KR102463217B1 - 4-aminoquinazoline-2-carboxamide derivatives as protein kinase inhibitors and compositions for preventing, improving or treating cancer containing the same - Google Patents

Abstract

The present invention provides a 4-aminoquinazoline-2-carboxamide derivative compound exhibiting excellent antiproliferative efficacy against cancer cells, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof, a method for preparing the same, and a method for preparing the same as an active ingredient It relates to a pharmaceutical composition for the prevention, alleviation or treatment of cancer metastasis and proliferative disease containing, and an anticancer composition for cancer cells, wherein the compound exhibits excellent anticancer activity and antiproliferative efficacy, thus inhibiting cancer cells as well as cancer cells. It is useful for the prevention of metastatic and proliferative diseases or for the treatment of cancer.

Description

4-aminoquinazoline-2-carboxamide derivative having protein kinase inhibitory activity, and pharmaceutical composition for preventing, improving or treating cancer comprising the same {4-AMINOQUINAZOLINE-2-CARBOXAMIDE DERIVATIVES AS PROTEIN KINASE INHIBITORS AND COMPOSITIONS FOR PREVENTING, IMPROVING OR TREATING CANCER CONTAINING THE SAME}

The present invention provides a compound selected from novel 4-aminoquinazoline-2-carboxamide derivatives having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof, and a method for preparing the compound, It relates to a pharmaceutical composition for preventing, alleviating or treating cancer caused by abnormal cell growth, comprising the compound as an active ingredient.

Discoidin domain receptor (Discoidin Domain Receptor, hereinafter referred to as ‘DDR’) is one of receptor tyrosine kinases having a discoidin homology domain in the extracellular part. It has a unique feature of using collagen, the only non-aqueous extracellular matrix among kinases, as a ligand. DDR exists as two subtypes (DDR1, DDR2), and DDR1 is reported to have five subtypes again. When collagen binds to DDR, DDR is activated, and key cell functions such as cell shape, growth, differentiation, migration, and invasion are controlled by the transmission of sub-signals activated by autophosphorylation.

Since collagen is a major component of the extracellular matrix tissue of solid cancer cancer cells, DDR is believed to play an important role in the interaction between cancer cells and tumor stromal cells. In addition, it has been reported that abnormal DDR1 or DDR2 receptor-mediated signaling is associated with diseases such as cancer, osteoarthritis, arteriosclerosis, pulmonary cirrhosis, liver cirrhosis, and rheumatism.

According to the ‘2016 Cancer Registration Statistics’ released by the National Cancer Center Central Cancer Registry, breast cancer occurred the most in women (19.9%). If breast cancer is detected and treated early, the 5-year survival rate reaches 91.3%, but once it recurs or metastasizes, the 5-year survival rate drops significantly to about 40%. Triple negative breast cancer is more aggressive than other types of breast cancer and has been reported to have a poor prognosis. Currently, the standard treatment for triple-negative breast cancer is chemotherapy, but the treatment efficiency is low and the survival rate is also low.

It has been reported that the level of DDR1 expression is high in triple-negative breast cancer patient tissue, and cell growth, invasion, and migration are inhibited when DDR1 expression is suppressed. In addition, there are statistical data that the survival rate is decreased when DDR2 expression is high among breast cancer patients, and there is a report that DDR2 plays an important role in breast cancer cell metastasis. According to previous studies, activation of DDR2 by collagen° in human lung fibroblasts can induce DDR1 expression. Therefore, simultaneous inhibition of DDR1 and DDR2 can be a promising anticancer treatment strategy.

Compounds previously reported as inhibitors of DDR1 or DDR2 include dasatinib, nilotinib, 7rh, DDR1-IN-1, and the like. Dasatinib and nilotinib effectively inhibit DDR1 or DDR2, but have the disadvantage that they can simultaneously inhibit various proteins and cause cytotoxicity.

J. Med. Chem. 2013, 56, 3281-3195, 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide compound (7rh) has selective inhibitory activity on DDR1, NCI-H23 non-small cell It has been disclosed that it exhibits effective anticancer activity against cancerous lung cancer cell lines.

However, there is still no document that confirms the protein kinase inhibitory activity of the aminoquinazoline compound and predicts that it can be used as a tumor treatment and prophylactic agent. In addition, there is no document reporting effective anticancer activity by treating breast cancer cells with a low molecular weight organic compound that inhibits DDR1 or DDR2.

J. Med. Chem. 2013, 56, 3281-3195

Therefore, the problem to be solved by the present invention is a novel compound having a specific substituent in the basic parent nucleus of 4-aminoquinazolin-2-carboxamide, a pharmaceutically acceptable salt thereof, and its It is intended to provide a hydrate, a solvate thereof, or a stereoisomer thereof.

In addition, one aspect of the present invention contains the above-described novel compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof as an active ingredient, and a pharmaceutical for preventing and treating diseases caused by abnormal cell growth It is intended to provide an enemy composition.

In addition, one aspect of the present invention is to provide a method for preparing the above-described novel compound.

In addition, one aspect of the present invention is to provide a novel intermediate compound synthesized in the process of performing the above-described manufacturing method, the present invention is a problem to be solved.

In addition, another object of the present invention is DDR1 and DDR2 containing a novel 4-aminoquinazoline-2-carboxamide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or an isomer thereof as an active ingredient. An object of the present invention is to provide a therapeutic agent for cancer diseases caused by the expression of

In order to solve the above problems, the present invention provides a compound selected from a 4-aminoquinazoline-2-carboxamide derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof :

[Formula 1]

In Formula 1,

A 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 A together with the nitrogen atom connected to R ₁ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, Or SO ₂ It may optionally include at least one, and at least one of a C ₁ -C ₁₃ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, a hydroxyl group, a halide group, and a cyano group. forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with a species;

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

B is a C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; or a 3-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;

R ₂ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl 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; or —C(O)—(C ₁ -C ₁₃ alkyl);

n is an integer from 0 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a 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 ₃ R ₄ ); 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); 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,

The R ₃ and R ₄ are 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.

The compound according to the present invention has excellent ability to inhibit the activity of DDR1 and DDR2 protein kinase. Therefore, it can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth.

The compound according to the present invention, a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient exhibit low cytotoxicity and selectively high inhibitory activity and antiproliferative effect on cancer cells Therefore, it can be usefully used for the prevention or treatment of cancer.

Cancer diseases that can be treated, prevented and alleviated by treatment with the compound according to the present invention may include breast cancer, renal cell cancer, non-small cell lung cancer, esophageal cancer, astrocytoma, prostate cancer, liver cancer, and Hodgkins lymphoma.

The compound according to the present invention exhibits a kinase inhibitory effect showing excellent selectivity for DDR 1 and 2.

The compound according to the present invention exhibits excellent metabolic stability and excellent drug efficacy due to excellent in vivo stability.

The compound according to the present invention exhibits a high stability pharmacology profile of drug interaction (5 CYPs) in vitro. Therefore, side effects due to drug interactions are not induced.

The compound according to the present invention exhibits excellent selective activity, particularly against triple-negative breast, and shows the effect of reducing side effects.

1 is a kinase profiling result of Experimental Example 1 of the present invention.

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.

As a result of continuing research to solve the above problems, the present inventors have found that an anticancer compound exhibiting excellent inhibitory activity against cancer cells, particularly 4-aminoquinazoline-2-carbox useful for the prevention or treatment of cancer as a selective inhibitor of kinase activity An amide derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof and a stereoisomer thereof, or a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer including the same as an active ingredient have been developed.

One aspect of the present invention provides a compound selected from a 4-aminoquinazoline-2-carboxamide derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:

[Formula 1]

In Formula 1,

A 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 A together with the nitrogen atom connected to R ₁ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, Or SO ₂ It may optionally include at least one, and at least one of a C ₁ -C ₁₃ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₃ -C ₁₀ heteroaryl group, a hydroxyl group, a halide group, and a cyano group. forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with a species;

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

B is a C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; or a 3-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;

R ₂ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl 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; or —C(O)—(C ₁ -C ₁₃ alkyl);

n is an integer from 0 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a 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 ₃ R ₄ ); 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); 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,

The R ₃ and R ₄ are 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, B is a C ₁ -C ₆ alkyl group, benzene, cyazole, thiophene, pyrazole, benzothiophene, pyridazine, pyrazine, imidazole, oxadiazole, triazole, furan, pyri It may be any one selected from the group consisting of midine, oxazole, pyrrole, pyridine, oxadiazole, triazine, cyadiazole, isoxazole, and tetrazole.

In one aspect of the present invention, R ₂ is halogen, substituted or unsubstituted C ₁ -C ₃ alkyl group, trifluor, substituted or unsubstituted C ₁ -C ₃ alkoxy group, benzene group, pyridine group, piperazine group, sulfo It is selected from a nyl group and an imidazole group, and the substituted C ₁ -C ₃ alkyl group or the substituted C ₁ -C ₃ alkoxy group is selected from hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; And it may include one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group.

In one aspect of the present invention, the compound is a 4-aminoquinazoline-2-carboxamide derivative compound represented by Formula 1, characterized in that any one selected from the group consisting of Compound Nos. 1 to 35, Provided are compounds selected from pharmaceutically acceptable salts, hydrates thereof and stereoisomers thereof:

(Compound No. 1) N- (3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)thiazole-4-carboxamide;

(Compound No. 2) 6-(5-acetamido-2-methylphenyl)-4-amino-5-fluoroquinazoline-2-carboxamide;

(Compound No. 3) 4-amino-6-(5-(5-bromothiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxamide;

(Compound No. 4) N -(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)-2-(pyridin-4-yl)thiazole-4 -carboxyamide;

(Compound No. 5) 4-amino-5-fluoro-6-(2-methyl-5-(1-phenyl-5-(trifluoromethyl) -1H -pyrazole-4-carboxyamido) phenyl)quinazoline-2-carboxyamide;

(Compound No. 6) 4-amino-6-(5-(benzo[ b ]thiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;

(Compound No. 7) 4-amino-6-(5-benzamido-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;

(Compound No. 8) 4-amino-5-fluoro-6-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 9) 4-amino-5-fluoro-6-(2-methyl-5-(2,3,4-trifluorobenzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 10) 4-amino-5-fluoro-6-(2-methyl-5-(4-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 11) 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide ;

(Compound No. 12) 4-amino-6-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;

(Compound No. 13) 4-amino-5-fluoro-6-(2-methyl-5-(3-(methylsulfonyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 14) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide ;

(Compound No. 15) 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 16) 4-amino-5-fluoro-6-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)quinazoline-2-carboxyamide ;

(Compound No. 17) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl) benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 18) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido) phenyl)quinazoline-2-carboxyamide;

(Compound No. 19) 4-amino-6-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;

(Compound No. 20) 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamido) phenyl)quinazoline-2-carboxyamide;

(Compound No. 21) 4-amino-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benz amido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 22) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methyl-) 1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 23) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin) Razin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 24) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin) Razin-1-yl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 25) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-((4-methyl) piperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 26) 4-amino-6-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)benzamido)- 2-methylphenyl)-N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-5-fluoroquinazoline-2-carboxyamide;

(Compound No. 27) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(5-(4-((4-hydroxypiperidine) -1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)quinazoline-2-carboxyamide;

(Compound No. 28) 4-amino-5-fluoro- N -methyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;

(Compound No. 29) 4-amino- N -cyclopropyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide ;

(Compound No. 30) 4-Amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-( oxetan -3-yl)quina zoline-2-carboxyamide;

(Compound No. 31) 4-amino-5-fluoro- N , N -dimethyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2- carboxyamide;

(Compound No. 32) N -(3-(4-amino-5-fluoro-2-(morpholine-4-carbonyl)quinazolin-6-yl)-4-methylphenyl)-3-(trifluoro methyl)benzamide;

(Compound No. 33) 4-amino- N -cyclohexyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide ;

(Compound No. 34) 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl) -N -phenylquinazoline-2-carboxyamide; and

(Compound No. 35) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl) )benzamido)phenyl)quinazoline-2-carboxyamide.

A pharmaceutically acceptable salt of the heteroarylamine compound represented by Formula 1 according to the present invention may be prepared by a conventional method in the art. Pharmaceutically acceptable salts should have low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, and the like. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used in the preparation of organic base addition salts are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used to prepare the amino acid addition base are natural amino acids such as alanine and glycine.

The heteroarylamine compound represented by Formula 1 according to the present invention includes all hydrates and solvates in addition to the pharmaceutically acceptable salts described above. Hydrates and solvates are crystallized after the heteroarylamine compound represented by Formula 1 is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and then added with a free acid or a free base. Or it may be recrystallized. In such cases, solvates (especially hydrates) may be formed. Accordingly, the compounds of the present invention include stoichiometric solvates including hydrates in addition to various amounts of water-containing compounds that can be prepared by methods such as freeze-drying.

In the definition of a substituent in the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may 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.

In one embodiment, the 'alkyl group' refers to methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl, i - from 1 to 8 including pentyl, neopentyl, t-pentyl, cyclopentyl, cyclobutylmethyl, n-hexyl, i-hexyl, cyclohexyl, cyclopentylmethyl, heptyl, cyclohexylmethyl, octyl, etc. It means a linear, branched or cyclic aliphatic saturated hydrocarbon group having carbon atoms.

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. In one embodiment, the term 'aryl group' refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, including phenyl, naphthyl, anthraniryl, phenanthrinyl, and the like. can

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 the alkoxy group include a (C1-C6)alkoxy group 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, -O-t-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl. In one embodiment, the term 'alkoxy group' refers to C1-C8, including methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, and t-butoxy. It may be a hydroxy group in which a hydrogen atom is substituted by a substituent selected from an alkyl group.

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 'amine 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 group' means fluorine, chlorine, bromine or iodine.

In one embodiment, the 'haloalkyl group' refers to an alkyl group in which a hydrogen atom is substituted with one or more halogen atoms, such as a trifluoromethyl group.

The term 'heterocycle 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 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. In one embodiment, the 'heteroaryl group' is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadia Zolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzofurazanyl, dibenzofuranyl, isobenzofuranyl, indazolyl, benzimi Dazolyl, benzoxazolyl, benzisooxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, chinolinyl, It may be a monocyclic, bicyclic, or tricyclic aromatic heterohydrocarbon group including at least one heteroatom selected from N, O and S, including quinazolinyl and the like. In one embodiment, the term 'heterocycloalkyl group' includes 5 or more heteroatoms selected from N and O, including morpholinyl, piperidinyl, piperazinyl, N-protected piperazinyl, and the like. It may be a hexagonal or hexagonal aliphatic heterohydrocarbon ring group, and the N-protecting group of piperazinyl may typically include an alkyl group.

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

N -(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)thiazole-4-carboxamide

6-(5-acetamido-2-methylphenyl)-4-amino-5-fluoroquinazoline-2-carboxamide

4-amino-6-(5-(5-bromothiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxamide

N -(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)-2-(pyridin-4-yl)thiazole-4-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(1-phenyl-5-(trifluoromethyl)-1 H -pyrazole-4-carboxyamido)phenyl)quinazoline- 2-Carboxamide

4-amino-6-(5-(benzo[ b ]thiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

4-Amino-6-(5-benzamido-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)quinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(2,3,4-trifluorobenzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(4-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-6-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(3-(methylsulfonyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)quinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(3-(4-wtyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl )quinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline- 2-Carboxamide

4-amino-6-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline- 2-Carboxamide

4-amino-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)phenyl) Quinazoline-2-carboxyamide

4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methyl- 1H -imidazole) -1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl) )-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl) )-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-Amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin-1-yl)phenyl) yl)methyl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-Amino-6-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)- N -(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoroquinazoline-2-carboxyamide

4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(5-(4-((4-hydroxypiperazin-1-yl) methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro- N -methyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino- N -cyclopropyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-( oxetan -3-yl)quinazoline-2-carboxy amide

4-Amino-5-fluoro- N , N -dimethyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

N -(3-(4-amino-5-fluoro-2-(morpholine-4-carbonyl)quinazolin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide

4-amino- N -cyclohexyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl) -N -phenylquinazoline-2-carboxyamide

4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido) Phenyl)quinazoline-2-carboxyamide

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 acid or an organic acid. Preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, and 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, salicylic acid, It may be at least one selected from the group consisting of 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 combined with a water molecule.

On the other hand, the present invention is characterized in that the method for preparing the compound represented by the formula (1). The manufacturing method according to the present invention will be described in detail as follows.

Manufacturing method 1

According to the preparation method according to Scheme 1, the compound represented by Chemical Formula 1 may be prepared by performing a three-step manufacturing process using the compound represented by the following Chemical Formula 2 as a starting material.

[Scheme 1]

In the manufacturing method according to Scheme 1, the first step process is performed under a heating condition of room temperature to 50° C. in the presence of ammonia. In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The two-step process of reducing the nitro group to the amine group proceeds by a general reduction reaction commonly performed in the field of organic synthesis. For example, hydrogen gas (H ₂ ) may be injected in the presence of Raney Ni, or the reduction reaction may be performed using tin chloride (SnCl ₂ ). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The binding reaction, which is a three-step reaction, may be carried out in a reaction solvent such as tetrahydrofuran, N , N -dimethylformamide, in the presence of additives, or in the absence of additives. In this case, as the additive, an organic base such as triethylamine, N , N -diisopropylethylamine, or an inorganic base such as K ₂ CO ₃ , NaHCO ₃ , or 1,3-dicyclohexylcarbodiimide (DCC) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-( 1H -7-azabenzotriazol1-yl)-1,1,3,3-tetramethyluronium A peptide bond reaction reagent such as hexafluorophosphate (HATU), or a catalyst such as N-hydroxybenzotriazole (HOBt), N , N -dimethylaminopyridine (DMAP), etc. can be used.

Manufacturing method 2

According to the preparation method according to Scheme 2 below, the compound represented by Chemical Formula 1 can be prepared by performing a four-step manufacturing process using the compound represented by the following Chemical Formula 2 as a starting material.

[Scheme 2]

In the manufacturing method according to Scheme 2, the first step process is performed under heating conditions of room temperature to 50° C. in the presence of an inorganic base. For example, it can be carried out using sodium hydroxide (NaOH) or lithium hydroxide (LiOH). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The binding reaction, which is a two-step reaction, may be performed in a reaction solvent such as tetrahydrofuran, N , N -dimethylformamide, or the like, in the presence of an additive, or in the absence of an additive. In this case, as the additive, an organic base such as triethylamine, N , N -diisopropylethylamine, or an inorganic base such as K ₂ CO ₃ , NaHCO ₃ , or 1,3-dicyclohexylcarbodiimide (DCC) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-( 1H -7-azabenzotriazol1-yl)-1,1,3,3-tetramethyluronium A peptide bond reaction reagent such as hexafluorophosphate (HATU), or a catalyst such as N-hydroxybenzotriazole (HOBt), N , N -dimethylaminopyridine (DMAP), etc. can be used.

Reduction of a nitro group to an amine group, which is a three-step process, proceeds by a general reduction reaction commonly performed in the field of organic synthesis. For example, hydrogen gas (H ₂ ) may be injected in the presence of Raney Ni, or the reduction reaction may be performed using tin chloride (SnCl ₂ ). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The binding reaction, which is a four-step reaction, may be carried out in a reaction solvent such as tetrahydrofuran, N , N -dimethylformamide, or the like, in the presence of additives or in the absence of additives. In this case, as the additive, an organic base such as triethylamine, N , N -diisopropylethylamine, or an inorganic base such as K ₂ CO ₃ , NaHCO ₃ , or 1,3-dicyclohexylcarbodiimide (DCC) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-( 1H -7-azabenzotriazol1-yl)-1,1,3,3-tetramethyluronium A peptide bond reaction reagent such as hexafluorophosphate (HATU), or a catalyst such as N-hydroxybenzotriazole (HOBt), N , N -dimethylaminopyridine (DMAP), etc. can be used.

Manufacturing method 3

According to the preparation method according to Scheme 3 below, the compound represented by Chemical Formula 1 may be prepared by performing a four-step manufacturing process using the compound represented by the following Chemical Formula 2 as a starting material.

[Scheme 3]

In the preparation method according to Scheme 3, the reaction for reducing the nitro group to the amine group, which is a one-step process, proceeds by a general reduction reaction commonly performed in the field of organic synthesis. For example, hydrogen gas (H ₂ ) may be injected in the presence of Raney Ni, or the reduction reaction may be performed using tin chloride (SnCl ₂ ). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The binding reaction, which is a two-step reaction, may be performed in a reaction solvent such as tetrahydrofuran, N , N -dimethylformamide, or the like, in the presence of an additive, or in the absence of an additive. In this case, as the additive, an organic base such as triethylamine, N , N -diisopropylethylamine, or an inorganic base such as K ₂ CO ₃ , NaHCO ₃ , or 1,3-dicyclohexylcarbodiimide (DCC) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-( 1H -7-azabenzotriazol1-yl)-1,1,3,3-tetramethyluronium A peptide bond reaction reagent such as hexafluorophosphate (HATU), or a catalyst such as N-hydroxybenzotriazole (HOBt), N , N -dimethylaminopyridine (DMAP), etc. can be used.

The three-step process is performed under heating conditions of room temperature to 50°C in the presence of an inorganic base. For example, it can be carried out using sodium hydroxide (NaOH) or lithium hydroxide (LiOH). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The binding reaction, which is a four-step reaction, may be carried out in a reaction solvent such as tetrahydrofuran, N , N -dimethylformamide, or the like, in the presence of additives or in the absence of additives. In this case, as the additive, an organic base such as triethylamine, N , N -diisopropylethylamine, or an inorganic base such as K ₂ CO ₃ , NaHCO ₃ , or 1,3-dicyclohexylcarbodiimide (DCC) , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-( 1H -7-azabenzotriazol1-yl)-1,1,3,3-tetramethyluronium A peptide bond reaction reagent such as hexafluorophosphate (HATU), or a catalyst such as N-hydroxybenzotriazole (HOBt), N , N -dimethylaminopyridine (DMAP), etc. can be used.

Manufacturing method 4

The compound represented by Chemical Formula 2 used as a starting material in Scheme 1, Scheme 2 and Scheme 3 may be prepared by a preparation method according to Scheme 4 below.

[Scheme 4]

In the preparation method according to Scheme 4, the reaction of reducing the nitro group to the amine group, which is a one-step process, proceeds by a general reduction reaction commonly performed in the field of organic synthesis. For example, hydrogen gas (H ₂ ) may be injected in the presence of palladium (Pd/C), or reduction reaction may be performed using tin chloride (SnCl ₂ ). In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, etc. may be used, and in the embodiment of the present invention, mainly ethanol Although an example using (EtOH) is specifically illustrated, the solvent of the present invention is by no means limited thereto.

The bromination reaction, which is a two-step process, is a process in which a bromo atom is introduced at the C5 position of the compound represented by Formula 12. Specifically, the bromination reaction is performed using a bromination reagent such as N -bromosuccinimide, trifluoroacetic acid (TFA) and sulfuric acid at room temperature.

In the Suzuki coupling reaction, which is a three-step process, Pd2(dba)3, Pd(OAc)2, PdCl2(PPh3)2, Pd(PPh3)4, etc. may be used as metal compounds. As ligands, Xantphos (Cas number: 161265-03-8), Davephos (Cas number: 213697-53-1), Johnphos (Cas number: 224311-51-7), X-phos (Cas number: 564483-18-7) ), tert-Butyl Xphos (Cas 564483-19-8), etc. can be used. And as the base, carbonates, sulfates, phosphates, alkoxides, etc. of alkali metals or alkaline earth metals can be used, and specifically, K2CO3, CsCO3, Na2CO3, K3PO4, NaOt-Bu, KOt-Bu, etc. can be used. As the reaction solvent, conventional organic solvents including tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylsulfoxide, 2-butanol, 2-pentanol and the like can be used. The reaction temperature is in the range of 50° C. to 200° C., and preferably, it is maintained in the range of 80° C. to 150° C.

In the four-step process, 4-amino-2-fluoro-2'-methyl-5'-nitro-[1,1'-biphenyl]- represented by Formula 15 above using ethyl carbonocyanidate reagent This is a step of generating a quinazoline skeleton by a cyclization reaction between the amino group and the acid group of 3-carboxylic acid.

The five-step process is a step of converting the oxygen atom of the compound represented by Chemical Formula 16 into a chlorine atom. This 5 step manufacturing process can be performed at high temperature (150 °C) using phosphorous oxychloride (POCl3) in the presence of N , N -dimethylaniline.

The six-step process is a step of converting the chlorine atom of the compound represented by Chemical Formula 17 into a nitrogen atom. This 6-step manufacturing process can be carried out at room temperature in the presence of ammonia. In this case, as the reaction solvent, a conventional organic solvent including tetrahydrofuran, dioxane, N , N -dimethylformamide, ethanol, 2-butanol, 2-pentanol, and the like may be used.

Another aspect of the present invention is a pharmaceutical composition for the prevention, alleviation or treatment of cancer, comprising a compound selected from the compound of Formula 1 according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a stereoisomer thereof as an active ingredient. to provide.

The pharmaceutical composition according to the present invention has excellent ability to inhibit the activity of protein kinase. Specifically, the protein kinase may include DDR1, DDR2, CRAF, BRAF, ARAF and EPHA2.

Therefore, the pharmaceutical composition of the present invention can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth. Cancer diseases that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention are gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer , head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenoma, and the like.

Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, wherein any one of the above compounds is included as an active ingredient.

In another aspect of the present invention, the pharmaceutical composition is applied to a patient having any one or more overexpression genes of DDR1, DDR2, CRAF, BRAF, ARAF, and EPHA2, and provides a pharmaceutical composition for preventing, alleviating or treating cancer.

In another aspect of the present invention, the cancer is endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, Thyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, hematologic cancer, lymphoma, and at least one selected from the group consisting of fibroadenoma, provides a pharmaceutical composition for preventing, alleviating or treating cancer.

In another aspect of the present invention, the cancer is breast cancer, it provides a pharmaceutical composition for preventing, alleviating or treating cancer.

In another aspect of the present invention, the pharmaceutical composition inhibits the proliferation of any one or more cell lines of MDA-MB-231, MDA-MB-468, MDA-MB-453 and HCC70, preventing, alleviating cancer Or it provides a pharmaceutical composition for treatment.

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

As used herein, 'treatment' refers to alleviation or amelioration of symptoms, reduction of 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, the 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, gastric 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, colon-rectal 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 represented by Formula 1 as an active ingredient, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be appropriately adjusted according to the selection of those skilled in the art according to the mode of use and the method of use of the pharmaceutical composition of the present invention.

For example, the pharmaceutical composition may contain the compound represented by Formula 1, a pharmaceutically acceptable salt, or hydrate thereof in an amount of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the composition. can be included as

A pharmaceutically acceptable salt or hydrate thereof of the compound represented by Formula 1 may be included alone in the pharmaceutical composition, or may be included together with other pharmaceutically acceptable carriers, excipients, diluents or sub-components.

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, extenders, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colors, glycerin , a fragrance, emulsifier or preservative may be further included.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be administered in combination with other anticancer agents for treating cancer or tumors to enhance the therapeutic effect of the anticancer agent.

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 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 are creams, lotions, ointments, ONITMENTS, 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, stabilizers, wetting agents or emulsification accelerators, 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 can 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 body weight, preferably 0.01 to 35 mg/kg 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 provides a method for treating cancer, comprising administering a compound represented by the following formula (1), a pharmaceutically acceptable salt, or hydrate thereof in a therapeutically effective amount.

Preferably, the treatment method may further include the step of identifying a patient in need of 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 patient's age, weight, general health, sex and diet, 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, once a day or divided into oral or parenteral routes. can do.

On the other hand, the present invention includes a pharmaceutical composition for the treatment, prevention and alleviation of cancer diseases comprising the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient.

Cancer diseases that can be prevented and treated by the compound according to the present invention include stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer , thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, or fibroadenoma etc. may be included.

The pharmaceutical composition of the present invention contains a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient therein. It can be formulated into formulations conventional in the pharmaceutical field, for example, tablets, capsules, troches, solutions, suspensions, etc., for oral administration or parenteral administration. Excipients that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, arginic acid, sodium Alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. In addition, the dosage of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally based on an adult patient weighing 70 kg. It is 0.01 to 1,000 mg/day, and may be administered in divided doses once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist. The present invention as described above will be described in more detail based on the following Examples, Experimental Examples and Formulation Examples, and the following Examples, Experimental Examples and Formulation Examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these is not limited by

Hereinafter, the present invention will be described in detail with reference to Preparation Examples, Examples and Experimental Examples. However, the following Preparation Examples, 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.

Preparation Example 1: Preparation of ethyl 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylate

Step 1: Preparation of 2-amino-6-fluorobenzoic acid

Pd/C (10.0 g) and methanol (1 L) were added to 2-fluoro-6-nitrobenzoic acid (100 g 540.0 mmol), and the mixture was stirred under hydrogen gas at room temperature for 12 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain the target compound (82.0 g, 99%).

MS(m/z): 156 [M+1]+.

Step 2: Preparation of 6-amino-3-bromo-2-fluorobenzoic acid

N,N of N-bromosuccinimide (NBS; 53.0 g, 300 mmol) in a solution of 2-amino-6-fluorobenzoic acid (42 g 270.7 mmol) in N,N-dimethylformamide (630 mL) -Dimethylformamide (210 mL) solution was slowly added dropwise at -10 °C. The reaction mixture was stirred at room temperature for 12 hours, and then extracted using ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (25.0 g, 39%).

MS(m/z): 236 [M+1]+.

Step 3: Preparation of 4-amino-2-fluoro-2'-methyl-5'-nitro-[1,1'-biphenyl]-3-carboxylic acid

6-amino-3-bromo-2-fluorobenzoic acid (25.0 g, 107.0 mmol) with [1,1'-bis(diphenylphosphino)ferrosine]dichloropalladium(II) (3.75 g, 4.5 mmol) ) and 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (30.9 g, 117 mmol) was dissolved in 1,4- A solution of dioxane (80 mL) and an aqueous solution (20 mL) of cesium carbonate (22.5 g, 165.0 mmol) were slowly added dropwise, and the reaction mixture was stirred at 90° C. for 8 hours. After the mixed solution was cooled to room temperature, the solution was dried and concentrated. The obtained residue was purified by column chromatography (petroleum ether/ethyl acetate, 100:0 → 3:1) to obtain the target compound (15.0 g, 48%) as a yellow solid.

MS(m/z): 291 [M+1]+.

Step 4: Preparation of ethyl 5-fluoro-6-(2-methyl-5-nitrophenyl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate

4-Amino-2-fluoro-2'-methyl-5'-nitro-[1,1'-biphenyl]-3-carboxylic acid (14.0 g 48.0 mmol) with HCl/HOAc (1 mL/340 mL) Ethyl carbonocyanidate (53.0 g, 300 mmol) was added to the solution, and the mixture was stirred at 90° C. for 8 hours. The mixed solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the target compound (10.0 g, 56%).

MS(m/z): 373 [M+1]+.

Step 5: Preparation of ethyl 4-chloro-5-fluoro-6- (2-methyl-5-nitrophenyl) quinazoline-2-carboxylate

Ethyl 5-fluoro-6-(2-methyl-5-nitrophenyl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate (10.0 g 26.0 mmol) was mixed with phosphoryl chloride (400 mL) ) solution, and stirred at 120° C. for 8 hours. The mixed solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the target compound (10.0 g, 99%).

MS(m/z): 390 [M+1]+.

Step 6: Preparation of ethyl 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylate

Ethyl 4-chloro-5-fluoro-6- (2-methyl-5-nitrophenyl) quinazoline-2-carboxylate (10.0 g 26.0 mmol) was placed in ammonia/methanol (100 mL) solution, 2 hours while stirring at room temperature. The mixed solution was filtered and concentrated under reduced pressure to obtain the target compound (7.0 g, 73%).

MS(m/z): 371 [M+1]+.

[Example] Method for preparing a compound of 4-aminoquinazoline-2-carboxamide derivative of Formula 1

Example 1: Preparation of N-(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)thiazole-4-carboxamide

Step 1. Preparation of 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxyamide

Ethyl 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylate (3.0 g, 8.10 mmol) was placed in ammonia/methanol (80 mL) solution, 2 It was stirred at 80 °C for hours. The mixed solution was filtered and concentrated under reduced pressure to obtain the target compound (2.46 g, 89%).

MS(m/z): 342 [M+1]+.

Step 2: Preparation of 4-amino-6-(5-amino-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxyamide (2.70 g, 7.91 mmol) in tin chloride (SnCl2; 15.0 g, 79.11 mmol) and ethanol (80 mL) was added and stirred at 60 °C for 2 hours. After cooling the mixed solution to room temperature, it was extracted using ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2.34 g, 95%).

MS(m/z): 312 [M+1]+.

Step 3: Preparation of N-(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)thiazole-4-carboxamide

4-Amino-6-(5-amino-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide (0.1 g, 0.32 mmol), 1-[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 0.25 g, 0.64 mmol), N,N-diisopropylethylamine (DIPEA; 0.3 mL, 1.60 mmol) ) and N,N-dimethylformamide (1 mL) was added dropwise to a mixed solution of thiazole-4-carboxylic acid (0.05 g, 0.47 mmol) and stirred at 0° C. for 1 hour. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (80 mg, 60%).

MS(m/z): 423 [M+1]+.

Example 2: Preparation of 6-(5-acetamido-2-methylphenyl)-4-amino-5-fluoroquinazoline-2-carboxamide

The target compound was obtained in the same manner as in Example 1, except that acetic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 354 [M+1]+.

Example 3: Preparation of 4-amino-6-(5-(5-bromothiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxamide

The target compound was obtained in the same manner as in Example 1, except that 5-bromothiophene-2-carboxylic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 500 [M+1]+.

Example 4: N-(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)-2-(pyridin-4-yl)thiazole-4- Preparation of Carboxamides

Except for using 2-(pyridin-4-yl)thiazole-4-carboxylic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, it was carried out in the same manner as in Example 1, The target compound was obtained.

MS(m/z): 500 [M+1]+.

Example 5: 4-amino-5-fluoro-6-(2-methyl-5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxyamido)phenyl) Preparation of quinazoline-2-carboxyamide

Except for using 1-phenyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid in step 3 of Example 1 instead of thiazole-4-carboxylic acid, It carried out in the same manner as in 1 to obtain the target compound.

MS(m/z): 550 [M+1]+.

Example 6: Preparation of 4-amino-6-(5-(benzo[b]thiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that benzo[b]thiophene-2-carboxylic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 472 [M+1]+.

Example 7: Preparation of 4-amino-6-(5-benzamido-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 416 [M+1]+.

Example 8: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that 3,4,5-trimethoxybenzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1 .

MS(m/z): 506 [M+1]+.

Example 9: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(2,3,4-trifluorobenzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that 2,3,4-trifluorobenzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 470 [M+1]+.

Example 10: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(4-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that 4-(trifluoromethyl)benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 484 [M+1]+.

Example 11: 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide Produce

In the same manner as in Example 1, except that 4-(4-methylpiperazin-1-yl)benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1, The target compound was obtained.

MS(m/z): 514 [M+1]+.

Example 12: Preparation of 4-amino-6-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

Except for using 3-(2-cyanopropan-2-yl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, it was carried out in the same manner as in Example 1, The target compound was obtained.

MS(m/z): 483 [M+1]+.

Example 13: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(3-(methylsulfonyl)benzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that 3-(methylsulfonyl)benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 494 [M+1]+.

Example 14: 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide Produce

In the same manner as in Example 1, except that 3-(4-methylpiperazin-1-yl)benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1, The target compound was obtained.

MS(m/z): 514 [M+1]+.

Example 15: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 1, except that 3-(trifluoromethyl)benzoic acid was used instead of thiazole-4-carboxylic acid in step 3 of Example 1.

MS(m/z): 484 [M+1]+.

Example 16: 4-amino-5-fluoro-6-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)quinazoline-2-carboxyamide Produce

Except for using 2-(3-(trifluoromethyl)phenyl)acetic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, it was carried out in the same manner as in Example 1, The compound was obtained.

MS(m/z): 498 [M+1]+.

Example 17: 4-Amino-5-fluoro-6-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzami Figure) Preparation of phenyl) quinazoline-2-carboxyamide

Except for using 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1 was carried out in the same manner as in Example 1 to obtain the target compound.

MS(m/z): 564 [M+1]+.

Example 18: 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl ) Preparation of quinazoline-2-carboxyamide

Except for using 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, the above In the same manner as in Example 1, the target compound was obtained.

MS(m/z): 582 [M+1]+.

Example 19: Preparation of 4-amino-6-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide

Except for using 4-chloro-3-(trifluoromethyl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, it was carried out in the same manner as in Example 1, The compound was obtained.

MS(m/z): 518 [M+1]+.

Example 20: 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamido)phenyl ) Preparation of quinazoline-2-carboxyamide

Except for using 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1, the above procedure In the same manner as in Example 1, the target compound was obtained.

MS(m/z): 582 [M+1]+.

Example 21: 4-Amino-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzami Figure) Preparation of phenyl) quinazoline-2-carboxyamide

Except for using 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid instead of thiazole-4-carboxylic acid in step 3 of Example 1 was carried out in the same manner as in Example 1 to obtain the target compound.

MS(m/z): 596 [M+1]+.

Example 22: 4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methyl-1H) Preparation of -imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

Step 1. Preparation of 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylic acid

Ethyl 4-amino-5-fluoro-6- (2-methyl-5-nitrophenyl) quinazoline-2-carboxylate (7.0 g, 19.0 mmol) was dissolved in a solution of tetrahydrofuran (140 mL), and then , 1N sodium hydroxide solution (38.0 mL, 38.0 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. 1N aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 6, and the resulting solid was filtered, dried and concentrated to obtain the target compound (4.5 g, 70%).

MS(m/z): 343 [M+1]+.

Step 2: 4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-nantrophenyl)quinazoline-2-carboxy Preparation of amides

4-Amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylic acid (3.0 g, 8.76 mmol), 1-[bis(dimethylamino)methylene]-1H -1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 6.66 g, 17.5 mmol), N,N-diisopropylethylamine (DIPEA; 7.63 mL, 43.8 mmol) and N,N-dimethylformamide (30 mL) were added dropwise to a solution of 4-(4-ethylpiperazin-1-yl)aniline (2.16 g, 10.52 mmol) and 1 at 0°C. stirred for hours. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (3.0 g, 65%).

MS(m/z): 530 [M+1]+.

Step 3: 4-amino-6-(5-amino-2-methylphenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoroquinazoline-2-carboxyamide Produce

4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-nantrophenyl)quinazoline-2-carboxyamide (2.50 g, 4.72 mmol) was added with tin chloride (SnCl2; 9.0 g, 47.2 mmol) and ethanol (50 mL), followed by stirring at 60 °C for 2 hours. After cooling the mixed solution to room temperature, it was extracted using ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (2.3 g, 97%).

MS(m/z): 500 [M+1]+.

Step 4: 4-Amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methyl-1H-) Preparation of imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-Amino-6-(5-amino-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide (0.1 g, 0.20 mmol), 1-[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 0.15 g, 0.40 mmol), N,N-diisopropylethylamine (DIPEA; 0.9 mL, 1.0 mmol) ) and N,N-dimethylformamide (1 mL), 3-(4-methyll-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid ( 0.65 g, 0.24 mmol) was added dropwise and stirred at 0° C. for 1 hour. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (77 mg, 63%).

MS(m/z): 752 [M+1]+.

Example 23: 4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazine) Preparation of -1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

3-(4-methylpiperazine-1-substituted for 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 4 of Example 22 above The target compound was obtained in the same manner as in Example 22, except that yl)-5-(trifluoromethyl)benzoic acid was used.

MS(m/z): 770 [M+1]+.

Example 24: 4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazine) Preparation of -1-yl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-(4-methylpiperazine-1-substituted for 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid in step 4 of Example 22 above The target compound was obtained in the same manner as in Example 22, except that yl)-3-(trifluoromethyl)benzoic acid was used.

MS(m/z): 770 [M+1]+.

Example 25: 4-Amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin) Preparation of razin-1-yl)methyl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

In step 4 of Example 22, 4-((4-methylpiperazine-1) instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid The target compound was obtained in the same manner as in Example 22, except that -yl)methyl)-3-(trifluoromethyl)benzoic acid was used.

MS(m/z): 784 [M+1]+.

Example 26: 4-amino-6-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)benzamido)-2 Preparation of -methylphenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoroquinazoline-2-carboxyamide

In step 4 of Example 22 above, 4-(((2-(dimethylamino ) Ethyl) (methyl) amino) methyl) -3- (trifluoromethyl) benzoic acid was carried out in the same manner as in Example 22, except that the target compound was obtained.

MS(m/z): 786 [M+1]+.

Example 27: 4-amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(5-(4-((4-hydroxypiperidine- Preparation of 1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)quinazoline-2-carboxyamide

In step 4 of Example 22 above, 4-((4-hydroxypiperidine) instead of 3-(4-methyll-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid The target compound was obtained in the same manner as in Example 22, except that -1-yl)methyl)-3-(trifluoromethyl)benzoic acid was used.

MS(m/z): 785 [M+1]+.

Example 28: Preparation of 4-amino-5-fluoro-N-methyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

Step 1. Preparation of ethyl 4-amino-6-(5-amino-2-ethylphenyl)-5-fluoroquinazoline-2-carboxylate

To ethyl 4-amino-5-fluoro-6-(2-methyl-5-nitrophenyl)quinazoline-2-carboxylate (2.30 g, 6.21 mmol) with tin chloride (SnCl2; 11.8 g, 62.1 mmol) Ethanol (60 mL) was added and stirred at 60 °C for 2 hours. After cooling the mixed solution to room temperature, it was extracted using ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (1.92 g, 91%).

MS(m/z): 341 [M+1]+.

Step 2: Preparation of ethyl 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxylate

Ethyl 4-amino-6-(5-amino-2-ethylphenyl)-5-fluoroquinazoline-2-carboxylate (1.5 g, 4.41 mmol), 1-[bis(dimethylamino)methylene]-1H -1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 3.35 g, 8.81 mmol), N,N-diisopropylethylamine (DIPEA; 3.83 mL, 22.1 mmol) and N,N-dimethylformamide (40 mL) were added dropwise to a solution of 3-(trifluoromethyl)benzoic acid (1.01 g, 5.29 mmol) and stirred at 0° C. for 1 hour. did. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (2.1 g, 91%).

MS(m/z): 513 [M+1]+.

Step 3: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxylic acid

Ethyl 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyl in a solution of tetrahydrofuran (30 mL) The rate (1.8 g, 3.53 mmol) was dissolved, and 1N sodium hydroxide solution (7.1 mL, 7.1 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. 1N aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 6, and the resulting solid was filtered, dried and concentrated to obtain a solid target compound (1.62 g, 95%).

MS(m/z): 485 [M+1]+.

Step 4: Preparation of 4-amino-5-fluoro-N-methyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide

4-Amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxylic acid (0.1 g, 0.21 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 0.16 g, 0.42 mmol), N,N- To a mixed solution of diisopropylethylamine (DIPEA; 0.18 mL, 1.05 mmol) and N,N-dimethylformamide (1 mL), methylamine hydrochloride (0.02 g, 0.25 mmol) was added dropwise and at 0°C. Stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (79 mg, 77%).

MS(m/z): 498 [M+1]+.

Example 29: 4-amino-N-cyclopropyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide Produce

The target compound was obtained in the same manner as in Example 28, except that cyclopropylamine was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 524 [M+1]+.

Example 30: 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-(oxetan-3-yl)quinazoline Preparation of -2-carboxyamide

The target compound was obtained in the same manner as in Example 28, except that oxetan-3-amine was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 540 [M+1]+.

Example 31: 4-amino-5-fluoro-N,N-dimethyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxy Preparation of amides

The target compound was obtained in the same manner as in Example 28, except that dimethylamine hydrochloride was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 512 [M+1]+.

Example 32: N-(3-(4-amino-5-fluoro-2-(morpholine-4-carbonyl)quinazolin-6-yl)-4-methylphenyl)-3-(trifluoromethyl ) Preparation of benzamide

The target compound was obtained in the same manner as in Example 28, except that morpholine was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 554 [M+1]+.

Example 33 of 4-amino-N-cyclohexyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide Produce

The target compound was obtained in the same manner as in Example 28, except that cyclohexylamine was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 566 [M+1]+.

Example 34: Preparation of 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-phenylquinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 28, except that aniline was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 560 [M+1]+.

Example 35: 4-Amino-N-(4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl) Preparation of benzamido)phenyl)quinazoline-2-carboxyamide

The target compound was obtained in the same manner as in Example 28, except that 4-(4-ethylpiperazin-1-yl)aniline was used instead of methylamine hydrochloride in step 4 of Example 28.

MS(m/z): 672 [M+1]+.

[Experimental example]

Experimental Example 1. Measurement of 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 in a full kinase panel composed of 347 kinases. As a test compound, as a representative compound according to the present invention, 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline in Example 15 -2-Carboxamide was used.

Table 1 below shows a list of kinases whose activity is inhibited by 90% or more by the compound of Example 1 when treated at a single concentration of 1 μM. In addition, FIG. 1 shows the result of kinase profiling that is inhibited by more than 90%.

List of kinases whose activity is inhibited by more than 90% DDR1 RAF1 DDR2 ARAF BRAF EPHA2

As a result of profiling 347 global kinases as described above, it was confirmed that excellent selectivity could be secured with less than 6 kinases inhibiting more than 90%.

Experimental Example 2. Evaluation of cancer cell proliferation inhibition ability

For the compound of the present invention, the proliferation inhibitory ability in cancer cell cell lines MDA-MB-231, MDA-MB-468, MDA-MB-453 and HCC70 was calculated as a GI ₅₀ value, and the results are shown in Table 2 below. It was.

test compound Proliferative inhibitory activity of MDA-MB-231
(GI ₅₀ , uM) Proliferative inhibitory activity of MDA-MB-468
(GI ₅₀ , uM) Proliferative inhibitory activity of MDA-MB-453
(GI ₅₀ , uM) HCC70 proliferation inhibitory activity
(GI ₅₀ , uM) Example 4 compound B B B B Example 8 compound B B B B Example 9 compound B B B B Example 15 compound B B B B Example 16 compound B B B B Example 18 compound B C C C Example 20 compound B B B B Example 21 compound B B B B Example 22 compound A B B A Example 23 compound A A A A Example 24 compound B A B B Example 25 compound A A B B Example 26 compound A A A A Example 27 compound B B B B Example 28 compound B B B B Example 29 compound B B B B Example 30 compound B B B A Example 35 compound B B B B

The activity values were expressed in three steps.

A: GI ₅₀ < 1 μM,

B: 1 μM < GI ₅₀ < 10 μM,

C: GI ₅₀ > 10 μM

Experimental Example 3. Evaluation of CYPs (cytochrome P450) inhibitory ability

For the above Examples 15, 25, 29 and 35 of the present invention, CYPs (cytochrome P450) inhibition (inhibition rate, %) was evaluated to confirm the possibility of drug interaction, and the results are shown in Table 3 below.

experimental species CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Example 15 compound > 100.0% 52.5% 67.3% 85.9% > 100.0% Example 25 compound 94.5% 91.1% 71.2% 59.7% > 100.0% Example 29 compound 89.6% 34.0% 58.1% 81.0% > 100.0% Example 35 compound > 100.0% 97.2% 85.5% 78.2% > 100.0%

As shown in Table 3, the compounds of the present invention exhibit a high stability drug interaction pharmacology profile.

Experimental Example 4. Evaluation of microsomal stability

Microsomal stability was evaluated for Examples 15, 25, 29 and 35 of the present invention, and the results are shown in Table 4 below.

experimental species Human Dog Rat Mouse Example 15 compound 99.4% 54.7% 96.7% 75.2% Example 25 compound 66.9% 26.1% 65.5% 78.8% Example 29 compound 97.5% 86.1% 93.1% 86.7% Example 35 compound 63.0% 43.3% 63.0% 70.3%

As shown in the table above, the compounds of the present invention show excellent in vivo stability.

Experimental Example 5. In vivo PK profile

4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide synthesized in Example 15 and the above Examples of 4-amino- N -cyclopropyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide synthesized in The in vivo PK (mouse PK/ICR mice) profile is as follows.

Mouse PK/ ICR Mice experimental species Dosage t _1/2 t _max C _max AUC ₍₀ - _t) AUC ₍₀ - _Δ) hr hr ng/mL ng/mL*hr ng/mL*hr Example 15 compound PO
10 mg/kg 1.00 0.63 84.50 144.27 124.62 Example 29 compound PO10 mg/kg 2.09 0.44 1540.00 3790.00 3356.97

[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 0.3 mg of polysorbate 80 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 Na2HPO4.12H2O, and 2974 mg of distilled water.

In the above, 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 may 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 4-aminoquinazoline-2-carboxamide derivative compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:
[Formula 1]

In Formula 1,
A is hydrogen; C ₁ -C ₆ alkyl group; 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 A together with the nitrogen atom connected to R ₁ is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, Or SO ₂ It may optionally include at least one of, C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a group and a cyano group;
R ₁ is hydrogen; C ₁ -C ₆ alkyl group; C ₁ -C ₁₃ alkyl group; C ₃ -C ₁₀ cyclyl group; or a C ₃ -C ₁₀ heterocyclyl group; or R ₁ together with the nitrogen atom connected to A is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) ₂ -, Or SO ₂ It may optionally include at least one of, C ₁ -C ₆ alkyl group, C ₁ -C ₁₃ alkyl group, C ₆ -C ₁₀ aryl group, C ₃ -C ₁₀ heteroaryl group, hydroxyl group, halide forming a 4 to 7 membered saturated, unsaturated or aromatic ring which may be optionally substituted with at least one of a group and a cyano group;
B is a C ₁ -C ₆ alkyl group; C ₁ -C ₁₃ alkyl group; C ₆ -C ₁₀ aryl group; or a 3-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;
R ₂ is hydrogen; hydroxyl group; halogen group; C ₁ -C ₆ alkyl group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; C ₁ -C ₆ alkenyl 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; or —C(O)—(C ₁ -C ₁₃ alkyl);
n is an integer from 0 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a 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 ₃ R ₄ ); 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; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); 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,
The R ₃ and R ₄ are 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.
The method of claim 1,
Wherein B is a C ₁ -C ₆ alkyl group, benzene, cyazole, thiophene, pyrazole, benzothiophene, pyridazine, pyrazine, imidazole, oxadiazole, triazole, furan, pyrimidine, oxazole, pyrrole, Any one selected from the group consisting of pyridine, triazine, cyadiazole, isoxazole, and tetrazole,
A compound selected from a 4-aminoquinazoline-2-carboxamide derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
3. The method of claim 2,
wherein R ₂ is selected from halogen, a substituted or unsubstituted C ₁ -C ₃ alkyl group, trifluor, a substituted or unsubstituted C ₁ -C ₃ alkoxy group, a benzene group, a pyridine group, a piperazine group, a sulfonyl group and an imidazole group becomes,
The substituted C ₁ -C ₃ alkyl group or the substituted C ₁ -C ₃ alkoxy group is hydrogen; hydroxyl group; halogen group; C ₁ -C ₁₃ alkyl group; C ₁ -C ₆ alkoxy group; an amino group (-NR ₃ R ₄ ); nitro group (-N(O) ₂ ); amide group (-(C=O)NR ₃ R ₄ ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR ₃ (C=O)NR ₄ -); sulfonamide group (-NHS(O) ₂ -); sulfide group (-S-); sulfonic group (-S(O) ₂ -); a phospyryl group (-P(O)R ₃ R ₄ ); C ₆ -C ₁₀ aryl group; C ₃ -C ₁₀ heteroaryl group; and one or more substituents selected from the group consisting of a C ₃ -C ₁₀ heterocyclyl group,
A compound selected from a 4-aminoquinazoline-2-carboxamide derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof .
The method of claim 1,
The compound is a 4-aminoquinazoline-2-carboxamide derivative compound represented by Formula 1, characterized in that any one selected from the group consisting of Compound Nos. 1 to 35, a pharmaceutically acceptable salt thereof, a compound selected from its hydrates and stereoisomers thereof:
(Compound No. 1) N- (3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)thiazole-4-carboxamide;
(Compound No. 2) 6-(5-acetamido-2-methylphenyl)-4-amino-5-fluoroquinazoline-2-carboxamide;
(Compound No. 3) 4-amino-6-(5-(5-bromothiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxamide;
(Compound No. 4) N -(3-(4-amino-2-carbamoyl-5-fluoroquinazolin-6-yl)-4-methylphenyl)-2-(pyridin-4-yl)thiazole-4 -carboxyamide;
(Compound No. 5) 4-amino-5-fluoro-6-(2-methyl-5-(1-phenyl-5-(trifluoromethyl) -1H -pyrazole-4-carboxyamido) phenyl)quinazoline-2-carboxyamide;
(Compound No. 6) 4-amino-6-(5-(benzo[ b ]thiophene-2-carboxyamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;
(Compound No. 7) 4-amino-6-(5-benzamido-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;
(Compound No. 8) 4-amino-5-fluoro-6-(2-methyl-5-(3,4,5-trimethoxybenzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 9) 4-amino-5-fluoro-6-(2-methyl-5-(2,3,4-trifluorobenzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 10) 4-amino-5-fluoro-6-(2-methyl-5-(4-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 11) 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide ;
(Compound No. 12) 4-amino-6-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;
(Compound No. 13) 4-amino-5-fluoro-6-(2-methyl-5-(3-(methylsulfonyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 14) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)benzamido)phenyl)quinazoline-2-carboxyamide ;
(Compound No. 15) 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 16) 4-amino-5-fluoro-6-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetamido)phenyl)quinazoline-2-carboxyamide ;
(Compound No. 17) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl) benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 18) 4-amino-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido) phenyl)quinazoline-2-carboxyamide;
(Compound No. 19) 4-amino-6-(5-(4-chloro-3-(trifluoromethyl)benzamido)-2-methylphenyl)-5-fluoroquinazoline-2-carboxyamide;
(Compound No. 20) 4-amino-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamido) phenyl)quinazoline-2-carboxyamide;
(Compound No. 21) 4-amino-5-fluoro-6-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benz amido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 22) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methyl-) 1 H -imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 23) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(4-methylpiperazin) Razin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 24) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-(4-methylpiperazin) Razin-1-yl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 25) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(4-((4-methyl) piperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 26) 4-amino-6-(5-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)benzamido)- 2-methylphenyl)-N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-5-fluoroquinazoline-2-carboxyamide;
(Compound No. 27) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(5-(4-((4-hydroxypiperidine) -1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)quinazoline-2-carboxyamide;
(Compound No. 28) 4-amino-5-fluoro- N -methyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide;
(Compound No. 29) 4-amino- N -cyclopropyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide ;
(Compound No. 30) 4-Amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-( oxetan -3-yl)quina zoline-2-carboxyamide;
(Compound No. 31) 4-amino-5-fluoro- N , N -dimethyl-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2- carboxyamide;
(Compound No. 32) N -(3-(4-amino-5-fluoro-2-(morpholine-4-carbonyl)quinazolin-6-yl)-4-methylphenyl)-3-(trifluoro methyl)benzamide;
(Compound No. 33) 4-amino- N -cyclohexyl-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinazoline-2-carboxyamide ;
(Compound No. 34) 4-amino-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl) -N -phenylquinazoline-2-carboxyamide; and
(Compound No. 35) 4-amino- N- (4-(4-ethylpiperazin-1-yl)phenyl)-5-fluoro-6-(2-methyl-5-(3-(trifluoromethyl) )benzamido)phenyl)quinazoline-2-carboxyamide.
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 a 4-aminoquinazoline-2-carboxamide derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
A pharmaceutical composition for preventing, alleviating or treating cancer, wherein the compound of any one of claims 1 to 5 is included as an active ingredient.
7. The method of claim 6,
The composition inhibits the activity of any one or more protein kinases selected from DDR1, DDR2, CRAF, BRAF, ARAF and EPHA2, a pharmaceutical composition for preventing, alleviating or treating cancer.
7. The method of claim 6,
The pharmaceutical composition is DDR1, DDR2, CRAF, BRAF, ARAF, and applied to a patient having any one or more overexpression genes of EPHA2, cancer prevention, alleviation or treatment pharmaceutical composition.
7. The method of claim 6,
The cancer is endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, Prostate cancer, urethral cancer, leukemia, multiple myeloma, hematological cancer, lymphoma, and at least one selected from the group consisting of fibroadenoma, cancer prevention, alleviation or treatment pharmaceutical composition.
7. The method of claim 6,
The cancer is breast cancer, a pharmaceutical composition for preventing, alleviating or treating cancer.
7. The method of claim 6,
The pharmaceutical composition is MDA-MB-231, MDA-MB-468, MDA-MB-453 and a pharmaceutical composition for the prevention, alleviation or treatment of cancer, characterized in that inhibiting the proliferation of any one or more cell lines of HCC70.

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