KR20200132317A - Novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivatives and use thereof - Google Patents

Abstract

The present invention relates to: a novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating MerTK-related diseases containing the same as an active component; and a method for preventing or treating MerTK-related diseases using the pharmaceutical composition.

Description

Novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivatives and use thereof {Novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivatives and use thereof}

The present invention is a novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical for preventing or treating MerTK-related diseases comprising the same as an active ingredient The composition, and the pharmaceutical composition relates to a method for preventing or treating MerTK-related diseases using.

The transmembrane receptor tyrosine kinase (RTK) contains an evolutionarily conserved family of structurally related proteins. The gene Mer is a member of the Tyro3/Axl/Mer (TAM) receptor kinase family and is a pre-oncogene, and its abnormal expression and activation causes various diseases such as human cancer, such as pituitary adenoma, mantle cell lymphoma and T-cell acute lymphoblastic leukemia. It is known to do. In particular, MerTK (Mer Tyrosine Kinase) is known to induce immune evasion of cancer cells by recognizing cancer cells that are mainly expressed in specific macrophages and dendritic cells and self-death, and by inducing an immune suppression reaction in the tumor microenvironment. Accordingly, it is expected that inhibitors thereof inhibit the activity of MerTK, thereby blocking immune evasion and promoting anticancer immune activation upon self-killing of cancer cells.

On the other hand, the ATP-binding site is similar for all protein kinases. Therefore, finding specific inhibitors for Mer is difficult. In this context, Compound 52, a 2,6,9-trisubstituted purine that occupies an ATP-binding site, is the first molecule that has been shown to have actually succeeded in inhibiting Mer (J. Struct. Biol., 2009, 165(2). ): 88-96). However, it showed limited efficacy and lacks selectivity. Accordingly, several compounds prepared by modifying the structure of Compound 52 such as UNC-569, UNC-1062 and UNC-2025 as MerTK inhibitors have been disclosed.

As a result of intensive research efforts to develop a novel small molecule compound capable of inhibiting or regulating MerTK activity, the present inventors showed that a series of 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivatives showed MerTK activity. Inhibition, and it was confirmed that it can effectively inhibit the proliferation of overexpressing cells, and the present invention was completed.

As one aspect for achieving the above object, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ is C _1-4 alkyl;

R ₂ is unsubstituted or substituted C _6-10 aryl, C _5-10 heterocyclyl or C _5-10 heteroaryl;

A is OR ₃ or NR ₄ R ₅ ;

R ₃ is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)- (C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _6-10 arylene)-(C _0-3 alkylene )-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-( C _5-10 heteroaryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkynylene)-(C _5-10 heteroaryl), -(C _{0- 2} alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-(C _5-10 heterocyclyl) or -(C _0-2 alkylene)-(C _6-10 arylene )-(C _1-3 alkynylene)-(C _5-10 heterocyclyl);

R ₄ and R ₅ are each one hydrogen and the other is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene )-(C _5-10 heteroarylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _{6 -10} arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _{6- 10} arylene)-(C _0-3 alkylene)-(C _5-10 heterocyclyl) to form a substituted heteroaryl;

The aryl, heterocyclyl and heteroaryl are each independently unsubstituted or C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkanoneyl, C _3-6 cycloalkyl, C ₅ May be substituted with one or more selected from the group consisting of _-10 heterocyclyl, amino, (C _1-4 alkyl)amino, di(C _1-4 alkyl)amino, and C _1-4 alkoxy.

For example, in the above formula, R ₁ may be ethyl.

For example, in the above formula, R ₂ may be unsubstituted or substituted phenyl, piperidinyl or pyrazolyl.

Specifically, in the above formula, R ₂ may be phenyl, morpholinophenyl, methylpiperidinyl, or methylpyrazolyl, but is not limited thereto.

For example, in the above formula, A is (methylpiperazinyl)biphenyloxy, ((methylpiperazinyl)methyl)biphenylmethyloxy, ((methylpiperazinyl)methyl)biphenyloxy, ((methylpiperazinyl) )Ethyl)biphenyloxy, ((methylpiperazinyl)propyl)biphenyloxy, ((methylpiperazinyl)ethyl)methylbiphenyloxy, ((methylpiperazinyl)ethyl)fluorobiphenyloxy, ( (Methylpiperazinyl)ethyl)methoxybiphenyloxy, ((methylpiperazinyl)methyl)perfluoromethylbiphenyloxy, ((methylpiperazinyl)oxoethyl)biphenyloxy, (dimethylamino)bi Phenyloxy, methoxybiphenyloxy, (imidazopyridazinylethynyl)phenyloxy, ((methylpiperazinyl)propynyl)phenyloxy, ((acetylpiperazinyl)methyl)biphenyloxy, ((cyclo Propylpiperazinyl)methyl)biphenyloxy, (((methylpiperazinyl)methyl)phenyl)pyridinyloxy, (((methylpiperazinyl)ethyl)phenyl)pyridinyloxy, (methylpiperazinyl)bi Phenylamino, ((methylpiperazinyl)methyl)biphenylmethylamino, ((methylpiperazinyl)methyl)biphenylamino, ((methylpiperazinyl)ethyl)biphenylamino, ((methylpiperazinyl) Propyl)biphenylamino, ((methylpiperazinyl)ethyl)methylbiphenylamino, ((methylpiperazinyl)ethyl)fluorobiphenylamino, ((methylpiperazinyl)ethyl)methoxybiphenylamino, ((Methylpiperazinyl)methyl)perfluoromethylbiphenylamino, ((methylpiperazinyl)oxoethyl)biphenylamino, (dimethylamino)biphenylamino, methoxybiphenylamino, (imidazopyrida) Zynylethynyl)phenylamino, ((methylpiperazinyl)propynyl)phenylamino, ((acetylpiperazinyl)methyl)biphenylamino, ((cyclopropylpiperazinyl)methyl)biphenylamino, ((( Methylpiperazinyl)methyl)phenyl)pyridinylamino, (((methylpiperazinyl)ethyl)phenyl)pyridinylamino, or (((methylpiperazinyl)methyl)phenyl)indolyl.

Specifically, the compound is

(1) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(2) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(3) 5-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yloxy)-6-ethyl-3-(1-methyl-1H-pyrazol-4-yl Amino)pyrazine-2-carboxamide;

(4) 6-ethyl-5-(4'-methoxy-[1,1'-biphenyl]-4-yloxy)-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine -2-carboxamide;

(5) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(4-methylpiperazin-1-yl)-[1,1'-bi Phenyl]-4-yloxy)pyrazine-2-carboxamide;

(6) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(7) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(8) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(9) 6-ethyl-5-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)phenylamino)-3-(1-methyl-1H-pyrazol-4-yl Amino)pyrazine-2-carboxamide;

(10) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(11) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(12) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(13) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4-(3-(4-methylpiperazin-1-yl)prop-1-ynyl) Phenylamino)pyrazine-2-carboxamide;

(14) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(3-(4-methylpiperazin-1-yl)propyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(15) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-3'-( Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(16) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(17) 6-ethyl-5-(2'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(18) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(3'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(19) 6-ethyl-5-(3'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(20) 5-(4'-((4-acetylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1-methyl -1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(21) 5-(4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1- Methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(22) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(phenyl Amino)pyrazine-2-carboxamide;

(23) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(1 -Methylpiperidin-4-ylamino)pyrazine-2-carboxamide;

(24) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(4 -Morpholinophenylamino)pyrazine-2-carboxamide;

(25) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -2-ylamino)pyrazine-2-carboxamide;

(26) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -3-ylamino)pyrazine-2-carboxamide;

(27) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenyl )Pyridin-2-ylamino)pyrazine-2-carboxamide;

(28) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-2- (Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(29) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl) )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(30) 6-ethyl-5-(2-methoxy-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino) -3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(31) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-3-yl)methylamino)pyrazine-2-carboxamide;

(32) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-4-yl)methylamino)pyrazine-2-carboxamide;

(33) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)- 1H-indol-1-yl)pyrazine-2-carboxamide; or

(34) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-3-ylamino)pyrazinecarboxamide;

May be, but is not limited thereto.

The compound of Formula 1 of the present invention includes not only a pharmaceutically acceptable salt thereof, but also all possible solvates and hydrates that may be prepared therefrom, and includes all possible isomers without limitation.

In addition, the compound of Formula 1 of the present invention may be prepared in a crystalline or amorphous form, and when these compounds are prepared in a crystalline form, it may be optionally hydrated or solvated. The present invention may include stoichiometric hydrates of the compounds of formula 1 as well as compounds containing varying amounts of water. That is, the solvate of the compound represented by Formula 1 according to the present invention includes both a stoichiometric solvate and a non-stoichiometric solvate.

In another aspect, the present invention includes an amine or a hydroxy group as a reactive functional group at one end of a 5-halo-6-alkyl-3-(substituted amino)pyrazine-2-carboxamide derivative represented by Formula 2 below. It provides a method for preparing the compound of Formula 1, comprising reacting with a substituted aryl or heteroaryl derivative:

[Formula 2]

In Chemical Formula 2,

R ₁ is C _1-4 alkyl;

R ₂ is unsubstituted or substituted C _6-10 aryl, C _5-10 heterocyclyl or C _5-10 heteroaryl;

X is halogen.

For example, the substituted aryl or heteroaryl derivative containing an amine or hydroxy group used in the reaction is (methylpiperazinyl)biphenylol, ((methylpiperazinyl)methyl)biphenylmethylol, ((methylpipera Genyl)methyl)biphenylol, ((methylpiperazinyl)ethyl)biphenylol, ((methylpiperazinyl)propyl)biphenylol, ((methylpiperazinyl)ethyl)methylbiphenylol, (( Methylpiperazinyl)ethyl)fluorobiphenylol, ((methylpiperazinyl)ethyl)methoxybiphenylol, ((methylpiperazinyl)methyl)perfluoromethylbiphenylol, ((methylpipera Genyl)oxoethyl)biphenylol, (dimethylamino)biphenylol, methoxybiphenylol, (imidazopyridazinylethynyl)phenylol, ((methylpiperazinyl)propynyl)phenylol, (( Acetylpiperazinyl)methyl)biphenylol, ((cyclopropylpiperazinyl)methyl)biphenylol, (((methylpiperazinyl)methyl)phenyl)pyridinylol, (((methylpiperazinyl)ethyl )Phenyl)pyridinylol, (methylpiperazinyl)biphenylamine, ((methylpiperazinyl)methyl)biphenylmethylamine, ((methylpiperazinyl)methyl)biphenylamine, ((methylpiperazinyl) )Ethyl)biphenylamine, ((methylpiperazinyl)propyl)biphenylamine, ((methylpiperazinyl)ethyl)methylbiphenylamine, ((methylpiperazinyl)ethyl)fluorobiphenylamine, ( (Methylpiperazinyl)ethyl)methoxybiphenylamine, ((methylpiperazinyl)methyl)perfluoromethylbiphenylamine, ((methylpiperazinyl)oxoethyl)biphenylamine, (dimethylamino)bi Phenylamine, methoxybiphenylamine, (imidazopyridazinylethynyl)phenylamine, ((methylpiperazinyl)propynyl)phenylamine, ((acetylpiperazinyl)methyl)biphenylamine, ((cyclo Propylpiperazinyl)methyl)biphenylamine, (((methylpiperazinyl)methyl)phenyl)pyridinylamine, (((methylpiperazinyl)ethyl)phenyl)pyridinylamine, or (((methylpipera It may be a genyl) methyl) phenyl) indole, but is not limited thereto.

For example, the reaction may be carried out in an organic solvent in the presence of 1 to 1.5 times the equivalent of a base of the reactant. Potassium carbonate, cesium carbonate, etc. may be used as the base, and N-methyl-2-pyrrolidine, dioxane, and the like may be used as the organic solvent, but are not limited thereto. Specifically, the reaction may be performed by stirring the reaction mixture solution at 70 to 120°C, but is not limited thereto. In a specific embodiment of the present invention, synthesis was performed using various bases, and it was confirmed that, in particular, when potassium carbonate was used, it was possible to synthesize at a high yield, but the present invention is not limited thereto. For example, in the above reaction, the type and amount of base, the type of solvent, and reaction conditions may be appropriately selected by a person skilled in the art in consideration of the reaction efficiency and/or the yield of the product.

Specifically, when a substituted aryl or heteroaryl derivative containing an amine is used as the reactant, the reaction may be performed by additionally including a palladium catalyst and a copper cocatalyst. For example, Pd(OAc) ₂ , or Pd ₂ (dba) ₃ as the palladium catalyst, and Xantphos, Xphos, BINAP ((1,1'-Binaphthalene-2, 2'-diyl)bis(diphenylphosphine)) may be used, but is not limited thereto. In a specific embodiment of the present invention, it was confirmed that the target compound can be obtained in high yield by using Pd(OAc) ₂ as a palladium catalyst and xantphos as a copper cocatalyst, The type and combination of are not limited thereto.

For example, when reacting with a substituted aryl or heteroaryl derivative containing an amine, the step of removing gas from the reaction mixture by ultrasonicating the reaction solution before adding the catalyst may be further performed, but is not limited thereto. For example, in a specific embodiment of the present invention, the target compound can be obtained in a higher yield by sonicating for several minutes before adding the catalyst.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating MerTK-related diseases comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

In Formula 1,

R ₁ is C _1-4 alkyl;

R ₂ is unsubstituted or substituted C _5-10 heteroaryl;

A is OR ₃ or NR ₄ R ₅ ;

R ₃ is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)- (C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _6-10 arylene)-(C _0-3 alkylene )-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-( C _5-10 heteroaryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkynylene)-(C _5-10 heteroaryl), -(C _{0- 2} alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-(C _5-10 heterocyclyl) or -(C _0-2 alkylene)-(C _6-10 arylene )-(C _1-3 alkynylene)-(C _5-10 heterocyclyl);

R ₄ and R ₅ are each one hydrogen and the other is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene )-(C _5-10 heteroarylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _{6 -10} arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl);

The aryl, heterocyclyl and heteroaryl are each independently unsubstituted or C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkanoneyl, C _3-6 cycloalkyl, C ₅ May be substituted with one or more selected from the group consisting of _-10 heterocyclyl, amino, (C _1-4 alkyl)amino, di(C _1-4 alkyl)amino, and C _1-4 alkoxy.

For example, the compound represented by Formula 1

(1) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(2) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(3) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(4-methylpiperazin-1-yl)-[1,1'-bi Phenyl]-4-yloxy)pyrazine-2-carboxamide;

(4) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(5) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(6) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(7) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(8) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(9) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;

(10) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4-(3-(4-methylpiperazin-1-yl)prop-1-ynyl) Phenylamino)pyrazine-2-carboxamide;

(11) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(3-(4-methylpiperazin-1-yl)propyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(12) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-3'-( Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(13) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(14) 6-ethyl-5-(2'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(15) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(3'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(16) 6-ethyl-5-(3'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(17) 5-(4'-((4-acetylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1-methyl -1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(18) 5-(4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1- Methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;

(19) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -2-ylamino)pyrazine-2-carboxamide;

(20) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -3-ylamino)pyrazine-2-carboxamide;

(21) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenyl )Pyridin-2-ylamino)pyrazine-2-carboxamide;

(22) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-2- (Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(23) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl) )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;

(24) 6-ethyl-5-(2-methoxy-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino) -3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide; or

(25) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-3-yl)methylamino)pyrazine-2-carboxamide; may be, but is not limited thereto.

The term "prevention" of the present invention refers to all actions of inhibiting or delaying the occurrence, spread, and recurrence of MerTK-related diseases by administration of the composition of the present invention, and "treatment" refers to the administration of the composition of the present invention. It can refer to any behavior in which the symptoms improve or are beneficially changed.

The composition of the present invention can prevent or treat MerTK-related diseases by inhibiting the activity of MerTK, thereby blocking immune evasion and promoting anti-cancer immunity when cancer cells self-kill, thereby preventing diseases caused by abnormal MerTK activity. Or it can be usefully used for treatment.

Preferably, the pharmaceutical composition according to the present invention contains a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient, in 0.1 to 75% by weight, more preferably 1 to 50, based on the total weight of the composition. It may contain by weight %.

The composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powders, granules, tablets, capsules, suspensions, emulsions, syrups, according to a conventional method for each purpose of use, It can be formulated and used in various forms such as oral formulations such as aerosols and injections of sterile injection solutions, and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the composition of the present invention may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Is formulated by mixing. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Examples of liquid formulations for oral use include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents. I can.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. The base for suppositories is Withepsol, Macrogol, and Tween61. Cacao butter, laurin paper, glycerogelatin, and the like may be used. Meanwhile, the injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, and preservatives.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the health condition of the patient, The type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. I can. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight daily or every other day or 1 It can be administered in 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the dosage amount is not limited by any method.

Specifically, the pharmaceutical composition of the present invention can exhibit its effect by inhibiting the activity of MerTK.

Specifically, the pharmaceutical composition of the present invention may be usefully used in the prevention or treatment of MerTK-related diseases such as immune diseases or cancer diseases.

The immune disease that can be prevented or treated using the pharmaceutical composition of the present invention may be infection or sepsis.

Cancer diseases that can be prevented or treated using the pharmaceutical composition of the present invention include colorectal cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer. , Biliary tract cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hematologic cancer, bladder cancer, kidney cancer, ovarian cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, anal muscle cancer, fallopian tube carcinoma, endometrial Carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, Brainstem glioma, pituitary adenoma, gliomas, subeducoma, anaplastic astrocytoma, medulloblastoma, cervical carcinoma, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangiothelial sarcoma, colorectal cancer, renal cell carcinoma, bile duct carcinoma, Choriocarcinoma, testicular tumor, testicular tumor, Wilm's tumor, Ewing tumor, hemangiosarcoma, endothelial sarcoma, adenocarcinoma, gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenocarcinoma, cystic adenosarcoma, bronchial carcinoma, medullary carcinoma, mast cell tumor , Mesothelioma, synovium, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodendrocyte, inner ear neurohematoma, hemangioblastoma, meningioma, pine cone adenoma, ventricular ventricular tumor, head pharyngeal carcinoma, epithelial carcinoma, embryonic carcinoma, squamous cell It may be carcinoma, basal cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, or metastatic cancer thereof.

For example, the compounds of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention is a concentration that is relatively non-toxic and harmless to patients, and side effects caused by this salt do not degrade the beneficial efficacy of the compound represented by formula (1). Means any organic or inorganic addition salt.

Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess acid aqueous solution, and precipitating this salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.

At this time, organic acids and inorganic acids can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid can be used as organic acids. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , Not limited to these.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, the metal salt is particularly suitable for preparing sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be manufactured through a method.

As a salt of the 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative of the present invention, as a pharmaceutically acceptable salt, 3-(substituted amino)-6-alkyl-pyrazine-2 Any salt of a 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative exhibiting inhibitory activity against MerTK equivalent to a carboxamide derivative compound may be used without limitation.

Furthermore, the pharmaceutical composition of the present invention may further include an immune checkpoint inhibitor, an anticancer agent, or both, in addition to the compound of Formula 1 above.

At this time, the available anticancer agents may be DNA alkylating agents, anti-cancer antibiotics, or plant alkaloids.

Specifically, non-limiting examples of anticancer agents that may be included in the pharmaceutical composition of the present invention include mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide ( cyclophosphamide), ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin , Carboplatin, dactinomycin: actinomycin D, doxorubicin: adriamycin, daunorubicin, idarubicin, mitoxantrone, plicamycin (plicamycin), mitomycin, C breomycin; Vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, and iridotecan.

In another aspect, the present invention provides a health functional food composition for preventing or improving MerTK-related diseases, comprising the compound of Formula 1 or a food pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula 1 is as defined in the above-described pharmaceutical composition.

At this time, the "MerTK-related disease" and "prevention" are the same as described above.

The term "improvement" of the present invention may mean any action that at least reduces the severity of a parameter related to the condition being treated, for example a symptom.

Foods include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health supplements And health foods and the like, and all foods in the usual sense are included.

Since the food composition of the present invention can be consumed on a daily basis, a high effect on the prevention or improvement of MerTK-related diseases can be expected, and thus can be very usefully used for health promotion purposes.

Functional food is the same term as food for special health use (FoSHU), and is a food with high medical and medical effects processed so that the bioregulatory function is effectively displayed in addition to nutrition supply. Means. Here, the term'function (sex)' means to control nutrients for the structure and function of the human body or to obtain useful effects for health purposes such as physiological actions. The food product of the present invention can be prepared by a method commonly used in the art, and during the production, raw materials and ingredients commonly added in the art may be added to prepare it. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time using natural substances as raw materials, and is excellent in portability. The food of the present invention can be consumed as an adjuvant to enhance the effect of improving MerTK-related diseases.

The health food refers to a food having an active health maintenance or promotion effect compared to general food, and a health supplement food refers to a food for health supplement purposes. In some cases, the terms health functional food, health food, and health supplement food are used interchangeably.

Specifically, the food composition is a food prepared by adding the compound of the present invention to food materials such as beverages, teas, spices, chewing gums, confectionery, or encapsulating, powdering, and suspending. It means bringing about, but unlike general drugs, it has the advantage of having no side effects that may occur when taking the drug for a long time by using food as a raw material.

The food composition may further include a food pharmaceutically acceptable carrier, and the type of the carrier is not particularly limited, and any carrier commonly used in the art may be used.

In addition, the health functional food may include additional ingredients that are commonly used in food compositions to improve smell, taste, vision, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, and valine.

In addition, the food composition includes preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching and highly bleaching, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisol (BHA), butylhydride, etc.) Oxytoleuene (BHT), etc.), coloring agent (tar color, etc.), coloring agent (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasoning (MSG sodium glutamate, etc.), sweetener (dulsin, cyclamate, saccharin, etc.) , Sodium, etc.), flavorings (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen stannate, etc.), reinforcing agents, emulsifying agents, thickening agents (thickening agents), coating agents, gum base agents, foam inhibitors, solvents, improving agents, etc. It may contain food additives. The additive may be selected according to the type of food and used in an appropriate amount.

As an example of the food composition of the present invention, it may be used as a health drink composition, and in this case, it may contain various flavoring agents or natural carbohydrates, etc. as an additional ingredient, such as a conventional beverage. The natural carbohydrates described above include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Polysaccharides such as dextrin and cyclodextrin; It may be a sugar alcohol such as xylitol, sorbitol, and erythritol. Sweeteners include natural sweeteners such as taumatin and stevia extract; Synthetic sweeteners such as saccharin and aspartame can be used. The ratio of the natural carbohydrate may be generally about 0.0001 to 0.4 g, specifically about 0.0002 to 0.3 g per 100 mL of the health beverage composition of the present invention.

In addition to the above, health beverage compositions include various nutrients, vitamins, electrolytes, flavoring agents, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, It may contain alcohol or a carbonation agent. In addition, it may contain flesh for the manufacture of natural fruit juice, fruit juice beverage, or vegetable beverage. These ingredients may be used independently or in combination. The ratio of these additives is not very important, but it is generally selected from 0.0001 to 0.10 parts by weight per 100 parts by weight of the health beverage composition of the present invention.

In another aspect, the present invention provides a method for preventing or treating MerTK-related diseases, comprising administering the pharmaceutical composition to an individual.

The term "individual" of the present invention refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, rabbits, or guineas, including humans in which the MerTK-related diseases are invented or may develop. It means all animals including pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention can be administered in combination with an existing therapeutic agent.

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration, but are not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells. Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections and the like. Injectables include aqueous solvents such as physiological saline solution and ring gel solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., oleic acid ethyl, etc.), alcohols (e.g. ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be prepared by using, and stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and for inhibiting the growth of microorganisms. Pharmaceutical carriers such as preservatives (eg, mercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.

The term "therapeutically effective amount" used in combination with an active ingredient in the present invention refers to a 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative compound effective in preventing or treating a target disease, or It means the amount of its pharmaceutically acceptable salt.

The pharmaceutical composition of the present invention is a 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative compound, or a pharmaceutically acceptable thereof, as an active ingredient, depending on the type of disease to be prevented or treated. It may further include known drugs used for the prevention or treatment of each known disease other than salt. For example, when used for the prevention or treatment of cancer diseases, a known anticancer agent other than a 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative compound, or a pharmaceutically acceptable salt thereof is used as an active ingredient. It may further include, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapy, immunotherapy, and the like.

The novel 3-(substituted amino)-6-alkyl-pyrazine-2-carboxamide derivative of the present invention inhibits MerTK and can inhibit the proliferation of cells that overexpress it, so that the overexpression or excessive activity of MerTK It can be usefully used in the treatment or prevention of immune or cancer diseases caused by.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

Commercially available reagents used were those purchased without further purification. In the present invention, room temperature refers to a temperature of 20 to 25°C, and concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.

<Method and conditions for analysis and purification>

In the present invention, a series of compounds synthesized from the examples were synthesized, purified by the following method, and the structure was analyzed.

1. For purification Medium pressure liquid chromatography (Medium Pressure Liquid Chromatography; MPLC)

Medium-pressure liquid chromatography was performed using CombiFlash Rf+UV from TELEEDYNE ISCO.

2. For analysis High performance liquid chromatography (High Performance Liquid Chromatography; HPLC) conditions

Waters' UPLC system (ACQUITY UPLC PDA Detector) was analyzed using a device equipped with a Mass QDA detector. The column used was ACQUITY UPLC ^® BEH C18 (1.7 μm, 2.1×50 mm) manufactured by Waters, and the column temperature was set to 30°C. Water containing 0.1% formic acid was used as mobile phase A, and acetonitrile containing 0.1% formic acid was used as mobile phase B. The gradient conditions were 10-100% B for 3 minutes, and the moving speed was 0.6 mL/minute.

3. Prep- for purification LCMS (Preparative-Liquid chromatography mass spectrometry)

Waters' Autopurification HPLC system (2767 sample manager, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a Mass QDA detector to purify the compound. The column used was SunFire ^® Prep C18 OBDTM (5 μm, 19×50 mm) manufactured by Waters, and the column temperature was maintained at room temperature. Water containing 0.035% trifluoroacetic acid was used as mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used as mobile phase B. The gradient conditions were 15-100% B for 10 minutes and the moving speed was 25 mL/minute.

4. Prep-150 LC system for purification (Preparative-Liquid chromatography UV spectrometry)

The compound was purified using Waters' Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III). The column used was XTERRA ^® Prep RP18 OBDTM (10 μm, 30×300 mm) manufactured by Waters, and the column temperature was maintained at room temperature.

5. NMR analysis

The NMR spectrum was recorded and analyzed using Bruker's AVANCEIII400 or AVANCEIII 400 HD, and the acquired data were expressed in ppm (parts per million, δ).

Manufacturing example 1: 5- as an intermediate Chloro -6-ethyl-3-(1- methyl -1H- Pyrazole -4- One amino ) Pyrazine -2-Preparation of carboxamide

Step 1- 1: 5 - Chloro -6-ethyl-3-(1- methyl -One H - Pyrazole -4- One amino ) Pyrazine -2- Carboxamide Produce

3,5-dichloro-6-ethylpyrazine-2-carboxamide (3,5-dichloro-6-ethylpyrazine-2-carboxamide, 106 mg, 0.484 mmol) and 1-methyl-1H-pyrazol-4-amine (1-methyl-1H-pyrazol-4-amine, 47 mg, 0.484 mmol) was dissolved in dioxane (2 mL), and then DIPEA (N,N-Diisopropylethylamine) was added to the solution at 110°C for 12 Stir for hours. After completion of the reaction, extraction was performed with ethyl acetate and water, the organic layer was recovered and concentrated, and then purified by MPLC (dichloromethane/methyl alcohol) to obtain the target compound (82 mg, 60%).

MS (m/z): 281.08 [M+1];

UPLC r.t. (min): 1.53.

Manufacturing example 2 to 4: a series of 5- Chloro -6-ethyl-3-(substituted amino) blood Preparation of ragin-2-carboxamide derivatives

In a method similar to Preparation Example 1, except that aniline, 1-methylpiperidin-4-amine and 4-morpholinoaniline were used respectively instead of 1-methyl-1H-pyrazol-4-amine. Reaction 5-chloro-6-ethyl-3- (phenylamino) pyrazine-2-carboxamide (5-chloro-6-ethyl-3- (phenylamino) pyrazine-2-carboxamide), 5-chloro-6- Ethyl-3-(1-methylpiperidin-4-ylamino)pyrazine-2-carboxamide (5-chloro-6-ethyl-3-(1-methylpiperidin-4-ylamino)pyrazine-2-carboxamide) And 5-chloro-6-ethyl-3- (4-morpholinophenylamino) pyrazine-2-carboxamide (5-chloro-6-ethyl-3- (4-morpholinophenylamino) pyrazine-2-carboxamide) Obtained.

Manufacturing example 5: 4'-((4- Methylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4-ol production

Step 5- 1: 1 -(4- Bromobenzyl )-4- Of methylpiperazine Produce

1-Bromo-4-(bromomethyl)benzene (3 g, 12.00 mmol) was diluted in DCM (15 mL) and then 1-methylpiperazine (2.4 g, 24.01 mmol) dissolved in DMC (30 mL). ) The solution was slowly added dropwise to the solution. After stirring at room temperature for 2 hours, water was added to remove the resulting solid by filtration, and extracted using DCM and water. The organic layer was recovered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (2.8 g, 87%), which was used in the next reaction without further purification.

MS (m/z): 269.06 [M+1];

UPLC r.t. (min): 0.96.

Step 5- 2: 1 - methyl -4-(4-(4,4,5,5- Tetramethyl -1,3,2- Dioxabororan -2 days) benzyl ) Preparation of piperazine

1-(4-bromobenzyl)-4-methylpiperazine (1-(4-bromobenzyl)-4-methylpiperazine, 2.8 g, 10.40 mmol) obtained in step 5-1 was 4,4,4', 4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4,4,4',4',5,5,5 Into dioxane (45 mL) with',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), 2.91 g, 11.44 mmol) and potassium acetate (3.06 g, 31.2 mmol) After dissolving, the gas was removed by ultrasonic treatment for 5 minutes under nitrogen. Pd(dppf)Cl ₂ ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 228 mg, 0.312 mmol) was added to the reaction mixture, followed by stirring at 110° C. for 3 hours. After completion of the reaction, it was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated and purified by MPLC (dichloromethane/methyl alcohol) to obtain the title compound (2.7 g, 82%).

MS (m/z): 317.23 [M+1];

UPLC r.t. (min): 1.09.

Step 5- 3: 4 '-((4- Methylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4-ol production

1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) piperazine (1) obtained in step 5-2 -methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, 201 mg, 0.636 mmol) to 4-bromophenol (100 mg , 0.578 mmol) and sodium percarbonate (Na ₂ H ₃ CO ₆ , 153 mg, 1.445 mmol) in a mixed solvent of 1 mL IPA (isopropyl alcohol) and 1 mL water, followed by ultrasonication for 5 minutes under nitrogen. The gas was removed by treatment. After adding 10% Pd/C (6.15 mg, 0.00578 mmol) to the reaction mixture, the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, it was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated and then purified by MPLC (dichloromethane/methyl alcohol) to obtain the title compound (140 mg, 78%).

MS (m/z): 283.17 [M+1];

UPLC r.t. (min): 0.86.

Manufacturing example 6: 1-(4- Bromophenethyl )-4- Of methylpiperazine Produce

Step 6- 1: 2 -(4- Bromophenyl )-1-(4- Methylpiperazine Preparation of -1-yl)ethan-1-one

2-(4-bromophenyl)acetic acid, 5 g, 23.25 mmol), 1-methylpiperazine (2.58 mL, 23.25 mmol), EDC (N-(3-dimethylaminopropyl) -N'-ethylcarbodiimide, 4.9 g, 25.6 mmol), DMAP (4-dimethylaminopyridine, 0.017 g, 0.14 mmol) was dissolved in DCM (dichloromethane, 60 mL), and then stirred at room temperature for 20 hours. After the reaction was completed, the mixture was washed with water and 1N HCl, and saturated Na ₂ CO ₃ was added thereto, followed by extraction with ethyl acetate. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain the target compound (6.84 g, 99%), which was used in the next reaction without further purification.

MS (m/z): 297.05 [M+1];

UPLC r.t. (min): 0.93.

Step 6- 2: 1 -(4- Bromophenethyl )-4- Of methylpiperazine Produce

2-(4-bromophenyl)-1-(4-methylpiperazin-1-yl)ethan-1-one (2-(4-bromophenyl)-1-(4-) obtained in step 6-1 After dissolving methylpiperazin-1-yl)ethan-1-one, 1.9 g, 6.39 mmol) in THF (tetrahydrofuran, 23 mL), LAH (lithium aluminum hydride, 0.485) diluted in THF (14 mL) at -20°C g, 12.79 mmol) was slowly added dropwise, followed by stirring at the same temperature for 30 minutes, warming to room temperature, and stirring for another 2 hours. After completion of the reaction, water (0.4 mL) and 6N NaOH (1.3 mL) were added, filtered through celite, and washed with ethyl acetate. After washing with brine, drying over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (1.7 g, 94%), which was used in the next reaction without further purification.

MS (m/z): 283.07 [M+1];

UPLC r.t. (min): 0.93.

Manufacturing example 7: 4'-((4- Methylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4-amine preparation

Step 7- 1: 4 -(4,4,5,5- Tetramethyl -1,3,2- Dioxabororan Preparation of -2-yl)aniline

4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1 ,3,2-dioxaborolane, 1 g, 4.01 mmol) was dissolved in methanol (20 mL), and then 10% Pd/C (0.107 g, 1.004 mmol) was added, followed by stirring under hydrogen at room temperature for 4 hours. After completion of the reaction, it was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated to obtain the target compound (850 mg, 97%), which was used in the next reaction without further purification.

MS (m/z): 220.14 [M+1];

UPLC r.t. (min): 1.45.

Step 7- 2: 4 '-((4- Methylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4- Amine Produce

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4-(4,4,5,5-) obtained in step 7-1 above tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 195 mg, 0.892 mmol) 1-(4-bromobenzyl)-4-methylpiperazine prepared according to step 5-1 of Preparation Example 5 (200 mg, 0.743 mmol) and 2 MK ₂ CO ₃ (1.11 mL, 2.229 mmol) were dissolved in DMF (N,N-dimethylformamide, 1.1 mL) and then sonicated under nitrogen for 5 minutes to remove the gas. . Pd(PPh ₃ ) ₄ (tetrakis(triphenylphosphine) palladium(0), 43 mg, 0.037 mmol) was added to the reaction mixture, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated and then purified by MPLC (dichloromethane/methyl alcohol) to obtain the title compound (153 mg, 73%).

MS (m/z): 282.19 [M+1];

UPLC r.t. (min): 0.33.

Example 1: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-((4- Methylpiperazine Preparation of -1-yl)methyl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

5-chloro-6-ethyl-3-(1-methyl-1H-pyrazol-4-ylnamino)pyrazine-2-carboxamide (12.00 mg, 0.043 mmol) prepared according to Preparation Example 1 and Preparation Example 5 4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ol (12.68 mg, 0.045 mmol) prepared according to the following was added potassium carbonate (6.5 mg, 0.047 mmol) ) And then dissolved in NMP (0.4 mL) and stirred at 100° C. for 2 hours. After completion of the reaction, extraction was performed with ethyl acetate and water, and the organic layer was recovered and dried over anhydrous sodium sulfate. The obtained filtrate was concentrated under reduced pressure and then purified by Prep-150 LC system to obtain the target compound (20 mg, 89%).

Example 2: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-((4- Methylpiperazine Preparation of -1-yl)methyl)-[1,1′-biphenyl]-4-ylamino)pyrazine-2-carboxamide

5-chloro-6-ethyl-3-(1-methyl-1H-pyrazol-4-ylnamino)pyrazine-2-carboxamide (11.4 mg, 0.041 mmol) prepared according to Preparation Example 1 and Preparation Example 7 4'-((4-methylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-amine (12.57 mg, 0.045 mmol) prepared according to the following was added potassium carbonate (28.1 mg, 0.203 mmol) ) And dissolved in dioxane (0.3 mL), and sonicated for 5 minutes under nitrogen to remove gas. Pd(OAc) ₂ (palladium(II) acetate, 0.912 mg, 0.0041 mmol) and xantphos (xantphos, 4.7 mg, 0.0082 mmol) were added to the reaction mixture, followed by stirring at 90° C. for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate and water, and the organic layer was recovered and dried over anhydrous sodium sulfate. The obtained filtrate was concentrated under reduced pressure and then purified by Prep-150 LC system to obtain the title compound (11 mg, 52%).

Hereinafter, the precursors synthesized according to Preparation Examples 1 to 4 and the precursors prepared by Examples 5 to 7 or a similar method were combined and reacted by the method of Example 1 or 2, and a series of 6-ethyl-3-(substituted The amino)-5-(oxy or amino)pyrazine-2-carboxamide derivatives were synthesized, and these compounds were identified through MS (m/z), NMR, yield and/or UPLC analysis, and the results were obtained from the structural formula It is summarized and shown below together with.

compound 1: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-((4- Methylpiperazine -1-yl)methyl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

MS (m/z): 527.3 [M+H] ⁺ ;

UPLC r.t. (min): 1.34;

Yields: 47%;

HPLC r.t. (min), Purity: 1.34;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.66 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H) , 7.67 (s, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 6.98 (s, 1H), 3.76-3.69 ( m, 2H), 3.47-3.36 (m, 2H), 3.34 (s, 3H), 3.12-2.93 (m, 4H), 2.87 (q, J = 7.5 Hz, 2H), 2.79 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H).

compound 2: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-((4- Methylpiperazine -1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 526.3 [M+H] ⁺ ;

UPLC r.t. (min): 2.74;

Yields: 45%;

HPLC r.t. (min), Purity: 1.22;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.69 (t, J = 8.1 Hz, 4H), 7.65-7.54 (m, 3H), 7.49 J 7.38 (m, 3H), 3.66 (s, 2H), 3.60 (s, 3H), 2.90-2.87 (m, 4H), 2.80 (q, J = 7.4 Hz, 2H), 2.73-2.65 (m, 4H), 2.57 (s, 3H), 1.37 (t, J = 7.4 Hz, 3H).

compound 3: 5 -(4'-( Dimethylamino )-[1,1'- Biphenyl ]-4- Oxy )-6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 458.2 [M+H] ⁺ ;

Yields: 48%;

HPLC r.t. (min), Purity: 1.92;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.63 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.5 Hz, 3H) , 7.31 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H), 6.93 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 2.96 (s, 6H), 2.93 (d, J = 3.7 Hz, 2H), 2.09 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H).

compound 4: 6 -Ethyl-5-(4'- Methoxy -[1,1'- Biphenyl ]-4- Oxy )-3-(1- methyl -1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 445.2 [M+H] ⁺ ;

Yields: 56%;

HPLC r.t. (min), Purity: 1.97;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 7.92 (s, 1H), 7.87-7.80 (m, 2H), 7.74-7.69 (m, 2H), 7.66 (s, 1H) ), 7.39-7.31 (m, 2H), 7.27 (s, 1H), 7.09-7.00 (m, 2H), 6.93 (s, 1H), 3.82 (s, 3H), 3.33 (s, 3H), 2.86 ( q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H).

compound 5: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(4- Methylpiperazine -1-yl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

MS (m/z): 513.3 [M+H] ⁺ ;

Yields: 54%;

HPLC r.t. (min), Purity: 1.39;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.63 (s, 1H), 7.91 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 9.2 Hz, 3H) , 7.32 (d, J = 8.6 Hz, 2H), 7.27 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 3.33-3.21 (m, 4H), 2.86 ( q, J = 7.5 Hz, 2H), 2.31-2.21 (m, 4H), 1.33 (t, J = 7.5 Hz, 3H).

compound 6: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(1-(4- Methylpiperazine -1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 540.3 [M+H] ⁺ ;

Yields: 55%;

HPLC r.t. (min), Purity: 1.24;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.69-7.65 (m, 4H), 7.63-7.60 (m, 3H), 7.46-7.43 (m, 3H), 3.61 (s, 3H), 2.80 (q , J = 7.4 Hz, 2H), 2.66 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H), 1.36 (t, J = 7.4 Hz, 3H).

compound 7: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(2-(4- Methylpiperazine -1-yl)-2-oxoethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3 [M+H] ⁺ ;

Yields: 42%;

HPLC r.t. (min), Purity: 1.23;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.69 (dd, J = 8.3, 11.7 Hz, 4H), 7.62-7.54 (m, 3H), 7.42 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 3.84 (s, 2H), 3.67-3.64 (m, 2H), 3.60-3.57 (m, 5H), 2.80 (q, J = 7.4 Hz, 2H), 2.44-2.41 (m, 2H) , 2.35-2.32 (m, 2H), 2.28 (s, 3H), 1.36 (t, J = 7.4 Hz, 3H).

compound 8: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 540.3 [M+H] ⁺ ;

Yields: 47%;

HPLC r.t. (min), Purity: 1.2;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.69 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.60-7.54 (m, 3H), 7.43 (s, 1H), 7.33 (d, J = 7.9 Hz, 2H), 3.58 (s, 3H), 2.92-2.86 (m, 7H), 2.83-2.77 (m, 7H), 2.56 (s, 3H), 1.36 (t , J = 7.4 Hz, 3H).

compound 9: 6 -Ethyl-5-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl ) Phenylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

Yields: 44%;

HPLC r.t.(min), Purity: 1.47.

compound 10: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(1-(4- Methylpiperazine -1-yl)ethyl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

MS (m/z): 541.3 [M+H] ⁺ ;

Yields: 51%;

HPLC r.t. (min), Purity: 1.35;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.65 (s, 1H), 7.92 (s, 1H), 7.90-7.83 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.66 ( s, 1H), 7.43-7.35 (m, 4H), 7.25 (s, 1H), 6.98 (s, 1H), 3.47-3.38 (m, 1H), 3.35 (s, 3H), 2.86 (q, J = 7.5 Hz, 2H), 2.35-2.32 (m, 4H), 2.17-2.15 (m, 4H), 1.34-1.28 (m, 6H).

compound 11: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

MS (m/z): 541.3 [M+H] ⁺ ;

Yields: 48%;

HPLC r.t. (min), Purity: 1.3;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.65 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.69 (s, 1H), 7.67 (s, 2H), 7.36 (dd, J = 8.3, 10.8 Hz, 4H), 7.26 (s, 1H), 6.95 (s, 1H), 2.86 (q, J = 7.5 Hz, 2H), 2.81-2.74 (m, 2H ), 2.56-2.54 (m, 6H), 2.37-2.28 (m, 4H), 2.16 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H).

compound 12: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(2-(4- Methylpiperazine -1-yl)-2-oxoethyl)-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide

MS (m/z): 553.3 [M+H] ⁺ ;

Yields: 49%;

HPLC r.t. (min), Purity: 1.34;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.65 (s, 1H), 7.92 (s, 1H), 7.91-7.85 (m, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.66 ( s, 1H), 7.41-7.31 (m, 4H), 7.26 (s, 1H), 6.94 (s, 1H), 3.77 (s, 2H), 3.51-3.48 (m, 4H), 2.87 (q, J = 7.5 Hz, 2H), 2.25-2.22 (m, 4H), 2.16 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H).

compound 13: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4-(3-(4- Methylpiperazine -1-yl)prop-1-ynyl)phenylamino)pyrazine-2-carboxamide

MS (m/z): 474.3 [M+H] ⁺ ;

Yields: 50%;

HPLC r.t. (min), Purity: 1.19;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.57 (s, 1H), 8.82 (s, 1H), 7.64 (s, 1H), 7.57-7.52 (m, 3H), 7.46-7.39 (m, 4H) ), 3.68 (s, 3H), 3.50 (s, 2H), 2.77 (q, J = 7.4 Hz, 2H), 2.57-2.54 (m, 2H), 2.35-2.33 (m, 4H), 2.16 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).

compound 14: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-(3-(4- Methylpiperazine -1-yl)propyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3 [M+H] ⁺ ;

Yields: 49%;

HPLC r.t. (min), Purity: 1.19;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.72-7.67 (m, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.60-7.53 (m, 3H), 7.43 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 3.59 (s, 3H), 2.82-2.79 (m, 6H), 2.74-2.71 (m, 4H), 2.63-2.56 (m, 2H), 2.53 (s, 3H), 1.96-1.93 (m, 4H), 1.37 (t, J = 7.4 Hz, 3H).

Compound 15: 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-3'-( Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 594.3 [M+H] ⁺ ;

Yields: 52%;

HPLC r.t. (min), Purity: 1.39;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.94 (d, J = 10.4 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.47 (s, 1H), 3.78 (s, 2H), 3.65 (s, 3H), 2.99-2.96 (m, 4H), 2.81 ( q, J = 7.4 Hz, 2H), 2.70-2.67 (m, 4H), 2.63 (s, 3H), 1.36 (t, J = 7.4 Hz, 3H).

compound 16: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(2'- methyl -4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3 [M+H] ⁺ ;

Yields: 51%;

HPLC r.t. (min), Purity: 1.25;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.70 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H) , 7.20 (d, J = 9.7 Hz, 2H), 7.15 (d, J = 7.9 Hz, 1H), 3.68 (s, 3H), 2.91-2.86 (m, 6H), 2.85-2.82 (m, 6H), 2.57 (s, 3H), 2.33 (s, 3H), 1.38 (t, J = 7.4 Hz, 3H).

Compound 17: 6-ethyl-5-(2'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 558.3 [M+H] ⁺ ;

Yields: 47%;

HPLC r.t. (min), Purity: 1.25;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.55 (s, 1H), 7.50 (d, J = 2.9 Hz, 4H), 7.38 (t, J = 8.1 Hz, 1H), 7.33 (s, 1H) , 7.08-6.99 (m, 2H), 3.55 (s, 3H), 2.83-2.80 (m, 6H), 2.70-2.68 (m, 8H), 2.47 (s, 3H), 1.27 (t, J = 7.4 Hz , 3H).

compound 18: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(3'- methyl -4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3 [M+H] ⁺ ;

Yields: 45%;

HPLC r.t. (min), Purity: 1.27;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.60 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.5 Hz, 3H), 7.42 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J = 7.9 Hz, 1H), 3.51 (s, 3H), 2.89-2.68 (m, 12H), 2.67-2.64 (m, 2H), 2.50 (s, 3H), 2.34 (s, 3H), 1.29 (t, J = 7.4 Hz, 3H).

Compound 19: 6-ethyl-5-(3'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 558.3 [M+H] ⁺ ;

Yields: 43%;

HPLC r.t. (min), Purity: 1.27;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.72 (d, J = 8.6 Hz, 2H), 7.67-7.58 (m, 3H), 7.51-7.44 (m, 2H), 7.44-7.35 (m, 2H ), 3.64 (s, 3H), 3.00-2.91 (m, 6H), 2.83-2.81 (m, 8H), 2.63 (s, 3H), 1.39 (t, J = 7.4 Hz, 3H).

compound 20: 5 -(4'-((4- Acetylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4- One amino )-6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3 [M+H] ⁺ ;

Yields: 57%;

HPLC r.t. (min), Purity: 1.19;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.61 (s, 1H), 8.83 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H) , 7.67 (d, J = 10.1 Hz, 4H), 7.58 (d, J = 7.8 Hz, 2H), 7.44 (s, 1H), 7.38 (s, 1H), 4.58-4.23 (m, 4H), 3.62 ( s, 3H), 3.17 (s, 2H), 3.16-3.05 (m, 2H), 3.02-2.85 (m, 2H), 2.80 (q, J = 7.4 Hz, 2H), 2.05 (s, 3H), 1.29 (t, J = 7.4 Hz, 3H).

compound 21: 5 -(4'-((4- Cyclopropylpiperazine -1 day) methyl )-[1,1'- Biphenyl ]-4-ylamino)-6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 552.3[M+H] ⁺ ;

Yields: 55%;

HPLC r.t. (min), Purity: 1.28;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.61 (d, J = 8.0 Hz, 4H), 7.53-7.46 (m, 3H), 7.40-7.33 (m, 3H), 3.67 (s, 2H), 3.51 (s, 3H), 2.79-2.52 (m, 10H), 1.73-1.64 (m, 1H), 1.27 (t, J = 7.4 Hz, 3H), 0.46-0.40 (m, 2H), 0.36 (q, J = 5.6, 6.8 Hz, 2H).

compound 22: 6 -Ethyl-5-(4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'- Biphenyl ]-4-ylamino)-3-(phenylamino)pyrazine-2-carboxamide

MS (m/z): 536.3 [M+H] ⁺ ;

Yields: 51%;

HPLC r.t. (min), Purity: 1.35;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.59 (d, J = 8.5 Hz, 2H), 7.54-7.43 (m, 6H), 7.26 (d, J = 7.9 Hz, 2H), 7.07 (t, J = 7.8 Hz, 2H), 6.86 (d, J = 7.4 Hz, 1H), 2.89-2.64 (m, 14H), 2.48 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H).

compound 23: 6 -Ethyl-5-(4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'- Biphenyl ]-4-ylamino)-3-(1-methylpiperidin-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 557.3 [M+H] ⁺ ;

Yields: 52%;

HPLC r.t. (min), Purity: 1.07;

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.77 (d, J = 8.5 Hz, 2H), 7.61 (dd, J = 8.2, 13.7 Hz, 4H), 7.33 (d, J = 7.9 Hz, 2H) , 4.09-4.00 (m, 1H), 2.99-2.87 (m, 4H), 2.85-2.70 (m, 13H), 2.50 (s, 3H), 2.34-2.22 (m, 2H), 1.86-1.72 (m, 2H), 1.38-1.28 (m, 5H).

compound 24: 6 -Ethyl-5-(4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'- Biphenyl ]-4-ylamino)-3-(4-morpholinophenylamino)pyrazine-2-carboxamide

MS (m/z): 621.4 [M+H] ⁺ ;

Yields: 55%;

HPLC r.t. (min), Purity: 1.32;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.74 (s, 1H), 8.72 (s, 1H), 7.65 (dd, J = 4.6, 8.6 Hz, 3H), 7.59 (d, J = 8.1 Hz, 4H), 7.36 (s, 1H), 7.31 (d, J = 8.3 Hz, 4H), 6.79 (dd, J = 3.4, 9.2 Hz, 2H), 3.75-3.71 (m, 4H), 3.02-2.98 (m , 4H), 2.85-2.79 (m, 4H), 2.58-2.51 (m, 6H), 2.36-2.32 (m, 4H), 2.15 (s, 3H), 1.28 (t, J = 7.4 Hz, 3H).

compound 25: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(5-(4-((4- Methylpiperazine -1-yl)methyl)phenyl)pyridin-2-ylamino)pyrazine-2-carboxamide

MS (m/z): 527.3 [M+H] ⁺ .

compound 26: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(6-(4-((4- Methylpiperazine -1-yl)methyl)phenyl)pyridin-3-ylamino)pyrazine-2-carboxamide

MS (m/z): 527.3 [M+H] ⁺ .

compound 27: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(5-(4-(1-(4- Methylpiperazine -1-yl)ethyl)phenyl)pyridin-2-ylamino)pyrazine-2-carboxamide

MS (m/z): 541.3 [M+H] ⁺ .

Compound 28: 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-2- (Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 608.3 [M+H] ⁺ .

compound 29: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(2- methyl -4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 554.3[M+H] ⁺ .

compound 30: 6 -Ethyl-5-(2- Methoxy -4'-(2-(4- Methylpiperazine -1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide

MS (m/z): 570.3 [M+H] ⁺ .

compound 31: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-((4'-((4- Methylpiperazine -1-yl)methyl)-[1,1'-biphenyl]-3-yl)methylamino)pyrazine-2-carboxamide

MS (m/z): 540.3 [M+H] ⁺ .

compound 32: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-((4'-((4- Methylpiperazine -1-yl)methyl)-[1,1'-biphenyl]-4-yl)methylamino)pyrazine-2-carboxamide

MS (m/z): 540.3 [M+H] ⁺ .

compound 33: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(5-(4-((4- Methylpiperazine -1-yl)methyl)phenyl)-1H-indol-1-yl)pyrazine-2-carboxamide

MS (m/z): 550.3 [M+H] ⁺ .

compound 34: 6 -Ethyl-3-(1- methyl -1H- Pyrazole -4- One amino )-5-(4'-((4- Methylpiperazine -1-yl)methyl)-[1,1'-biphenyl]-3-ylamino)pyrazinecarboxamide

MS (m/z): 526.3 [M+H] ⁺ .

Experimental example One: MerTK Evaluation of enzyme inhibitory activity

The inhibitory activity of compounds 1 to 34 synthesized according to the above example to MerTK was evaluated. Specifically, each compound was reacted with purified human MerTK (SignalChem #M51-11G-10) enzyme. As the reaction buffer, a composition of Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/mL BSA, and 50 μM DTT was used, and reactions of all test materials were performed on the reaction buffer. The compound was diluted 12 steps by a series dilution method of a stock solution (stock) dissolved in DMSO at a concentration of 10 mM, and the final 50, 10, 2, 0.4 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512, and 0.000001024 μM concentrations Enzyme activity was measured. In the test, human MerTK (25 ng) enzyme was reacted with purified ATP (10 μM) and enzyme substrate (0.2 μg) at 25° C. for 2 hours, and then enzymes were performed using an in vitro ADP-Glo™ kinase assay (Promega). The activity was confirmed. The enzyme activity reaction solution, the ADP-Glo reaction solution, and the enzyme activity detection solution were reacted at a ratio of 2:2:1 to measure the degree of inhibition of enzyme activity by Luminoscence. Using the solvent-treated group not treated with the compound as a control, the degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on its enzyme activity fluorescence. The concentration of each compound inhibiting 50%, IC ₅₀ (nM) was determined.

The enzyme inhibitory ability was measured as described above, and designated as the following four sections according to the calculated IC ₅₀ value, and is shown in Table 1 below:

0-10 nM = A; 10-100 nM = B; 100-1000 nM = C; >1000 nM = D

Compound# MerTK activity Compound# MerTK activity One B 2 A 3 D 4 D 5 C 6 A 7 A 8 A 9 D 10 B 11 B 12 B 13 A 14 B 15 C 16 B 17 B 18 A 19 A 20 A 21 A 22 D 23 D 24 D 25 A 26 A 27 A 28 B 29 A 30 A 31 C 32 D 33 D 34 D

As shown in Table 1, compounds 1 to 34 of the present invention were found to have an effect of inhibiting the activity of MerTK. This indicates that the compounds of the present invention can be usefully used in the prevention or treatment of MerTK-related diseases.

Experimental example 2: Ba /F3 cells Inhibitory activity against proliferation evaluation

The inhibitory activity of the compounds 1 to 34 synthesized according to the above examples on Ba/F3 proliferation expressing AXL, MerTK and Tyro3 (TAM family) kinase was evaluated. Specifically, the transduced Ba/F3 cells were cultured by adding 1 μg/mL puromycin (Invitrogen) to the same medium. The cells were dispensed into each well of a white transparent bottom 96-well plate (Corning) with 3000 to 5000 cells 24 hours before treatment with the compound. The compound was diluted in dimethylsulfoxide (DMSO) (diluted three times, to a total of 12 concentrations) and injected in 0.5 μL each so that the final concentration was 0.3 nM to 50 μM. After compound treatment has passed 72 hours, and to process the CellTiter-Glo ^® Luminescent Cell Viability Assay (Promega) stored at room temperature for 10 minutes and the reader measures the light emission intensity by (SynergyNeo, Biotek), and counted for viable cells. Each experiment was repeated three times. The resulting value was calculated as the percentage of cell growth compared to the control treated with the solvent. Graphs were derived using the GraphPad Prism program (version 5.0) and IC ₅₀ values were calculated.

The proliferation inhibitory activity of Ba/F3 cells expressing the TAM family kinase measured as described above was designated as the following four sections and is shown in Table 2 below:

<50 nM = A; 50-500 nM = B; 500-5000 nM = C; >5000 nM = D

Compound# MerTK Ba/F3 AXLc Ba/F3 Tyro3 Ba/F3 Naive Ba/F3 One C - - C 2 A C B C 3 D - - D 4 D - - D 5 C - - D 6 A C B C 7 A C B C 8 A C B C 9 D - - C 10 B - - C 11 B - - C 12 C - - C 13 A B B C 14 B C B C 15 B - - C 16 A C C C 17 A C C C 18 B C B C 19 A C B C 20 B B B B 21 B C B B 22 C - - C 23 C - - C 24 C - - D 25 B - - C 26 B - - C 27 C C C C 28 B C C C 29 B C C C 30 B - - C 31 B - - C 32 C - - C 33 B - - C 34 C - - C

Experimental example 3: various Inhibitory activity against kinase evaluation

The activities of compounds 1 to 34 synthesized according to the above examples were evaluated for more various enzymes. Specifically, the enzyme selectivity of Compound 2 prepared according to Example 2, which was selected as a representative material among the compounds of the present invention, was determined by requesting DiscoverX. For this, a panel for scanMAX™ Kinase analysis was used. At this time, as a drug treated with the enzyme, a solution prepared by dissolving in DMSO at a concentration of 1 μM was used, and the control percentage (% control) was determined by the method of Equation 1 below, and the results are shown in Table 3 below.

[Equation 1]

In the above formula, the positive control and the negative control refer to a compound showing a percentage control of 0% and 100% as DMSO, respectively. At this time, when the calculated control percentage value for each enzyme is less than 35%, it was determined to have inhibitory activity for the enzyme. Accordingly, among the series of enzymes tested, the enzymes that the compound of the present invention exhibits inhibitory activity are summarized and shown in Table 3 below together with the percentage control therefor.

Kinase Compound 2
(% cont @ 1 μM) Kinase Compound 2
(% cont @ 1 μM) AXL 0 CIT 0 FLT3(D835V) 0 PIKFYVE 0 TRKA 0 FLT3(N841I) 0.1 FLT3(ITD) 0.15 FLT3(ITD,D835V) 0.15 INSRR 0.25 GCN2(Kin.Dom.2,S808G) 0.3 ALK(C1156Y) 0.35 SLK 0.4 RET(V804L) 0.6 INSR 0.65 ABL1(T315I)-phosphorylated 0.7 FLT3(D835Y) 0.7 TRKC 0.7 ULK3 0.75 EPHB6 0.9 RET 0.9 ALK 1.1 LOK 1.1 MKNK2 1.3 JAK2 (JH1domain-catalytic) 1.4 MAP4K2 1.4 RIPK4 1.4 RET(M918T) 1.6 ROS1 1.8 BIKE 1.9 MEK1 2 DLK 2.2 RIOK1 2.3 TRKB 2.5 RIOK3 2.7 PLK4 3.1 RET(V804M) 3.2 RIOK2 3.2 HIPK2 3.3 HIPK3 3.5 JNK3 3.5 JAK1
(JH2domain-pseudokinase) 3.7 ANKK1 3.9 CDKL2 3.9 FLT3(ITD,F691L) 3.9 HASPIN 3.9 FLT3(D835H) 4 FLT3(K663Q) 4 PIM3 4.3 FLT3 4.4 MERTK 4.5 TAK1 4.5 MEK2 4.8 SRPK1 5 LTK 5.2 MEK5 5.2 ABL1(T315I)
-nonphosphorylated 5.5 JNK1 5.5 PIM1 5.5 IRAK3 5.6 MET 5.6 ABL1(H396P)
-nonphosphorylated 5.9 ABL1(Q252H)-phosphorylated 6.1 IGF1R 6.3 MEK3 6.7 JAK3 (JH1domain-catalytic) 7 MET(M1250T) 7.4 AURKA 7.9 FLT3-autoinhibited 8.7 MET(Y1235D) 9.2 ADCK4 9.7 LRRK2(G2019S) 10 CSNK2A2 11 MARK3 11 PAK4 11 RIPK5 11 ABL1(H396P)-phosphorylated 12 ABL1(M351T)-phosphorylated 12 ABL1-phosphorylated 12 ALK(L1196M) 12 TNIK 12 MINK 13 AAK1 14 ABL1(E255K)-phosphorylated 14 TYK2 (JH1domain-catalytic) 15 PAK7 16 CDK7 17 GAK 17 NDR1 17 KIT(V559D,T670I) 18 NEK10 18 ACVR1 19 FLT4 19 JNK2 19 RSK1(Kin.Dom.1-N-terminal) 19 STK35 19 PAK3 20 TYK2
(JH2domain-pseudokinase) 20 IRAK1 21 LZK 21 MST4 21 TIE1 21 TXK 21 CSNK2A1 22 EGFR(L858R,T790M) 22 GSK3A 22 HIPK1 23 PIP5K2B 23 SYK 23 RSK2
(Kin.Dom.1-N-terminal) 24 ABL1(Y253F)
-phosphorylated 25 PAK2 25 ABL1(Q252H)
-nonphosphorylated 26 PDGFRB 26 TTK 27 BLK 28 KIT(L576P) 28 MAP4K4 28 MLK3 28 SRC 28 BUB1 29 MYO3B 29 KIT(D816V) 30 SRPK3 30 FLT3(R834Q) 31 EGFR(T790M) 31 TNK1 31 GRK4 31 LRRK2 32 MARK1 32 PRP4 32 FLT1 34 LCK 34

Claims (23)

A compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is C _1-4 alkyl;
R ₂ is unsubstituted or substituted C _6-10 aryl, C _5-10 heterocyclyl or C _5-10 heteroaryl;
A is OR ₃ or NR ₄ R ₅ ;
R ₃ is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)- (C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _6-10 arylene)-(C _0-3 alkylene )-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-( C _5-10 heteroaryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkynylene)-(C _5-10 heteroaryl), -(C _{0- 2} alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-(C _5-10 heterocyclyl) or -(C _0-2 alkylene)-(C _6-10 arylene )-(C _1-3 alkynylene)-(C _5-10 heterocyclyl);
R ₄ and R ₅ are each one hydrogen and the other is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene )-(C _5-10 heteroarylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _{6 -10} arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _{6- 10} arylene)-(C _0-3 alkylene)-(C _5-10 heterocyclyl) to form a substituted heteroaryl;
The aryl, heterocyclyl and heteroaryl are each independently unsubstituted or C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkanoneyl, C _3-6 cycloalkyl, C ₅ May be substituted with one or more selected from the group consisting of _-10 heterocyclyl, amino, (C _1-4 alkyl)amino, di(C _1-4 alkyl)amino, and C _1-4 alkoxy.
The method of claim 1,
R ₁ is ethyl, a compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₂ is unsubstituted or substituted phenyl, piperidinyl or pyrazolyl, a compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₂ is phenyl, morpholinophenyl, methylpiperidinyl or methylpyrazolyl, a compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
A is (methylpiperazinyl)biphenyloxy, ((methylpiperazinyl)methyl)biphenylmethyloxy, ((methylpiperazinyl)methyl)biphenyloxy, ((methylpiperazinyl)ethyl)biphenyl Oxy, ((methylpiperazinyl)propyl)biphenyloxy, ((methylpiperazinyl)ethyl)methylbiphenyloxy, ((methylpiperazinyl)ethyl)fluorobiphenyloxy, ((methylpiperazinyl) )Ethyl)methoxybiphenyloxy, ((methylpiperazinyl)methyl)perfluoromethylbiphenyloxy, ((methylpiperazinyl)oxoethyl)biphenyloxy, (dimethylamino)biphenyloxy, methoxy Biphenyloxy, (imidazopyridazinylethynyl)phenyloxy, ((methylpiperazinyl)propynyl)phenyloxy, ((acetylpiperazinyl)methyl)biphenyloxy, ((cyclopropylpiperazinyl) Methyl)biphenyloxy, (((methylpiperazinyl)methyl)phenyl)pyridinyloxy, (((methylpiperazinyl)ethyl)phenyl)pyridinyloxy, (methylpiperazinyl)biphenylamino, (( Methylpiperazinyl)methyl)biphenylmethylamino, ((methylpiperazinyl)methyl)biphenylamino, ((methylpiperazinyl)ethyl)biphenylamino, ((methylpiperazinyl)propyl)biphenylamino , ((Methylpiperazinyl)ethyl)methylbiphenylamino, ((methylpiperazinyl)ethyl)fluorobiphenylamino, ((methylpiperazinyl)ethyl)methoxybiphenylamino, ((methylpipera Genyl)methyl)perfluoromethylbiphenylamino, ((methylpiperazinyl)oxoethyl)biphenylamino, (dimethylamino)biphenylamino, methoxybiphenylamino, (imidazopyridazinylethynyl)phenyl Amino, ((methylpiperazinyl)propynyl)phenylamino, ((acetylpiperazinyl)methyl)biphenylamino, ((cyclopropylpiperazinyl)methyl)biphenylamino, (((methylpiperazinyl) Methyl) phenyl) pyridinyl amino, (((methylpiperazinyl) ethyl) phenyl) pyridinyl amino, or (((methylpiperazinyl) methyl) phenyl) indolyl, or a pharmaceutically acceptable compound thereof Possible salts.
The method of claim 1,
The compound is
(1) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(2) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(3) 5-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yloxy)-6-ethyl-3-(1-methyl-1H-pyrazol-4-yl Amino)pyrazine-2-carboxamide;
(4) 6-ethyl-5-(4'-methoxy-[1,1'-biphenyl]-4-yloxy)-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine -2-carboxamide;
(5) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(4-methylpiperazin-1-yl)-[1,1'-bi Phenyl]-4-yloxy)pyrazine-2-carboxamide;
(6) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(7) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(8) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(9) 6-ethyl-5-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)phenylamino)-3-(1-methyl-1H-pyrazol-4-yl Amino)pyrazine-2-carboxamide;
(10) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(11) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(12) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(13) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4-(3-(4-methylpiperazin-1-yl)prop-1-ynyl) Phenylamino)pyrazine-2-carboxamide;
(14) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(3-(4-methylpiperazin-1-yl)propyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(15) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-3'-( Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(16) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(17) 6-ethyl-5-(2'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(18) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(3'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(19) 6-ethyl-5-(3'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(20) 5-(4'-((4-acetylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1-methyl -1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(21) 5-(4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1- Methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(22) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(phenyl Amino)pyrazine-2-carboxamide;
(23) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(1 -Methylpiperidin-4-ylamino)pyrazine-2-carboxamide;
(24) 6-ethyl-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino)-3-(4 -Morpholinophenylamino)pyrazine-2-carboxamide;
(25) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -2-ylamino)pyrazine-2-carboxamide;
(26) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -3-ylamino)pyrazine-2-carboxamide;
(27) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenyl )Pyridin-2-ylamino)pyrazine-2-carboxamide;
(28) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-2- (Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(29) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl) )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(30) 6-ethyl-5-(2-methoxy-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino) -3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(31) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-3-yl)methylamino)pyrazine-2-carboxamide;
(32) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-4-yl)methylamino)pyrazine-2-carboxamide;
(33) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)- 1H-indol-1-yl)pyrazine-2-carboxamide; or
(34) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-3-ylamino)pyrazinecarboxamide; The compound or a pharmaceutically acceptable salt thereof.
A substituted aryl or heteroaryl derivative containing an amine or hydroxy group as a reactive functional group at one end of a 5-halo-6-alkyl-3-(substituted amino)pyrazine-2-carboxamide derivative represented by the following formula (2) and Comprising the step of reacting,
A method for preparing the compound of any one of claims 1 to 6:
[Formula 2]

In Chemical Formula 2,
R ₁ is C _1-4 alkyl;
R ₂ is unsubstituted or substituted C _6-10 aryl, C _5-10 heterocyclyl or C _5-10 heteroaryl;
X is halogen.
The method of claim 7,
The substituted aryl or heteroaryl derivative containing an amine or hydroxy group is (methylpiperazinyl)biphenylol, ((methylpiperazinyl)methyl)biphenylmethylol, ((methylpiperazinyl)methyl)biphenyl Ol, ((methylpiperazinyl)ethyl)biphenylol, ((methylpiperazinyl)propyl)biphenylol, ((methylpiperazinyl)ethyl)methylbiphenylol, ((methylpiperazinyl)ethyl )Fluorobiphenylol, ((methylpiperazinyl)ethyl)methoxybiphenylol, ((methylpiperazinyl)methyl)perfluoromethylbiphenylol, ((methylpiperazinyl)oxoethyl)bi Phenylol, (dimethylamino)biphenylol, methoxybiphenylol, (imidazopyridazinylethynyl)phenylol, ((methylpiperazinyl)propynyl)phenylol, ((acetylpiperazinyl)methyl )Biphenylol, ((cyclopropylpiperazinyl)methyl)biphenylol, (((methylpiperazinyl)methyl)phenyl)pyridinylol, (((methylpiperazinyl)ethyl)phenyl)pyridinylol , (Methylpiperazinyl)biphenylamine, ((methylpiperazinyl)methyl)biphenylmethylamine, ((methylpiperazinyl)methyl)biphenylamine, ((methylpiperazinyl)ethyl)biphenylamine , ((Methylpiperazinyl)propyl)biphenylamine, ((methylpiperazinyl)ethyl)methylbiphenylamine, ((methylpiperazinyl)ethyl)fluorobiphenylamine, ((methylpiperazinyl) Ethyl)methoxybiphenylamine, ((methylpiperazinyl)methyl)perfluoromethylbiphenylamine, ((methylpiperazinyl)oxoethyl)biphenylamine, (dimethylamino)biphenylamine, methoxybi Phenylamine, (imidazopyridazinylethynyl)phenylamine, ((methylpiperazinyl)propynyl)phenylamine, ((acetylpiperazinyl)methyl)biphenylamine, ((cyclopropylpiperazinyl)methyl )Biphenylamine, (((methylpiperazinyl)methyl)phenyl)pyridinylamine, (((methylpiperazinyl)ethyl)phenyl)pyridinylamine, or (((methylpiperazinyl)methyl)phenyl) That is indole, the manufacturing method.
The method of claim 7,
The reaction is carried out in an organic solvent in the presence of 1 to 1.5 times the equivalent of a base of the reactant.
The method of claim 7,
When reacting with a substituted aryl or heteroaryl derivative containing an amine, the reaction is performed by further comprising a palladium catalyst and a copper cocatalyst.
The method of claim 7,
In the case of reacting with a substituted aryl or heteroaryl derivative containing an amine, the method further comprises removing gas from the reaction mixture.
A pharmaceutical composition for the prevention or treatment of MerTK-related diseases comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Formula 1,
R ₁ is C _1-4 alkyl;
R ₂ is unsubstituted or substituted C _5-10 heteroaryl;
A is OR ₃ or NR ₄ R ₅ ;
R ₃ is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)- (C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _6-10 arylene)-(C _0-3 alkylene )-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-( C _5-10 heteroaryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkynylene)-(C _5-10 heteroaryl), -(C _{0- 2} alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-(C _5-10 heterocyclyl) or -(C _0-2 alkylene)-(C _6-10 arylene )-(C _1-3 alkynylene)-(C _5-10 heterocyclyl);
R ₄ and R ₅ are each one hydrogen and the other is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene )-(C _5-10 heteroarylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _{6 -10} arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl);
The aryl, heterocyclyl and heteroaryl are each independently unsubstituted or C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkanoneyl, C _3-6 cycloalkyl, C ₅ May be substituted with one or more selected from the group consisting of _-10 heterocyclyl, amino, (C _1-4 alkyl)amino, di(C _1-4 alkyl)amino, and C _1-4 alkoxy.
The method of claim 12,
The compound is
(1) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(2) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-[1,1 '-Biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(3) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(4-methylpiperazin-1-yl)-[1,1'-bi Phenyl]-4-yloxy)pyrazine-2-carboxamide;
(4) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(5) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(6) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(7) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(1-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(8) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1 ,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(9) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)-2-oxoethyl )-[1,1'-biphenyl]-4-yloxy)pyrazine-2-carboxamide;
(10) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4-(3-(4-methylpiperazin-1-yl)prop-1-ynyl) Phenylamino)pyrazine-2-carboxamide;
(11) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(3-(4-methylpiperazin-1-yl)propyl)-[1 ,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(12) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-((4-methylpiperazin-1-yl)methyl)-3'-( Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(13) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(14) 6-ethyl-5-(2'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(15) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(3'-methyl-4'-(2-(4-methylpiperazin-1-yl) Ethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(16) 6-ethyl-5-(3'-fluoro-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino )-3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(17) 5-(4'-((4-acetylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1-methyl -1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(18) 5-(4'-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4-ylamino)-6-ethyl-3-(1- Methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide;
(19) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -2-ylamino)pyrazine-2-carboxamide;
(20) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine -3-ylamino)pyrazine-2-carboxamide;
(21) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(5-(4-(1-(4-methylpiperazin-1-yl)ethyl)phenyl )Pyridin-2-ylamino)pyrazine-2-carboxamide;
(22) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(4'-(2-(4-methylpiperazin-1-yl)ethyl)-2- (Trifluoromethyl)-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(23) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-(2-methyl-4'-(2-(4-methylpiperazin-1-yl)ethyl) )-[1,1'-biphenyl]-4-ylamino)pyrazine-2-carboxamide;
(24) 6-ethyl-5-(2-methoxy-4'-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-ylamino) -3-(1-methyl-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide; or
(25) 6-ethyl-3-(1-methyl-1H-pyrazol-4-ylamino)-5-((4'-((4-methylpiperazin-1-yl)methyl)-[1, 1'-biphenyl]-3-yl)methylamino)pyrazine-2-carboxamide; which, the pharmaceutical composition.
The method of claim 12,
To inhibit the activity of MerTK, pharmaceutical composition.
The method of claim 12,
The MerTK-related disease is an immune disease or cancer disease, the pharmaceutical composition.
The method of claim 15,
The immune disease is an infection or sepsis, the pharmaceutical composition.
The method of claim 15,
The cancer diseases include colon cancer, pancreatic cancer, stomach cancer, liver cancer, breast cancer, cervical cancer, thyroid cancer, parathyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, blood. Cancer, bladder cancer, kidney cancer, ovarian cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine Adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral carcinoma, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, gliomas, subeducational tumors , Anaplastic astrocytoma, medulloblastoma, cervical carcinoma, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangiocarcinoma, colorectal cancer, renal cell carcinoma, cholangiocarcinoma, chorionic carcinoma, testicular tumor, testicular tumor, Wilm tumor, Ewing Tumor, hemangiosarcoma, endothelial sarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenocarcinoma, cystic adenosarcoma, bronchial carcinoma, medullary carcinoma, mastocytoma, mesothelioma, synovoma, leiomyosarcoma, rhabdomyosarcoma, nerve Blastoma, retinoblastoma, oligodendrocyte tumor, inner ear neurosis, hemangioblastoma, meningioma, pineal adenoma, ventricular adenoma, head pharyngoma, epithelial carcinoma, embryonic carcinoma, squamous cell carcinoma, basal cell carcinoma, fibrosarcoma, myxoma, myxosarcoma , Liposarcoma, chondrosarcoma, osteosarcoma or metastatic cancer thereof, the pharmaceutical composition.
The method of claim 12,
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient or diluent.
The method of claim 12,
The pharmaceutical composition further comprises an immune checkpoint inhibitor, an anticancer agent, or both.
The method of claim 19,
The anticancer agent is any one or more selected from the group consisting of DNA alkylating agents, anti-cancer antibiotics, and plant alkaloids.
The method of claim 19,
The anticancer agents are mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU). ), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D) , Doxorubicin (adiamycin), daunorubicin, daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C Breomycin (C Bleomycin); From the group consisting of vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan, and iridotecan Any one or more selected, the pharmaceutical composition.
A health functional food composition for preventing or improving MerTK-related diseases comprising a compound represented by the following Formula 1 or a food pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Formula 1,
R ₁ is C _1-4 alkyl;
R ₂ is unsubstituted or substituted C _5-10 heteroaryl;
A is OR ₃ or NR ₄ R ₅ ;
R ₃ is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)- (C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _6-10 arylene)-(C _0-3 alkylene )-(C=O) _0-1 -(C _5-10 heterocyclyl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-( C _5-10 heteroaryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _1-3 alkynylene)-(C _5-10 heteroaryl), -(C _{0- 2} alkylene)-(C _6-10 arylene)-(C _1-3 alkenylene)-(C _5-10 heterocyclyl) or -(C _0-2 alkylene)-(C _6-10 arylene )-(C _1-3 alkynylene)-(C _5-10 heterocyclyl);
R ₄ and R ₅ are each one hydrogen and the other is -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 aryl), -(C _0-2 alkylene )-(C _5-10 heteroarylene)-(C _6-10 aryl), -(C _0-2 alkylene)-(C _6-10 arylene)-(C _6-10 arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl), or -(C _0-2 alkylene)-(C _5-10 heteroarylene)-(C _{6 -10} arylene)-(C _0-3 alkylene)-(C=O) _0-1 -(C _5-10 heterocyclyl);
The aryl, heterocyclyl and heteroaryl are each independently unsubstituted or C _1-4 alkyl, C _1-4 haloalkyl, halogen, C _1-4 alkanoneyl, C _3-6 cycloalkyl, C ₅ May be substituted with one or more selected from the group consisting of _-10 heterocyclyl, amino, (C _1-4 alkyl)amino, di(C _1-4 alkyl)amino, and C _1-4 alkoxy.
A method for preventing or treating MerTK-related diseases, comprising administering the pharmaceutical composition of claim 12 to an individual other than human.