Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase, and does not inhibit the activity of VEGFR2 kinase, that is, Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase. Since the kinase selectively exhibits excellent inhibitory activity, it can be usefully used as a therapeutic agent for the prevention, alleviation or treatment of hematologic cancers, particularly chronic myelogenous leukemia (CML).

In one embodiment of the present invention, as a result of analyzing the protein kinase inhibitory activity of pyrrolopyrimidine, pyrrolopyridine, and indazole compounds, which are novel compounds represented by the [Formula 1], ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PEAK1, PKA, PYK2, RAF1, RET, RIPK3, RIPK4, ROS, RSK1, RSK2, SLK, STK21, TAOK1, TAOK2, TESK1, TAOK2, TESK1 It was confirmed that there is excellent inhibitory activity against kinases such as TIE2, TNK1, TYK1, TYRO3, YES, and ZAK (Experimental Example 1).

In addition, it was confirmed that the novel pyrrolopyrimidine, pyrrolopyridine, and indazole compounds exhibit excellent inhibitory activity against Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase (Experimental Example 2).

In addition, the novel pyrrolopyrimidine, pyrrolopyridine, and indazole compounds were treated with wt-Bcr-Abl Ba/F3, T315I-Bcr-Abl Ba/F3, VEGFR2 Ba/F3 cell lines. As a result, wt-Bcr- It was confirmed that the proliferation of Abl Ba/F3 and T315I-Bcr-Abl Ba/F3 cell lines was excellently inhibited, whereas it was confirmed that the cell proliferation inhibitory activity was weak for the VEGFR2 Ba/F3 cell lines (Experimental Example 3).

As such, the novel pyrrolopyrimidine, pyrrolopyridine, and indazole compounds represented by [Formula 1] according to the present invention inhibit Bcr-Abl, a causative protein of chronic myelogenous leukemia (CML). Since it has activity, it is not only useful as a target drug for CML, but also has a strong inhibitory activity against the mutant T315I-Bcr-Abl, so it can be seen that the drug resistance is also excellent. At the same time, it was found that the inhibitory activity was low with respect to VEGFR2 kinase, that is, it was selective for Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase, and the possibility of inducing drug side effects was significantly low.

Therefore, the novel compound represented by [Formula 1] according to the present invention has excellent inhibitory activity against Bcr-Abl, which is a causative gene of chronic myeloid leukemia, and its point mutant T315I-Bcr-Abl, and against VEGFR2 kinase It has been demonstrated that it can be used as a useful pharmaceutical composition for the treatment, prevention and alleviation of chronic myelogenous leukemia, which does not exhibit inhibitory activity, and simultaneously reduces drug resistance and side effects.

In another aspect of the present invention, the pharmaceutical composition provides a pharmaceutical composition for preventing, alleviating or treating cancer, characterized in that it is administered to a patient having a Bcr-Abl gene or a T315I-Bcr-Abl gene.

The pharmaceutical composition may be applied to experimental animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto, preferably primates including humans, more preferably humans.

As used herein, 'treatment' refers to alleviation or amelioration of symptoms, reduction in the scope of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease state, partial or complete recovery, prolongation of survival, and other beneficial therapeutic results, etc. may be used in the meaning of including all of them.

In addition, as used herein, treatment of cancer refers to treatment of all cancer cells, and cancer includes angiogenesis of endothelial cells and mitosis (solid tumors, tumor metastases and benign tumors). For example, cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital organ cancer, esophageal cancer, laryngeal cancer, glioblastoma, stomach cancer, skin cancer, keratoacytoma, lung cancer, squamous cell carcinoma, large cell carcinoma, Small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated cancer, papillary cancer, seminomas, melanoma, sarcoma, bladder cancer, liver and bile duct cancer, kidney cancer, myeloid disease, lymphoid Disease, Hodgkin's disease, hair cell cancer, oral cancer, pharyngeal (oral) cancer, labial cancer, tongue cancer, small intestine cancer, colorectal cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma or sarcoidosis suppurativa may include, but is not limited thereto.

The content of the compound selected from the compound represented by the above [Formula 1] as an active ingredient, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof according to the usage aspect and method of the pharmaceutical composition of the present invention is According to the selection of a person skilled in the art, it may be appropriately adjusted and used.

In one example, the pharmaceutical composition is 0.1 to 10% by weight based on the total weight of the compound selected from the compound represented by [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, more Preferably, it may be included in an amount of 0.5 to 5% by weight.

The compound represented by the above [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, and a compound selected from a stereoisomer thereof may be included alone in the pharmaceutical composition, or other pharmaceutically acceptable carriers, excipients, It may be included together with a diluent or accessory ingredient.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , dextrin, calcium carbonate, propylene glycol, liquid paraffin, and at least one selected from the group consisting of physiological saline, but is not limited thereto, and all conventional carriers, excipients or diluents may be used. In addition, the pharmaceutical composition may contain conventional fillers, bulking agents, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and its salts, pectic acid and its salts, protective colors, glycerin , a fragrance, emulsifier or preservative may be further included.

The compound of [Formula 1] according to the present invention is a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, and a compound selected from a stereoisomer thereof is administered in combination with another anticancer agent for treating cancer or tumor. Treatment of an anticancer agent effect can be enhanced.

Specifically, the pharmaceutical composition may be used as a combination therapy applied at the same time or at the same time by further including one or more other anticancer agents or other therapeutic agents known to be effective for the treatment or prevention of cancer in addition to the active ingredient. Other anticancer agents or other therapeutic agents that may be applied to the combination therapy include, for example, Gleevec ^® , imatinib, Sutent ^® , sunitinib), Herceptin ^® , Trastuzumab, Velcade ^® , Bortezomib), dexamethasone, Nexavar (Nexavar ^® , Sorafenib), may include one or more compounds selected from the group consisting of aromatase inhibitors or kinase inhibitors, but is not limited thereto.

The method of administering the pharmaceutical composition may be oral or parenteral, for example, it may be administered through several routes including oral, transdermal, subcutaneous, intravenous or intramuscular. In addition, the formulation of the composition may vary depending on the method of use, and it is formulated using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. can be In general, solid preparations for oral administration include tablets (TABLETS), pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS), and granules (GRANULES), and such preparations include one or more An excipient, for example, may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions (SUSTESIONS), internal solutions, emulsions (EMULSIONS), and syrups (SYRUPS). Sweetening agents, flavoring agents, preservatives, and the like may be included. Forms for parenteral administration include creams, lotions, ointments, PLASTERS, LIQUIDS AND SOULTIONS, aerosols, FRUIDEXTRACTS, and elixirs. (ELIXIR), infusions (INFUSIONS), sachets (SACHET), patches (PATCH) or injections (INJECTIONS) may be in the form of, etc., and preferably in the form of an isotonic aqueous solution or suspension in the case of an injection formulation. .

The pharmaceutical composition may further contain adjuvants such as sterilizing agents, preservatives, stabilizing agents, wetting agents or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and conventional mixing, granulation Alternatively, it may be formulated according to a coating method, and in addition, it may be formulated using an appropriate method known in the art.

In addition, the dosage of the pharmaceutical composition may be determined in consideration of the administration method, the age, sex, severity, condition of the patient, the absorption of the active ingredient in the body, the inactivation rate, and the drug to be used in combination, once or several times. It can be administered in divided doses. As an active ingredient of the pharmaceutical composition, preferably in an amount of 0.001 to 100 mg/kg of body weight, preferably 0.01 to 35 mg/kg of body weight, per day to mammals including humans, once a day or divided into oral or parenteral It may be administered by the oral route.

Another embodiment of the present invention, administering a therapeutically effective amount of a compound selected from the compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof It provides a method of treating cancer, including.

Preferably, the treatment method may further include the step of identifying a patient in need of the prevention or treatment of the cancer before the administering step.

The "therapeutically effective amount" of the present invention means an amount of an active ingredient for a mammal that is effective for the prevention or treatment of cancer, and the therapeutically effective amount includes the type of disease, the severity of the disease, the active ingredient and other ingredients contained in the composition. It can be adjusted according to various factors including the type and content of the drug, the type of dosage form, and the age, weight, general health condition, sex and diet of the patient, administration time, administration route and blood clearance of the composition, treatment period, and concurrently used drugs. However, preferably, as described above, in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, per day, once a day or divided into oral or parenteral routes can do.

On the other hand, the pyrrolopyrimidine, pyrrolopyridine, and indazole compounds represented by the [Formula 1] according to the present invention are newly synthesized compounds based on the compounds disclosed in Korean Patent No. 10-1116756, and the [Formula 1] The novel compound represented by 1] can be easily synthesized and used based on the preparation method disclosed in Korea Patent Registration No. 10-1116756 or a method known in the art.

Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, the following Examples, Formulation Examples, and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples. It will be apparent to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention.

In addition, those of ordinary skill in the art to which the present invention pertains may prepare the target compound by various methods based on the structure of [Formula 1], and all of these methods are included in the scope of the present invention. should be interpreted That is, the compound of the present invention can be prepared by arbitrarily combining the synthetic methods specifically described in the following examples or various synthetic methods disclosed in the prior art, which are understood to fall within the scope of the present invention, and the preparation of the compound of the present invention The method is not limited by the specific examples below.

[Example] Synthesis of protein kinase inhibitory compounds

Example 1: N -(3-(1-(6-aminopyridin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound No. 1)

Step 1: 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborane

In a round-bottom flask, 3-bromo-4-methyl-1-nitrobenzene (15.0 g, 0.069 mol), bis(pinacolato)diborane (19.4 g, 0.076 mol), potassium acetate (27.0 g, 0.276) mol), Pd(dppf)Cl ₂ -dichloromesane (5.6 g, 0.0069 mol) was added, and 1,4-dioxane (400 mL) was added and dissolved. After stirring at 100° C. for 6 hours, when the reaction was completed, it was filtered through celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography (ethyl acetate:hexane = 8:92) to obtain a white target compound (14.6 g, 80%). LCMS (ESI) m/z 264 [M + H] ⁺ .

Step 2: 6-(2-methyl-5-nitrophenyl)-1 H -pyrrolo[3,2-c]pyridine

6-bromo-1H -indole (500 mg, 2.36 mmol) was put in a round-bottom flask, and 1,2-dimethoxyethane (8 mL) was added and dissolved. Then, 4,4,5,5-tetramethyl-2- (2-methyl-5-nitrophenyl) -1,3,2-dioxaborane (930 mg, 3.54 mmol), Pd (PPh ₃ ) ₄ (1.64 g, 1.42 mmol) and 2 M aqueous sodium carbonate solution (5.9 mL, 11.8 mmol) were added. After stirring at 100° C. for 6 hours, when the reaction was completed, it was filtered through celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography (ethyl acetate:hexane = 1:4) to obtain a yellow target compound (400 mg, 67%). LCMS (ESI) m/z 254 [M + H] ⁺ .

Step 3: 1-(6-Chloropyrimidin-4-yl)-6-(2-methyl-5-nitrophenyl)-1 H -pyrrolo[3,2-c]pyridine

6 To a round bottom flask was added (2-methyl-5-nitro-phenyl) -1 H - pyrrolo [3,2-c] pyridin-indole (3.0 g, 0.012 mol), 4,6- chloro limiter Dean (2.6 g , 0.0178 mol) was dissolved in dimethylformamide (140 mL). NaH (1.44 g, 0.036 mol) was added slowly at 0°C. When the reaction was completed after stirring at room temperature for 4 hours, it was solidified using ice water. Filtration and drying gave a yellow target compound (2.61 g, 60%). LCMS (ESI) m/z 264 [M + H] ⁺ .

Step 4: 6-(6-(2-methyl-5-nitrophenyl)-1 H Indol-1-yl)pyrimidin-4-amine

The chamber tube 1- (6-chloro-pyrimidin-4-yl) -6- (2-methyl-5-nitro-phenyl) -1 H - pyrrolo [3,2-c] pyridine (3.0 g, 0.008 mol ), and dimethyl sulfoxide (60 mL) was added and dissolved. Then 2 M ammonia isopropanol solution (60 mL, 0.123 mol) was added. After stirring at 100° C. for 12 hours, when the reaction was completed, it was solidified using ice water. Filtration and drying gave a gray target compound (2.61 g, 93%). LCMS (ESI) m/z 347 [M + H] ⁺ .

Step 5: 6-(6-(5-amino-2-methylphenyl)-1 H -Pyllolo[3,2-c]pyridin-1-yl)pyrimidin-4-amine

(Phenyl) -1 H-indol-1-yl 6- (2-methyl-5-nitro) 6 To a round bottom flask into a pyrimidin-4-amine (3.3 g, 0.0095 mol), ethanol (120 mL) was added and dissolved. Then, SnCl ₂ (10.69 g, 0.0475 mol) was added and stirred at 100° C. for 3 hours. When the reaction was completed, the mixture was diluted with an aqueous solution of ethyl acetate and sodium bicarbonate, and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate, concentrated, solidified using diethyl isomer, and filtered to obtain a gray target compound (2.71 g, 90%). LCMS (ESI) m/z 317 [M + H] ⁺ .

Step 6: N -(3-(1-(6-aminopyridin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide

To a round bottom flask was added 6- (6- (5-amino-2-methylphenyl) -1 H - Peel pyrrolo [3,2-c] pyridin-1-yl) pyrimidin-4-amine (40 mg, 0.127 mmol) , 3-(trifluoromethyl)benzoic acid (36 mg, 0.191 mmol), HATU (97 mg, 0.254 mmol) were added, and dimethylformamide (1.3 mL) was added thereto and dissolved. Then diethylisopropylamine (0.06 mL, 0.318 mmol) was added. After the reaction was completed after stirring at room temperature for 2 hours, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography gave a white target compound (49 mg, 80%). LCMS (ESI) m/z 489 [M + H] ⁺ .

Example 2: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2-methoxybenzamide (Compound No. 2)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 451 (M + H) ⁺ .

Example 3: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(trifluoromethyl)benzamide (Compound No. 3)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 489 (M + H) ⁺ .

Example 4: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-cyanobenzamide (Compound No. 4)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 446 (M + H) ⁺ .

Example 5: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -2-chlorobenzamide (Compound No. 5)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 455 (M + H) ⁺ .

Example 6: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-chlorobenzamide (Compound No. 6)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 455 (M + H) ⁺ .

Example 7: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-chlorobenzamide (Compound No. 7)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 455 (M + H) ⁺ .

Example 8: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-nitrobenzamide (Compound No. 8)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 466 (M + H) ⁺ .

Example 9: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-nitrobenzamide (Compound No. 9)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 466 (M + H) ⁺ .

Example 10: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-fluorbenzamide (Compound No. 10)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 438 (M + H) ⁺ .

Example 11: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-methoxybenzamide (Compound No. 11)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 451 (M + H) ⁺ .

Example 12: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(dimethylamino)benzamide (Compound No. 12)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 464 (M + H) ⁺ .

Example 13: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)thiophene-2-carboxamide (Compound No. 13)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 427 (M + H) ⁺ .

Example 14: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2,4-dimethoxybenzamide (Compound No. 14)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 481 (M + H) ⁺ .

Example 15: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-5-bromofuran-2-carboxamide (Compound No. 15)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 489 (M + H) ⁺ .

Example 16: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-bromo-5-(trifluoromethyl)benzamide (Compound No. 16)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 567 (M + H) ⁺ .

Example 17: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)cyazole-4-carboxamide (Compound No. 17)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 428 (M + H) ⁺ .

Example 18: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-5-methicisoxazole-3-carboxamide (Compound No. 18)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 426 (M + H) ⁺ .

Example 19: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2-(pyridin-4-yl)cyazole-4-carboxamide (Compound No. 19)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 505 (M + H) ⁺ .

Example 20: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-1-phenyl-5-(trifluoromethyl)-1 H -Pyrazole-4-carboxamide (Compound No. 20)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 555 (M + H) ⁺ .

Example 21: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-5-bromothiophene-2-carboxamide (Compound No. 21)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 505 (M + H) ⁺ .

Example 22: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 22)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 569 (M + H) ⁺ .

Example 23: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)benzamide (Compound No. 23)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 421 (M + H) ⁺ .

Example 24: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-methylbenzamide (Compound No. 24)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 435 (M + H) ⁺ .

Example 25: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide (Compound No. 25)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 523 (M + H) ⁺ .

Example 26: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(2-cyanopropen-2-yl)benzamide (Compound No. 26)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 488 (M + H) ⁺ .

Example 27: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2,5-dimethylfuran-3-carboxamide (Compound No. 27)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 439 (M + H) ⁺ .

Example 28: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (Compound No. 28)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 574 (M + H) ⁺ .

Example 29: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamide (compound number 29)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 588 (M + H) ⁺ .

Example 30: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(dimethylamino)-5-(trifluoromethyl)benzamide (Compound No. 30)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 560 (M + H) ⁺ .

Example 31: (S)- N -(3-(1-(6-aminomethylpyridin-4-yl)-1 H -Pyloro[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 31)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 601 (M + H) ⁺ .

Example 32: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound number 32)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 601 (M + H) ⁺ .

Example 33: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (Compound No. 33)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 587 (M + H) ⁺ .

Example 34: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 34)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 587 (M + H) ⁺ .

Example 35: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-3-(trifluoromethyl)benzamide (Compound No. 35)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 589 (M + H) ⁺ .

Example 36: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(2,4-dimethyl-1 H -imidazol-1-yl)-3-(trifluoromethyl)benzamide (Compound No. 36)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 583 (M + H) ⁺ .

Example 37: N -(3-(1-(6-aminopyridin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(4-methyl-1 H -Imidazol-1-yl)-3-(trifluoromethyl)benzamide (Compound No. 37)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 569 (M + H) ⁺ .

Example 38: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(dimethylamino)-3-(trifluoromethyl)benzamide (Compound No. 38)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 532 (M + H) ⁺ .

Example 39: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (Compound No. 39)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 589 (M + H) ⁺ .

Example 40: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(2,4-dimethyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 40)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 583 (M + H) ⁺ .

Example 41: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(dimethylamino)-5-(trifluoromethyl)benzamide (Compound No. 41)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 532 (M + H) ⁺ .

Example 42: tert-butyl-4-(4-((3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)carbamoyl)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound No. 42)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 687 (M + H) ⁺ .

Example 43: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (Compound No. 43)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 503 (M + H) ⁺ .

Example 44: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-fluoro-3-(trifluoromethyl)benzamide (Compound No. 44)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 507 (M + H) ⁺ .

Example 45: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-((4-hydroxypiperidin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound No. 45)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 602 (M + H) ⁺ .

Example 46: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(morpholinomethyl)-3-(trifluoromethyl)benzamide (Compound No. 46)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 588 (M + H) ⁺ .

Example 47: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-morpholino-3-(trifluoromethyl)benzamide (Compound No. 47)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 6 of Example 1. LCMS (ESI): 574 (M + H) ⁺ .

Example 48: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(2-methoxyphenyl)urea (Compound No. 48)

Instead of step 6 of Example 1, the corresponding isocyanate (2 eq), THF (0.1 M) was used to introduce the urea functionality. LCMS (ESI): 466 (M + H) ⁺ .

Example 49: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (Compound No. 49)

Instead of step 6 of Example 1, the corresponding isocyanate (2 eq), THF (0.1 M) was used to introduce the urea functionality. LCMS (ESI): 504 (M + H) ⁺ .

Example 50: N -(4-methyl-3-(1-(6-(methylamino)pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound No. 50)

The experimental method is the same except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in step 4 of Example 1. LCMS (ESI): 503 (M + H) ⁺ .

Example 51: 3-(4-methyl-1 H -imidazol-1-yl)- N -(4-methyl-3-(1-(6-(methylamino)pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-5-(trifluoromethyl)benzamide (Compound No. 51)

The experimental method is the same as in Example 22, except that in step 4 of Example 1, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI): 583 (M + H) ⁺ .

Example 52: N -(4-methyl-3-(1-(6-(methylamino)pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-3-morpholino-5-(trifluoromethyl)benzamide (Compound No. 52)

The experimental method is the same as in Example 28, except that in step 4 of Example 1, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI): 588 (M + H) ⁺ .

Example 53: N -(3-(1-(6-(cyclopropylamine)pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 53)

The experimental method is the same as in Example 22, except that in step 4 of Example 1, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI): 609 (M + H) ⁺ .

Example 54: N-(3-(1-(6-((furan-2-ylmethyl)amino)pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 54)

The experimental method is the same as in Example 22, except that in step 4 of Example 1, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI): 649 (M + H) ⁺ .

Example 55: N -(3-(1-(7) H -pyrrolo[2,3-d]pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 55)

Except for step 2 and step 6 of Example 1, the experimental method is the same. LCMS (ESI): 593 (M + H) ⁺ . Steps 2 and 6 of Example 1 are replaced and performed as follows.

Step 2: (4-(6-(2-methyl-5-nitrophenyl)-1 H -pyrrolo[3,2-c]pyridin-1-yl)-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

To a round bottom flask was added 6- (2-methyl-5-nitro-phenyl) -1 H - pyrrolo [3,2-c] pyridin-indole (1 g, 4.2 mmol), (4- chloro -7 H - pyrrolo [2,3- d ]pyrimidin-7-yl)methyl pivalate (1.35 g, 5.04 mmol), K ₂ CO ₃ (1.74 g, 12.6 mmol), Xantphos (365 mg, 0.63 mmol) and Pd(OAc) ₂ (95 mg, 0.42 mmol) was dissolved in 1,4-dioxane (28 mL). NaH (1.44 g, 0.036 mol) was added slowly at 0°C. After stirring at 120° C. for 1 hour, when the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography (ethyl acetate:hexane = 1:2) to obtain a yellow target compound (1.84 g, 90%). LCMS (ESI) m/z 485 [M + H] ⁺ .

step 6 : N -(3-(1-(7) H -pyrrolo[2,3-d]pyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide

(4-(6-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-1H-pyrrolo[ 3,2-c]pyridin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1 eq), 1 N NaOH (0.05 M) and methanol (0.05 M) was added and stirred at room temperature for 2 hours. When the reaction was completed, the organic layer was washed with brine after dilution with ethal acetate. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography to obtain the target compound. LCMS (ESI) m/z 593 [M + H] ⁺ .

Example 56: N -(3-(7-(6-aminopyrimidin-4-yl)-7 H -pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 56)

Step 1: 2-(2-methyl-5-nitrophenyl)-7 H -pyrrolo[2,3-d]pyrimidine

To a round bottom flask was added 2-chloro -7 H - pyrrolo [2,3-d] pyrimidine (1 g, 6.0 mmol), 4,4,5,5- tetramethyl-2- (2-methyl-5 Nitrophenyl)-1,3,2-dioxaborane (2.5 g, 9.8 mmol), Pd(PPh ₃ ) ₄ (1.38 g, 1.2 mmol), cesium carbonate (5.85 g, 18 mmol) were added, 1, 4-dioxane: water (10:1, 25 mL) was added and dissolved. After stirring at 100° C. for 3 hours, when the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography (ethyl acetate:hexane = 1:4) to obtain a brown target compound (1.3 g, 85%). LCMS (ESI) m/z 255 [M + H] ⁺ .

Step 2: 7-(6-Chloropyrimidin-4-yl)-2-(2-methyl-5-nitrophenyl)-7 H -Pylolo[2,3-d]pyrimidine

2 - To a round bottom flask was added (2-methyl-5-nitro-phenyl) -7 H - pyrrolo [2,3-d] pyrimidine (500 mg, 1.96 mmol), 4,6- dichloro-pyrimidine (437 mg, 2.95 mmol), K ₂ CO ₃ (810 mg, 5.88 mmol) was added, and dimethylformamide (14 mL) was added and dissolved. After stirring at 80° C. for 30 minutes, when the reaction was completed, it was solidified using ice water. Filtration and drying gave a yellow target compound (2.61 g, 93%). LCMS (ESI) m/z 367 [M + H] ⁺ .

Step 3: 6-(2-(2-methyl-5-nitrophenyl)-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)pyrimidin-4-amine

The chamber tube 7- (6-chloro-pyrimidin-4-yl) -2- (2-methyl-5-nitro-phenyl) -7 H - Peel-pyrrolo [2,3-d] pyrimidine (500 mg) into , dimethyl sulfoxide (10 mL) was added and dissolved. Then 2 M ammonia isopropanol solution (10 mL) was added. After stirring at 100° C. for 12 hours, when the reaction was completed, it was solidified using ice water. Filtration and drying gave a gray target compound (402 mg, 85%). LCMS (ESI) m/z 348 [M + H] ⁺ .

Step 4: 6-(2-(5-amino-2-methylphenyl)-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)pyrimidin-4-amine

6 To a round bottom flask was added (2- (2-methyl-5-nitro-phenyl) -7 H - pyrrolo [2,3-d] pyrimidin-7-yl) pyrimidin-4-amine (1.1 g, 3.17 mmol) was added, and ethanol (40 mL) was added to dissolve. Then, SnCl ₂ (3.56 g, 15.8 mol) was added and stirred at 100° C. for 3 hours. When the reaction was completed, the mixture was diluted with an aqueous solution of ethyl acetate and sodium bicarbonate, and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate, concentrated, solidified using diethyl isomer, and filtered to obtain a gray target compound (1.0 g, 88%). LCMS (ESI) m/z 318 [M + H] ⁺ .

Step 5: N -(3-(7-(6-aminopyrimidin-4-yl)-7 H -pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(fluoromethyl)benzamide

To a round bottom flask was added 6- (2- (5-amino-2-methylphenyl) -7 H - pyrrolo [2,3-d] pyrimidin-7-yl) pyrimidin-4-amine (40 mg, 0.127 mmol ), 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (51 mg, 0.191 mmol), HATU (97 mg, 0.254 mmol), and di Methylformamide (1.3 mL) was added and dissolved. Then diethylisopropylamine (0.06 mL, 0.318 mmol) was added. After stirring at room temperature for 2 hours, when the reaction was completed, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The target compound was obtained by purification by chromatography (50 mg, 70%). LCMS (ESI) m/z 570 [M + H] ⁺ .

Example 57: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 57)

Step 1: 6-(2-methyl-5-nitrophenyl)-1 H -indazole

6-bromo-1H-indazole (200 mg, 1.02 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3, in a round bottom flask 2-dioxaborane (348 mg, 1.326 mmol), cesium carbonate (998 mg, 3.06 mmol), Pd(PPh ₃ ) ₄ (236 mg, 0.204 mmol) was added, and 1,4-dioxane: water (10: 1, 10 mL) was added and dissolved. After stirring at 110° C. for 2 hours, when the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, concentrated, and purified by chromatography (ethyl acetate: hexane = 1:3) to obtain a light yellow target compound (206 mg, 80%). LCMS (ESI) m/z 254 [M + H] ⁺ .

Step 2: 1-(6-Chloropyrimidin-4-yl)-6-(2-methyl-5-nitrophenyl)-1 H -indazole

6 To a round bottom flask was added (2-methyl-5-nitro-phenyl) -1 H - indazole (500 mg, 1.96 mmol), 4,6- dichloro-pyrimidine (437 mg, 2.95 mmol), K 2 CO ₃ (810 mg, 5.88 mmol) was added, and dimethylformamide (14 mL) was added and dissolved. When the reaction was completed after stirring at 60° C. for 30 minutes, it was solidified using ice water. It was filtered and dried to obtain the target compound. LCMS (ESI) m/z 366 [M + H] ⁺ .

Step 3: 6-(6-(2-methyl-5-nitrophenyl)-1 H -Indazol-1-yl)pyrimidin-4-amine

The chamber tube 1- (6-chloro-pyrimidin-4-yl) -6- (2-methyl-5-nitro-phenyl) -1 H - indazol-put (500 mg), dimethyl sulfoxide (10 mL ) was added and dissolved. Then 2 M ammonia isopropanol solution (10 mL) was added. When the reaction was completed after stirring at 100° C. for 12 hours, it was solidified using ice water. Filtration and drying gave the target compound (402 mg, 85%). LCMS (ESI) m/z 347 [M + H] ⁺ .

Step 4: 6-(6-(5-amino-2-methylphenyl)-1 H -Indazol-1-yl)pyrimidin-4-amine

6 To a round bottom flask was added (6- (2-methyl-5-nitro-phenyl) -1 H - indazol-1-yl) into the pyrimidin-4-amine (1.1 g, 3.17 mmol), ethanol (40 mL) was added and dissolved. Then, SnCl ₂ (3.56 g, 15.8 mol) was added and stirred at 100° C. for 3 hours. When the reaction was completed, the mixture was diluted with an aqueous solution of ethyl acetate and sodium bicarbonate, and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate, concentrated, solidified using diethyl ester, and filtered to obtain the target compound. LCMS (ESI) m/z 317 [M + H] ⁺ .

Step 5: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide

(-Indazol-1-yl 6- (5-amino-2-methylphenyl) -1 H) pyrimidin-4-amine (40 mg, 0.127 mmol), 3- (4- methyl-6-To a round bottom flask 1 H -imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (51 mg, 0.191 mmol), HATU (97 mg, 0.254 mmol) were added, and dimethylformamide (1.3 mL) was added. melted Then diethylisopropylamine (0.06 mL, 0.318 mmol) was added. After stirring at room temperature for 2 hours, when the reaction was completed, it was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The target compound was obtained by purification by chromatography. LCMS (ESI) m/z 569 [M + H] ⁺ .

Example 58: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound No. 58)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 5 of Example 57. LCMS (ESI): 489 (M + H) ⁺ .

Example 59: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound No. 59)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 5 of Example 57. LCMS (ESI): 601 (M + H) ⁺ .

Example 60: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-3-(dimethylamino)-5-(trifluoromethyl)benzamide (Compound No. 60)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 5 of Example 57. LCMS (ESI): 532 (M + H) ⁺ .

Example 61: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-6-(trifluoromethyl)nicotinamide (Compound No. 61)

The experimental method is the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid in step 5 of Example 57. LCMS (ESI): 490 (M + H) ⁺ .

Example 62: N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-3-(2,4-dimethyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 62)

The experimental method is the same as in Example 57, except that in step 3 of Example 57, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI) m/z 583 [M + H] ⁺ .

Example 63: 3-(2,4-dimethyl-1 H -imidazol-1-yl)- N -(4-methyl-3-(1-(6-(methylamino)pyrimidin-4-yl)-1 H -Indazol-6-yl)phenyl)-5-(trifluoromethyl)benzamide (Compound No. 63)

The experimental method is the same as in Example 63, except that in step 3 of Example 57, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI) m/z 597 [M + H] ⁺ .

Example 64: 3-(2,4-dimethyl-1 H -imidazol-1-yl)- N -(3-(1-(6-((2-hydroxyethyl)amino)pyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (Compound No. 64)

The experimental method is the same as in Example 63, except that in step 3 of Example 57, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI) m/z 627 [M + H] ⁺ .

Example 65: 3-(2,4-dimethyl-1 H -imidazol-1-yl)- N -(3-(1-(6-((furan-2-ylmethyl)amino)pyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (Compound No. 65)

The experimental method is the same as in Example 63, except that in step 3 of Example 57, the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution. LCMS (ESI) m/z 663 [M + H] ⁺ .

Example 66: N -(3-(2-(6-aminopyrimidin-4-yl)-2 H -Indazol-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 66)

It was synthesized using the isomer of step 2 of Example 57. LCMS (ESI) m/z 569 [M + H] ⁺ .

[Experimental example]

Inhibition of protein kinase activity was verified by the following Experimental Examples 1 and 2 for the compounds of Compound Nos. 1 to 66 synthesized in the Examples of the present invention, and Bcr-Abl, T315I as oncogenes by Experimental Example 3 -Bcr-Abl or VEGFR2 kinase-injected Ba / F3 cell line to confirm the anticancer activity.

Experimental Example 1: Measurement of protein kinase inhibitory activity

In order to measure the inhibitory activity (% inhibitory capacity) of protein kinases for the compounds of the present invention, biochemical assays were performed on a full kinase panel composed of 369 kinases. As the test compound synthesized in Example 57 N - (3- (1- ( 6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (4 -Methyl-1H -imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 57) was used.

Specifically, the inhibitory efficacy of the kinase was measured by treating the compound of Example 57 at a single concentration of 1 μM, and the residual enzyme activity value (%) was calculated. Table 1 below shows a list of kinases in which the residual enzyme activity value (%) calculated when the compound of Example 57 was treated at a single concentration of 1 μM was inhibited by 30% or less, that is, 70% or more.

List of kinases whose activity is inhibited by more than 70% ABL1 ABL2 ALK ARAF BRAF BRK MER SRC CSK DDR1 DDR2 EPHA1-8 EPHB1-4 ERBB2 ERBB4 FGFR1 FGFR2 FGR FMS FRK GCK HCK JAK1 JAK2 LCK LIMK1 LIMK2 LOK LYN LYNB MLCK2 MUSK P38a P38b P70S6K PDGFR PEAK1 PKA PYK2 RAF1 RET RIPK3 RIPK4 ROS RSK1 RSK2 SLK STK21 TAOK1 TAOK2 TAOK3 TESK1 TIE2 TNK1 TYK1 TYRO3 YES ZAK

According to the results of Table 1, the compounds of the present invention are protein kinases, specifically ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PEAK1, PKA, PYK2 It was found that the ability to inhibit the activity of RAF1, RET, RIPK3, RIPK4, ROS, RSK1, RSK2, SLK, STK21, TAOK1, TAOK2, TAOK3, TESK1, TIE2, TNK1, TYK1, TYRO3, YES, and ZAK was excellent. .

Experimental Example 2: Evaluation of wt-BCR-ABL and T315I-BCR-ABL kinase inhibitory activity

For the compounds of Compound No. 1, Compound No. 16, Compound Nos. 22 to 25, and Compound Nos. 28 to 34, wt (wild type)-BCR-ABL, T315I-BCR-ABL IC ₅₀ value by measuring the inhibitory ability against two kinases was calculated. The calculated IC ₅₀ values are shown in Table 2 below.

test compound wt-BCR-ABL
(IC ₅₀ , μM) T315I-Bcr-AbL
(IC ₅₀ , μM) compound number 1 B A compound number 16 A A compound number 22 A A compound number 23 C C compound number 24 C C compound number 25 C A compound number 28 B A compound number 29 A A compound number 30 B A compound number 31 B A compound number 32 B B compound number 33 B A compound number 34 A A

* IC ₅₀ values were expressed in 3 steps.

A: IC ₅₀ < 0.1 μM

B: 0.1 μM < IC ₅₀ < 1.0 μM

C: IC ₅₀ > 1.0 μM

According to the results in Table 2, it can be seen that the compound of the present invention inhibits the BCR-ABL tyrosine kinase and the point mutation of BCR-ABL, specifically, the activity of the point mutation of T315I-Bcr-AbL, and the effect is remarkable. there was. Therefore, it was found that the compound of the present invention inhibits the activation of BCR-ABL tyrosine kinase and its mutant activation, and thus can be utilized as a therapeutic agent for cancer, particularly chronic myelogenous leukemia, caused by BCR-ABL tyrosine kinase activity and its mutation.

Experimental Example 3: Evaluation of cancer cell proliferation inhibitory activity

Secondary mutations in which amino acids of the target protein are substituted induce drug resistance. In order to confirm the efficacy of the new drug for secondary mutation, the cancer cell proliferation inhibitory activity was evaluated using the Ba/F3 cell line, a cell line model that is widely used. Specifically, the parental Ba/F3 cell line was injected with wild-type (wt)-Bcr-Abl, T315I-Bcr-Abl and vascular endothelial growth factor receptor 2 (VEGFR2) kinase, respectively. Ba/F3 cell line, that is, wt-Bcr -Abl Ba / F3, T315I-Bcr-Abl Ba / F3, VEGFR2 Ba / F3 cell lines of the present invention (Compound Nos. 1 to 57, and Compound No. 66) by measuring the proliferation inhibitory ability by the cell line GI ₅₀ value was calculated. . The calculated GI ₅₀ values are shown in Table 3 below. At this time, imatinib and ponatinib were used as positive controls.

test compound wt-BCR-ABL T315I-BCR-ABL VEGFR2 test compound wt-BCR-ABL T315I-BCR-ABL VEGFR2 imatinib B C A compound number 29 A A A ponatinib A A C compound number 30 B B A compound number 1 B A B compound number 31 unmeasured A A compound number 2 C C A compound number 32 A A B compound number 3 C C A compound number 33 C A A compound number 4 C C A compound number 34 B A A compound number 5 C C A compound number 35 B C A compound number 6 C C A compound number 36 A B A compound number 7 C C A compound number 37 A B A compound number 8 C C A compound number 38 A B A compound number 9 C C A compound number 39 A B A compound number 10 C C A compound number 40 A B A compound number 11 C C A compound number 41 B C A compound number 12 C C A compound number 42 C C A compound number 13 C C A compound number 43 B B A compound number 14 C C A compound number 44 B C A compound number 15 C C A compound number 45 B B A compound number 16 B B B compound number 46 B B A compound number 17 C C A compound number 47 A A B compound number 18 C C A compound number 48 C C A compound number 19 C C A compound number 49 C C A compound number 20 B B A compound number 50 C A A compound number 21 C C A compound number 51 B A A compound number 22 A A A compound number 52 B A A compound number 23 C C A compound number 53 A A A compound number 24 C C C compound number 54 C B A compound number 25 C B A compound number 55 B B A compound number 26 B A B compound number 56 C C A compound number 27 C C A compound number 57 A A A compound number 28 B A A compound number 66 B A A

_{* The GI 50} values calculated by measuring the proliferation inhibitory ability of the Ba/F3 cell lines injected with wt-BCR-ABL and T315I-BCR-ABL were displayed in three steps as follows.

A: GI ₅₀ < 0.1 μM

B: 0.1 μM < GI ₅₀ < 1.0 μM

C: GI ₅₀ > 1.0 μM

_{* The GI 50} value calculated by measuring the proliferation inhibitory ability of the Ba/F3 cell line injected with VEGFR2 kinase was displayed in the following three steps.

A: GI ₅₀ > 1.0 μM

B: 0.1 μM < GI ₅₀ < 1.0 μM

C: GI ₅₀ < 0.1 μM

According to the results of Table 3, the ponatinib drug strongly inhibited the proliferation of wild-type Bcr-Abl-injected Ba/F3 cell lines and T315I-Bcr-Abl-injected Ba/F3 cell lines, and at the same time, VEGFR2 kinase It was confirmed that the injected Ba/F3 cell line also had a strong proliferation inhibitory activity.

However, the toxicity of antiangiogenic tyrosine kinase inhibitors as a mechanism of side effects is the so-called 'off-targets', but the target kinase is expressed not only in tumor endothelial cells but also in normal endothelial cells, resulting in toxicity. This usually happens because it doesn't work properly. Accordingly, it was found that ponatinib can induce cardiovascular diseases such as hypertension, suppression of myelogenesis, and pancreatitis as side effects commonly caused by ponatinib.

In addition, it was confirmed that the proliferation of the wt-Bcr-Abl-injected Ba/F3 cell line and the T315I-Bcr-Abl-injected Ba/F3 cell line was excellently inhibited by the compounds of the present invention (Compound Nos. 1 to 57, and Compound No. 66). did. On the other hand, it was confirmed that the cell proliferation inhibitory activity was weak with respect to the VEGFR2 kinase-injected Ba/F3 cell line, and thus it was found that the possibility of inducing drug side effects was significantly low by the compounds of the present invention.

Therefore, through the above series of results, the compounds of the present invention have inhibitory activity against Bcr-Abl, the causative protein of CML, and thus are useful as target drugs for chronic myelogenous leukemia (CML) as well as mutant species. Since it has a strong inhibitory activity against T315I-Bcr-Abl, it can be seen that the drug resistance is also excellent. At the same time, it was found that the inhibitory activity for VEGFR2 kinase was low, so that the side effects of the drug could be reduced.

[Formulation example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation Example 1: Tablet (Direct Pressurization)

After sieving 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation Example 2: Tablet (wet granulation)

After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 800.3 mg of polysorbate in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3: Powder and Capsule

After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. Mix the mixture into a solid No. using a suitable device. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, _{26 mg of Na 2} HPO ₄ ·12H ₂ O, and 2974 mg of distilled water.

In the above, the embodiments of the present invention have been described, but those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (11)

A compound selected from a compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof:
[Formula 1]

In Formula 1,
X ₁ , X ₂ and X ₃ are each independently CH or nitrogen, and at least one of _{X 1} , X ₂ and X _{3 is nitrogen,}
L is -NR ⁵ -; -NR ⁵ CH ₂ -; -NHR ⁵ -; -NR ⁵ C(O)-; -C(O)NR ⁵ -; -NR ⁵ C(O)NR ⁵ -; -S(O) ₂ -; -NR ⁵ S(O) ₂ -; and -S(O) ₂ NR ⁵ -;
A is a C ₆ -C ₁₀ aryl group; or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;
R ¹ is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ¹ may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{2 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}
R ² is hydrogen; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ cyclyl group; C ₃ -C ₁₀ heteroaryl group; C ₃ -C ₁₀ heterocyclyl group; -C(O)-(C ₁ -C ₁₃ alkyl); or R ² may optionally include at least one of N, O, NH, C=N, C=O or SO ₂ together with a nitrogen atom connected to R ^{1 ,} _{and a C 1} -C ₁₃ alkyl group, C ₆ -C forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a ₁₀ aryl group, a C ₃ -C _{10 heteroaryl group, a hydroxyl group, a halide group and a cyano group;}
R ³ is hydrogen; halogen; C ₁ -C ₁₃ alkyl group; or a C ₃ -C ₁₀ cyclyl group;
R ⁴ is hydrogen; hydroxyl group; halogen group; amino group; nitro; cyano group; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₆ -C ₁₀ aryl group; C ₁ -C ₆ alkoxy group; C ₃ -C ₁₀ heteroaryl group; or a C ₃ -C ₁₀ heterocyclyl group;
R ⁵ is hydrogen; C ₁ -C ₆ alkyl group; and an oxazole group; selected from the group consisting of;
m is an integer from 1 to 3,
The C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group or C ₃ -C ₁₀ cyclyl group may be selected from the group consisting of hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it comprises one or more substituents selected from the group consisting of _{C 3} -C _{10 heterocyclyl group,}
The C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, or C ₃ -C ₁₀ heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R ⁶ R ⁷ ); _{a C 1} -C ₃ alkyl group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; _{a C 1} -C ₃ alkoxy group unsubstituted or substituted with a halogen or C ₃ -C ₁₀ heterocyclyl group; C ₆ -C ₁₀ phenoxy; amino group (-NR ⁶ R ⁷ ); amide group (-(C=O)NR ⁶ R ⁷ ); C ₆ -C ₁₀ aryl group; Containing one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heteroaryl group and a C ₃ -C _{10 heterocyclyl group,}
said R ⁶ and R ⁷ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkenyl group; C ₁ -C ₆ alkynyl group; C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it includes at least one selected from the group consisting of a _{C 3} -C _{10 heterocyclyl group,}
The C ₃ -C ₁₀ heteroaryl group and the C ₃ -C ₁₀ heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.
According to claim 1,
wherein L is -NHC(O)-; -C(O)NH-; and -NHC(O)NH-,
Wherein R ³ is CH _{3 And}
Wherein A is any one of benzene, thiophene, furan, cyazole, oxazole, pyrazole and pyridine.
According to claim 1,
The compound represented by the [Formula 1] is a compound selected from the group consisting of the following compound numbers 1 to 66:
(Compound No. 1) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(trifluoromethyl)benzamide;
(Compound No. 2) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -methoxybenzamide;
(Compound No. 3) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(trifluoromethyl)benzamide;
(Compound No. 4) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -cyanobenzamide;
(Compound No. 5) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -chlorobenzamide;
(Compound No. 6) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -chlorobenzamide;
(Compound No. 7) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -chlorobenzamide;
(Compound No. 8) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -nitrobenzamide;
(Compound No. 9) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -nitrobenzamide;
(Compound No. 10) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluorbenzamide;
(Compound No. 11) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methoxybenzamide;
(Compound No. 12) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -4 -(dimethylamino)benzamide;
(Compound No. 13) N-thiophene between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -2-carboxamide;
(Compound No. 14) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,4-dimethoxybenzamide;
(Compound No. 15) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromofuran-2-carboxamide;
(Compound No. 16) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -bromo-5-(trifluoromethyl)benzamide;
(Compound No. 17) N-triazolo between - (pyrrolo [3,2-c] pyridin-6-yl) -4-phenyl 3- (1- (6-amino-pyrimidin-4-yl) -1 H) -4-carboxamide;
(Compound No. 18) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -Meticisoxazole-3-carboxamide;
(Compound No. 19) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 -(pyridin-4-yl)cyazole-4-carboxamide;
(Compound No. 20) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-1 -phenyl-5- (tri-fluoro methyl) -1 H-pyrazole-4-carboxamide;
(Compound No. 21) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -5 -bromothiophene-2-carboxamide;
(Compound No. 22) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 23) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) benzamide ;
(Compound No. 24) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -methylbenzamide;
(Compound No. 25) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -chloro-3-(trifluoromethyl)benzamide;
(Compound No. 26) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-cyanopropen-2-yl)benzamide;
(Compound No. 27) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-2 ,5-dimethylfuran-3-carboxamide;
(Compound No. 28) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -morpholino-5-(trifluoromethyl)benzamide;
(Compound No. 29) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 30) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;
(Compound No. 31) (S) - N - (3- (1- (6- aminomethyl-pyridin-4-yl) -1 H - pillow as [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 32) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;
(Compound No. 33) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide;
(Compound No. 34) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 35) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((2-(dimethylamino)ethyl)(methyl)amino)-3-(trifluoromethyl)benzamide;
(Compound No. 36) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(2,4-dimethyl- 1H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;
(Compound No. 37) N - (3- (1- (6- amino-pyridin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methyl-phenyl) -4- (4-methyl-1 H -imidazol-1-yl)-3-(trifluoromethyl)benzamide;
(Compound No. 38) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(dimethylamino)-3-(trifluoromethyl)benzamide;
(Compound No. 39) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide;
(Compound No. 40) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2,4-dimethyl- 1H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 41) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(dimethylamino)-5-(trifluoromethyl)benzamide;
(Compound No. 42) tert-butyl-4- (4 - ((3- (1- (6-amino-pyrimidin-4-yl) -1 H-pyrrolo [3,2-c] pyridin-6-yl )-4-methylphenyl)carbamoyl)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate;
(Compound No. 43) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -methyl-3-(trifluoromethyl)benzamide;
(Compound No. 44) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -fluor-3-(trifluoromethyl)benzamide;
(Compound No. 45) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -((4-hydroxypiperidin-1-yl)methyl)-3-(trifluoromethyl)benzamide;
(Compound No. 46) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -(morpholinomethyl)-3-(trifluoromethyl)benzamide;
(Compound No. 47) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4 -morpholino-3-(trifluoromethyl)benzamide;
(Compound No. 48) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3 -(2-methoxyphenyl)urea;
(Compound No. 49) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4-methylphenyl) -3 -(3-(trifluoromethyl)phenyl)urea;
(Compound No. 50) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-(trifluoromethyl)benzamide;
(Compound No. 51) 3- (4-methyl -1 H-imidazol -1-) - N - (4-methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) - 1 H -pyrrolo[3,2-c]pyridin-6-yl)phenyl)-5-(trifluoromethyl)benzamide;
(Compound No. 52) N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) phenyl)-3-morpholino-5-(trifluoromethyl)benzamide;
(Compound No. 53) N - (3- (1- (6- ( cyclopropylamine) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridin-6-yl) -4- methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 54) N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine -6 -yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 55) N - (3- (1- (7 H - pyrrolo [2,3-d] pyrimidin-4-yl) -1 H - pyrrolo [3,2-c] pyridine-6 yl)-4-methylphenyl)-3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 56) N - (3- (7- (6- amino-pyrimidin-4-yl) -7 H-pyrrolo [2,3-d] pyrimidin-2-yl) -4-methylphenyl) - 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 57) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 58) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (tri-fluoro methyl) benzamide ;
(Compound No. 59) N -(3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-4-((4-methylpiperazine) -1-yl)methyl)-3-(trifluoromethyl)benzamide;
(Compound No. 60) N- (3-(1-(6-aminopyrimidin-4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-3-(dimethylamino)-5 -(trifluoromethyl)benzamide;
(Compound No. 61) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -6- (tri-fluoro methyl) nicotinamide ;
(Compound No. 62) N - (3- (1- (6- amino-pyrimidin-4-yl) -1 H - indazol-6-yl) -4-methylphenyl) -3- (2,4-dimethyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide;
(Compound No. 63) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (4- methyl-3- (1- (6- (methylamino) pyrimidin-4 yl) -1 H - indazol-6-yl) phenyl) -5- (tri-fluoro methyl) benzamide;
(Compound No. 64) 3- (2,4-dimethyl -1 H-imidazol -1-) - N - (3- ( 1- (6 - ((2- hydroxyethyl) amino) pyrimidin- 4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide;
(Compound No. 65) 3- (2,4-dimethyl -1 H - imidazol-1-yl) - N - (3- (1- (6 - (( furan-2-ylmethyl) amino) pyrimidine -4-yl)-1 H -indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide; and
(Compound No. 66) N - (3- (2- (6- amino-pyrimidin-4-yl) -2 H - indazol-6-yl) -4-methylphenyl) -3- (4-methyl -1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamide.
According to claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, a salt of an inorganic or organic acid selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; A compound selected from the compound represented by [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof.
A pharmaceutical composition for preventing, alleviating or treating cancer, comprising the compound of any one of claims 1 to 4 as an active ingredient.
6. The method of claim 5,
The pharmaceutical composition is applied to a cancer patient having a Bcr-Abl gene or a T315I-Bcr-Abl gene, a pharmaceutical composition for preventing, alleviating or treating cancer.
6. The method of claim 5,
The pharmaceutical composition inhibits Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase activity, and does not inhibit VEGFR2 kinase activity, cancer prevention, alleviation or treatment pharmaceutical composition.
6. The method of claim 5,
The pharmaceutical composition is ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PEAK1, PKA, PYK2, RAF1, RET, RIPK3, RIPK4, ROSK2, RSK SLK, STK21, TAOK1, TAOK2, TAOK3, TESK1, TIE2, TNK1, TYK1, TYRO3, YES, and inhibits the activity of any one or more protein kinases of ZAK, cancer prevention, alleviation or treatment pharmaceutical composition.
6. The method of claim 5,
The cancer is blood cancer, lymphoma, bladder cancer, breast cancer, melanoma, endometrial cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, Renal cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, and will be selected from the group consisting of fibroadenoma, a pharmaceutical composition for preventing, alleviating or treating cancer.
10. The method of claim 9, wherein the hematologic cancer is chronic myelogenous leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia will be selected from the group consisting of, cancer prevention, alleviation or therapeutic pharmaceutical composition.
The pharmaceutical composition for preventing, alleviating or treating cancer according to claim 10, wherein the hematologic cancer is chronic myeloid leukemia.