KR102286701B1 - Pyrido[2,3-d]pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient - Google Patents

Abstract

A pyrido[2,3-d]pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient, wherein the derivative exhibits inhibitory activity against various kinases, in particular, Since it exhibits high inhibitory activity against EGFR (epidermal growth factor receptor) wild-type or mutant, it can be usefully used for the treatment of diseases related to the activity of various kinases, in particular, cancers in which EGFR wild-type or EGFR mutations are expressed.

Description

Pyrido [2,3-d] pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient {Pyrido [2,3-d] pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient}

It relates to a pyrido[2,3-d]pyrimidine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

The development of cancer is related to various environmental factors, including chemicals, radiation, and viruses, and changes in oncogenes, tumor suppressor genes, and genes involved in apoptosis and DNA repair. By understanding the mechanism, a new treatment, targeted chemotherapy, became possible.

Targeted therapeutics are generally made to show the effect by targeting molecules characteristic of cancer cells, and the molecular targets are the signal transduction pathway, angiogenesis, and interstitium of cancer cells. (matrix), cell cycle regulator (cell cycle regulator), apoptosis (apoptosis) and related genes. Currently, there are 'signaling pathway inhibitors' and 'angiogenesis inhibitors', including tyrosine kinase inhibitors, that are being used as important targeted therapeutics in treatment.

Protein tyrosine kinase has been shown to play an important role in many malignancies, and in particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the erbB family, is non-small cell lung cancer. It is aberrantly activated in many epithelial cell tumors, including NSCLC, breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, live rectal carcinoma, head and neck cancer, gastric cancer and prostate cancer, and the EGFR-tyrosine kinase It has been known that activation causes sustained cell proliferation, invasion of surrounding tissues, distant metastasis, and angiogenesis, and increases cell survival.

Specifically, the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER-2, ErbB-3, ErbB-4), an extracellular ligand-binding domain and a tyrosine kinase domain. It is a transmembrane tyrosine kinase having an intracellular domain including (tyrosine kinase domain). When a ligand binds to a homodimer or heterodimer receptor, intracellular tyrosine kinase is activated, and the signal stimulated by EGFR is phosphatidylinositol 3-kinase (PI3K)/ Activates AKT/mTOR, RAS/RAF/MAPK, JAK/STAT) signaling pathways (Nat Rev Cancer 2007; 7:169-81).

In particular, EGFR is overexpressed in more than half of non-small cell lung cancer (NSCLC), and many studies have been conducted as a therapeutic target. EGFR tyrosine kinase inhibitor (TKI) that inhibits EGFR tyrosine kinase activity has been developed, and representative drugs include gefitinib (IRESSA™), erlotinib (TARCEVA™), and lapatinib (TYKERB™, TYVERB™).

Meanwhile, in 2004, it was reported that an activating mutation of EGFR correlates with the response to gefitinib therapy in non-small-cell lung cancer (NSCLC) (Science [2004] Vol.304, 1497-500). and New England Journal of Medicine [2004] Vol. 350, 2129-39).

Specifically, the EGFR mutation is largely divided into a sensitizing mutation and a resistant mutation. The deletion of exon 19 and the L858R point mutation of exon 21 are the most important sensitive mutations, about 85 to 90. %, and exon 19 del mutation is known to be more sensitive to TKI. On the other hand, the T790M point mutation in exon 20 is the most important resistance mutation and is known to be found in more than 50% of acquired resistance patients (Clin Cancer Res 2006;12:6494-6501.).

Somatic mutations identified so far include in-frame deletions in exon 19 or insertions in exon 20, as well as point mutations in which a single nucleic acid residue is altered in the expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q) ( Fukuoka et al. JCO 2003; Kris et al JAMA 2003 and Shepherd et al NEJM 2004).

Despite the initial clinical effects of gefitinib/erlotinib in NSCLC patients with EGFR mutations, most patients eventually develop advanced cancer while receiving therapy for these agents. Early studies of relapsed specimens identified a secondary EGFR mutation, T790M, that renders gefitinib and erlotinib an ineffective inhibitor of EGFR kinase activity (Kobayashi et al NEJM 2005 and Pao et al PLOS Medicine 2005). Subsequent studies have demonstrated that the EGFR T790M mutation is found in approximately 50% (24/48) of patient-derived tumors that have acquired resistance to gefitinib or erlotinib (Kosaka et al CCR 2006; Balak et al CCR 2006 and Engelman et al Science 2007). This secondary genetic modification results in a location similar to the 'gatekeeper' residue and its associated secondary resistance allele in patients treated with kinase inhibitors (eg, T315I in ABL in imatinib-resistant CML).

It has been known for a long time that EGFR mutations, EGFR_del19 or EGFR_L858R, are the main cause of non-small cell lung cancer and head and neck cancer. However, when these drugs were used in patients, acquired resistance resulting from secondary mutations in EGFR based on the structure of the drug was observed, and it was also found that this is the main cause of drug resistance. When EGFR first-generation inhibitors are used for an average of 10 months, acquired resistance called the T790M mutation located in the gatekeeper of EGFR kinase occurs, so that the first-generation EGFR inhibitors are not effective. That is, the EGFR_del19_T790M or EGFR_L858R_T790M double mutation occurs, preventing the existing therapeutic agent from exhibiting its efficacy.

One object of the present invention is to provide a pyrido[2,3-d]pyrimidine derivative.

Another object of the present invention is to provide a method for preparing a pyrido[2,3-d]pyrimidine derivative.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing a pyrido[2,3-d]pyrimidine derivative as an active ingredient.

In order to achieve the above object,

According to one aspect of the present invention, there is provided a compound represented by Formula 1 below, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

wherein R ¹ , R ² , R ³ , R ⁴ , A ¹ , A ² and n are as defined herein).

According to another aspect of the present invention, as shown in Scheme 1 below,

A method for preparing a compound represented by Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 1 to prepare a compound represented by Formula 1:

[Scheme 1]

(In Scheme 1,

wherein R ¹ , R ² , R ³ , R ⁴ , A ¹ , A ² and n are as defined herein).

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

According to another aspect of the present invention, there is provided a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

According to another aspect of the present invention, a pharmaceutical composition or health functional food containing the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need A method for preventing or treating cancer comprising administering is provided.

According to another aspect of the present invention, in the prevention or treatment of cancer, a pharmaceutical composition containing the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, or health Uses of nutraceuticals are provided.

The pyrido[2,3-d]pyrimidine derivative according to the present invention exhibits inhibitory activity against various kinases, and, in particular, exhibits high inhibitory activity against EGFR (epidermal growth factor receptor) wild-type or mutant, and thus the activity of various kinases. It can be usefully used in the treatment of diseases related to EGFR, in particular, cancers in which EGFR wild-type or EGFR mutations are expressed.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by the following Chemical Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

은 단일결합 또는 이중결합이고;

is a single bond or a double bond;

로 이루어지는 군으로부터 선택되는 하나 이상으로 치환될 수 있고;R ¹ is hydrogen, linear or branched C _{1- 10} alkyl, linear or branched C _{1- 10} alkyl, straight or branched C _{1- 10} alkoxy C _{1 - 2} alkyl, C _{3- 7} cycloalkyl, C _{6- 10} aryl, C _{6- 10} aryl C _{1 - 2} alkyl, or N, O, and heteroaryl of 5 to 10 atoms including one or more heteroatoms selected from the group consisting of S, wherein the aryl or heteroaryl aryl is a straight chain or C _{1- 6} alkoxy C _{1- 6} alkyl, straight- or branched-chain and branched-chain

may be substituted with one or more selected from the group consisting of;

R ² is hydrogen or linear or branched C _1-10 alkoxy;

이고;R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ contains hydrogen, halogen or one or more heteroatoms selected from the group consisting of N, O and S and heterocycloalkyl of 3-7 atoms which, this time, the heterocycloalkyl can be optionally substituted by one or more C _1-6 alkyl, straight or branched chain, R ⁵ is C _{1- 10} of hydrogen or straight or branched chain alkoxy C _{1 -2} alkyl;

A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently C _{1- 6} alkyl, hydrogen or a linear or branched, wherein said alkyl may be substituted one or more by one or more substituted with C _{1- 6} alkyl unsubstituted or straight or branched chain amine , R ^a and R ^b or R ^c and R ^d are each taken together with the N atom to which they are attached to form a 3-7 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S number, and wherein said heterocycloalkyl may be substituted with one or more selected from the group consisting of C _{1- 6} alkyl, di (straight-chain or branched-chain C _1-6 alkyl) amino, and acetyl in the straight-chain or branched-chain;

를 형성할 수 있고,When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,

,

또는

를 형성할 수 있다.When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

,

or

can form.

In Formula 1,

로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있다.Wherein R ¹ is hydrogen, linear or branched C _{1- 6} alkyl, C _{1- 6} alkoxy linear or branched C _{1- 6} alkoxy, linear or branched chain C _{1 - 2} alkyl, C _{3- 6} cycloalkyl , phenyl, phenylC _{1 - 2} alkyl or 5 or 6 membered heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S, wherein the phenyl or heteroaryl is a straight or branched chain C _{1- 4} alkyl, linear or branched C _{1- 4} alkoxy, and

It may be substituted with one or more substituents selected from the group consisting of.

로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있다.In addition, the R ¹ is hydrogen, linear or branched C _{1- 4} alkyl, linear or branched C _{1- 4} alkoxy group of C _1-4 alkoxy, straight or branched chain C _{1 - 2} alkyl, C _{5- 6} cycloalkyl, and heteroaryl of 5 or 6 atoms including phenyl, benzyl or one or more N atoms, wherein the phenyl, benzyl or heteroaryl C _{1- 2} alkyl, C _{1- 2} alkoxy and

It may be substituted with one or more substituents selected from the group consisting of.

로 이루어지는 군으로부터 선택되는 하나 이상의 치환기로 치환될 수 있다.In addition, R ¹ is hydrogen, methyl, ethyl, methoxyethyl, cyclopentyl, cyclohexyl, phenyl, benzyl or pyridinyl, wherein the phenyl, benzyl or pyridinyl is methyl, methoxy and

It may be substituted with one or more substituents selected from the group consisting of.

,

,

,

또는

일 수 있다.In addition, the R ¹ is hydrogen, methyl, ethyl, methoxyethyl, cyclopentyl, cyclohexyl,

,

,

,

or

can be

In Formula 1,

Wherein R ² may be a C _{1- 6} alkoxy of hydrogen or straight-chain or branched-chain.

In addition, the R ² may be hydrogen or C _{1- 4} alkoxy group linear or branched.

In addition, R ² may be hydrogen or methoxy.

In Formula 1,

Wherein A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ is hydrogen, halogen or one or more heteroatoms selected from the group consisting of N, O and S and heterocycloalkyl of 3-6 atoms containing, this time, the heterocycloalkyl can be optionally substituted by one or more C _{1- 4} alkyl, a linear or branched, R ⁵ is C _1- hydrogen or a straight or branched chain _It may be 6 alkoxyC _{1-2 alkyl.}

In addition, A ¹ is -C(R ⁴ )=, -N=, or -N(R ⁵ )-, wherein R ⁴ is a 5-6 membered heterocyclo containing at least one hydrogen, halogen, or N atom. alkyl, wherein the heterocycloalkyl can be optionally substituted by one or more C _{1- 2} alkyl, R ⁵ is C _{1- 4} alkoxy C ₁ hydrogen or a straight-chain or _branched-may be a _2-alkyl.

In addition, A ¹ is -C(R ⁴ )=, -N=, or -N(R ⁵ )-, wherein R ⁴ is hydrogen, F or piperazinyl substituted with methyl, and R ⁵ is hydrogen or methoxyethyl.

이고, R⁵는 수소 또는 메톡시에틸일 수 있다.In addition, the A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ is hydrogen, F or

and R ⁵ may be hydrogen or methoxyethyl.

In Formula 1,

wherein A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d are independently c _{1- 4} alkyl, hydrogen or a linear or branched, wherein said alkyl may be substituted one or more by one or more substituted with c _{1- 4} alkyl unsubstituted or straight or branched chain amine or R ^a and R ^b or R ^c and R ^d are each taken together with the N atom to which they are attached to form a 3-6 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S may, where the heterocycloalkyl may be substituted with one or more selected from the group consisting of straight chain or C _{1- 4} alkyl, di (C _1-4 straight or branched chain alkyl) amino and acetyl branched .

In addition, A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , In this case, R ^a and R ^b are independently hydrogen or C _{1- 2} alkyl, wherein said alkyl may be substituted one or more by one or more substituted with C _{1- 2} alkyl unsubstituted or straight or branched chain amine, R ^a and R ^b are they It may form a heterocycloalkyl of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N and O, together with the N bonding atom, and wherein said heterocycloalkyl is C _{1- 2} alkyl, dimethylamino And may be substituted with one or more selected from the group consisting of acetyl, R ^c and R ^d together with the N atom to which they are attached may form a 5-6 membered heterocycloalkyl comprising at least one N atom, wherein said heterocycloalkyl may be substituted with one or more of a C _{1- 2} alkyl.

In addition, A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , In this case, R ^a and R ^b is independently hydrogen, ethyl substituted with methyl or dimethylamino, or R ^a and R ^b together with the N atom to which they are attached may form piperidinyl, piperazinyl or morpholinyl, wherein said piperidinyl or piperazinyl may be substituted with one or more selected from the group consisting of methyl, ethyl, dimethylamino and acetyl, and R ^c and R ^d together with the N atom to which they are attached form a methyl substituted piperazinyl. can

In Formula 1,

를 형성할 수 있고, n이 1 일 때, A¹ 및 A²의 결합구조는

또는

를 형성할 수 있다.Wherein n is 0 or 1, and when n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form, and when n is 1, the bonding structure of ^{A 1} and A ^{2 is}

or

can form.

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

<1> N-(5-((6-cyano-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<2> N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<3> N-(5-((6-cyano-8-(2-methoxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<4> N-(5-((6-cyano-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<5> N-(5-((8-benzyl-6-cyano-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<6> N-(5-((6-cyano-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<7> N-(5-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<8> N-(5-((6-cyano-7-oxo-8-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<9> N-(5-((6-cyano-8-(4-methoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<10> N-(5-((6-cyano-8-cyclohexyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<11> N-(5-((6-cyano-8-(6-methylpyridin-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- 2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

<12> N-(3-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-5 -(4-methylpiperazin-1-yl)phenyl)acrylamide;

<13> N-(3-(6-cyano-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine -8(7H)-yl)phenyl)acrylamide;

<14> N-(3-(6-cyano-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<15> N-(3-(6-cyano-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<16> N-(3-(6-cyano-2-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<17> N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<18> N-(3-(6-cyano-2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8( 7H)-yl)phenyl)acrylamide;

<19> N-(3-(6-cyano-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<20> N-(3-(6-cyano-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide;

<21> N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide.

The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

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

In addition, bases can be used to prepare pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like, which can be prepared therefrom.

The term “hydrate” refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolec μLar forces. or salts thereof. The hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably, 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.

The term “solvate” means a compound of the invention or a salt thereof which contains either a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.

The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or sterically. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.

Another aspect of the present invention, as shown in Scheme 1 below,

Provided is a method for preparing a compound represented by Formula 1, which includes preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 1.

[Scheme 1]

(In Scheme 1,

R ¹ , R ² , R ³ , R ⁴ , A ¹ , A ² and n are the same as defined in Formula 1 above).

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

In the preparation method of Scheme 1, the methylsulfinyl of the compound of Formula 2 and the primary amine of the compound of Formula 3 react by reacting by heating in the presence of an organic solvent after adding a starting material to N-aryl This is a step in which the compound represented by Chemical Formula 1 is prepared. The organic solvent may be toluene, but is not limited thereto. The specific manufacturing method may be carried out similarly to step 1 of Example 1 below, but this is only an example and is not limited thereto.

이고, R¹에

가 포함되지 않을 경우, 하기 반응식 2와 같은 제조방법으로 화학식 1로 표시되는 화합물의 유도체를 제조할 수 있다.In addition, in the compound represented by Formula 1, R ³ is

and in R ¹

If is not included, a derivative of the compound represented by Formula 1 may be prepared by the preparation method as shown in Scheme 2 below.

preparing a compound represented by Formula 5 by reacting a compound represented by Formula 2 with a compound represented by Formula 6 (step 1);

preparing a compound represented by Formula 4 by reacting the compound represented by Formula 5 obtained in step 1 (step 2); and

A method for preparing a compound represented by Formula 1a, comprising the step of reacting the compound represented by Formula 4 obtained in Step 2 with acryloyl chloride to prepare a compound represented by Formula 1a:

[Scheme 2]

In Scheme 2,

가 포함되지 않고; 및R ¹ , R ² , R ⁴ , A ¹ , A ² and n are as defined in Formula 1 above, but in R ¹

not included; and

The compound represented by the formula (1a) is a derivative of the compound represented by the formula (1).

Hereinafter, the preparation method of Scheme 2 will be described in detail.

In Scheme 2, the detailed description of step 1 is the same as the preparation method of Scheme 1.

In Scheme 2, step 2 is a step of preparing a compound represented by Formula 4 by reacting the compound represented by Formula 5 under a catalyst to reduce NO ₂ to NH _{2 .} The conditions of the reduction reaction _{are not limited as long as it is a condition capable of reducing NO 2} to NH ₂ , and in the present invention, a metal catalyst (Rickel catalyst, palladium catalyst, iron catalyst, titanium catalyst, zinc catalyst, tin catalyst, etc.) was used. , specifically, tin chloride was used, but this is only an example and is not limited thereto.

In Scheme 2, in step 3, the compound represented by Formula 4 and acryloyl chloride are reacted in the presence of a base, and the primary amine of the compound represented by Formula 4 and Cl of acryloyl chloride react with N-alkylation. This is a step in which the compound represented by Formula 1a is prepared. The base is N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) ) and an organic base or an inorganic base such as sodium bicarbonate, sodium hydroxide, or potassium hydroxide, and these may be used alone or in combination, in equivalent amounts or in excess.

이 아니고고, R¹이

가 치환된 페닐일 경우, 하기 반응식 3과 같은 제조방법으로 화학식 1로 표시되는 화합물의 유도체를 제조할 수 있다.In addition, in the compound represented by Formula 1, R ³ is

Not , R ¹ is

When is a substituted phenyl, a derivative of the compound represented by Formula 1 may be prepared by a preparation method as shown in Scheme 3 below.

preparing a compound represented by Formula 8 by reacting a compound represented by Formula 10 with a compound represented by Formula 9 (step 1);

preparing a compound represented by Formula 7 by reacting the compound represented by Formula 8 obtained in Step 1 (step 2); and

A method for preparing a compound represented by Formula 1b, comprising the step of reacting the compound represented by Formula 7 obtained in Step 2 with acryloyl chloride to prepare a compound represented by Formula 1b:

[Scheme 3]

In Scheme 3,

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

The compound represented by Formula 1b is a derivative of the compound represented by Formula 1.

Hereinafter, the preparation method of Scheme 3 will be described in detail.

In Scheme 3, the detailed description of step 1 is the same as the preparation method of Scheme 1.

In Scheme 3, step 2 is a step of removing the amine protecting group Boc of the compound represented by Formula 8 through a deprotection reaction to prepare the final compound represented by Formula 1b, and the reaction conditions for the deprotection reaction are the type of the amine protecting group , and it can be carried out using conventional deprotection reaction conditions.

Acid conditions were used in the present invention, and hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like may be used as the acid.

In Scheme 3, detailed description of step 3 is the same as step 3 of Scheme 2 above.

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

The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer It may be one or more selected from the group, and the cancer may be one in which a mutation is expressed for EGFR.

In addition, the compound can inhibit EGFR (epidermal growth factor receptor) mutation, wherein the EGFR mutation is EEGFR Del19, EGFR Del19/T790M, EGFR Del19/T790M/C797S, EGFR L858R, EGFR T790M/L858R and EGFR L858R/ It may be at least one selected from the group consisting of T790M/C797S.

In addition, the pharmaceutical composition may be administered as an individual therapeutic agent or may be used in combination with other anticancer agents in use.

In addition, the pharmaceutical composition may enhance the anticancer effect by co-administration with an anticancer agent.

In the pharmaceutical composition, the cancer may be related to protein kinase activity.

At this time, the protein kinase is AAK1, ABL1 (E255K)-phosphorylated. ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(M351T) (Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVR1B, ACVR2A1B, ACVR2A ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC, AURKB BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF(V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2A, CAMK2A, CAMK2, CAMK2B, K CAMK2, CAMK2B, K CAMK2 , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CLK2, C , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, FRRK2, EG DYK2, DRAK2, DRAK1, DYRK1 -A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R, T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB2, EPHB3 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 (D835H) D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICKK IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-c atalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P) ), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2(G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK5, MEK4, MAST1, MEK, MEK MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-beta delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFTAIRE2, PFTK1, PHKG1 PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R ), PIK3CA(E542K), PIK3CA(E545A), PIK3CA(E545K), PIK3CA(H1047L), PIK3CA(H1047Y), PIK3CA(I800L), PIK3CA(M1043I), PIK3CD PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M. , PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, OKRIOK2, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4(Kin.Dom.1-N-terminal), RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.1-N- terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1, N-terminal), RSK1(Kin.Dom.2-C-terminal), RSK2(Kin.Dom.1- N-terminal), RSK2 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.2-C-terminal), RSK4 (Kin.Dom. 1-N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, STK39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKB, TRKB, TRKB TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, YANK3, WNK4, YANK It may be at least one selected from the group consisting of YES, YSK1, YSK4, ZAK and ZAP70.

In addition, the compound is ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(Q252H)-nonphosphorylated, BLK, BTK, CSF1R-autoinhibited, CSNK2A1, CSNK2A2, EGFR, EGFR(E746-A750del), EGFR(E746-A750G719C) ), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q) , EGFR (S752-I759del), EGFR (T790M), ERBB2, ERBB4, GAK, ITK, JAK3 (JH1domain-catalytic), KIT, KIT (L576P), KIT (V559D), KIT-autoinhibited, MRCKB, NLK, PKMYT1, It may exhibit inhibitory activity against one or more kinases selected from the group consisting of RPS6KA4 (Kin.Dom.2-C-terminal) and TXK.

The compound represented by Formula 1 of the present invention exhibits excellent inhibitory activity against EGFR (T790M/L858R) (see Experimental Example 1), and also exhibits excellent inhibitory activity in the wild-type EGFR in Ba/F3 cell line, as well as EGFR single, double or It shows high inhibitory ability even against triple mutation and, in particular, shows excellent inhibitory ability against EGFR L858, EGFR T790M / L858, EGFR Del19 / T790M (see Experimental Example 3), the compound represented by Formula 1 according to the present invention is EGFR ( epidermal growth factor receptor) wild-type or mutant, as it exhibits high inhibitory ability, not only EGFR wild-type, but also EGFR Del19, EGFR Del19/T790M, EGFR Del19/T790M/C797S, EGFR L858R, EGFR T790M/L858R and EGFR L858R/T790M/C797S EGFR mutations such as, in particular, EGFR L858, EGFR T790M / L858, EGFR Del19 / T790M can be usefully used for the treatment of expressed cancer.

In addition, the compound represented by Formula 1 of the present invention is ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(Q252H)-nonphosphorylated, BLK, BTK, CSF1R-autoinhibited, CSNK2A1, CSNK2A2, EGFR, EGFR (E746) -A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R, T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), ERBB2, ERBB4, GAK, ITK, JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), KIT-autoinhibited , MRCKB, NLK, PKMYT1, RPS6KA4 (Kin.Dom.2-C-terminal), and exhibits inhibitory activity against one or more kinases selected from the group consisting of TXK (see Experimental Example 2) bar, the kinase activity and It can be usefully used in the treatment of related cancers.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. depending on how

At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form. can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Another aspect of the present invention provides a health functional food for the prevention or improvement of cancer containing the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. .

The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer It may be one or more selected from the group, and the cancer may be one in which a mutation is expressed for EGFR.

The compound represented by Formula 1 according to the present invention, by exhibiting a high inhibitory ability against EGFR mutation, can be added to health functional food supplements such as food and beverage as a health functional food composition for the prevention or improvement of cancer.

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

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

Furthermore, in addition to the above, the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pects acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compound represented by Formula 1 of the present invention may contain natural fruit juice, fruit juice, and pulp for the production of fruit juice beverages and vegetable beverages.

In another aspect of the present invention, a pharmaceutical composition or health functional food containing the compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered to a subject in need. It provides a method for preventing or treating cancer comprising the step of:

Another aspect of the present invention is a pharmaceutical composition or health function containing a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer. Provides food use.

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

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

<Analysis and purification conditions>

1. HPLC analysis conditions ( A )

Device name: Shimadzu

Column: YMC-pack pro C18, 150x4.6 mm I.D., 5 νm, 40°C

mobile phase: 5% ->100% acetonitrile/H ₂ O + 0.1% TFA,

Analysis time: 9 minutes, flow rate: 1ml/min

UV detector: 254nm

2. HPLC analysis conditions ( B )

Instrument Name: Thermo Scientific Ultimate 3000RSLC

Column: Kinetex® 2.6 νM Biphenyl 100ÅA, 100x2.1mm

mobile phase: 5% ->100% acetonitrile/H ₂ O + 0.1% TFA,

Analysis time: 4.5 minutes, flow rate: 1.2ml/min

UV detector: 254nm

3. LC-MS analysis conditions

Device name: Shimadzu LCMS-2020

Column: ACE Excel2 C18, 75x2.1 mm

Mobile phase: acetonitrile/H ₂ O + 0.1% TFA

Flow rate: 1mL/min

UV detector: 254nm

4. MPLC Purification Conditions

Device Name: CombiFlash®Rf+

UV detector: 254nm

5. Prep-HPLC Purification Conditions

Device name: Gilson GX-281, 321 pump, UV/VIS-155

Column: Luna® 10 νM C18 (2) 100 ÅA, 250x21.2 mm

Mobile phase: acetonitrile/0.1% TFA HO

Flow rate: 15mL/min

UV detector: 254nm

6. ¹ H NMR

Device Name: Brucker Avance (400 MHz)

The compound represented by Formula 2 of the present invention can be prepared by a preparation method according to the following Reaction Scheme a or Scheme b.

[Scheme a]

[Scheme b]

<Preparation Example 1> tert-butyl(3-(6-cyano-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carba manufacture of mates

Step 1: Preparation of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5.0 g, 21.5 mmol) was dissolved in dimethyl formamide (30 mL), followed by tert-butyl (3-aminophenyl) carbamate (4.92 g) , 23.6 mmol) and potassium carbonite (5.94, 43.0 mmol) were added at room temperature and stirred at 80 °C for 5 hours. After the reaction mixture was cooled to room temperature, it was extracted using ethyl acetate and saturated sodium hydrogen carbonate solution. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the target compound (7.8 g, quant) as a yellow solid without purification.

MS m/z: 405 [M+H]

Step 2: Preparation of tert-butyl(3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

The compound prepared in step 1 (7.4 g, 18.3 mmol) was dissolved in tetrahydrofuran (50 mL), 1M lithium aluminum hydride (36.6 ml, 36.6 mmol) ^{was added at 0 o} C, and then transferred to room temperature 2 stirred for hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture at 0 ^o C, followed by extraction using ethyl acetate and saturated sodium hydrogen carbonate solution. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the target compound (6.0 g, quant) as a yellow solid without purification.

MS m/z : 363 [M+H]

Step 3: Preparation of tert-butyl(3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

After dissolving the compound (4.4 g, 18.3 mmol) prepared in step 2 in chloroform (50 mL), manganese (IV) oxide After addition, the mixture was stirred at room temperature for 12 hours. After the reaction mixture was filtered through Celite, the separated filtrate was concentrated under reduced pressure to obtain the target compound (3.7 g, quant) as a yellow solid without purification.

MS m/z: 361 [M+H]

Step 4: Preparation of tert-butyl(3-(6-cyano-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

In a 100 mL two-neck flask under nitrogen, 1M lithium bis(trimethylsilyl)amide (8.32 mL, 8.32 mmol) and tetrahydrofuran (15 mL) ^{were stirred under -78 o} C, followed by ethyl cyanoacetate (0.650 mL, 6.10 mmol). ) was slowly added over 25 minutes. The compound prepared in step 3 (1.0 g, 2.77 mmol) ^{was poured at a time under -78 o} C, then moved to room temperature and stirred for 24 hours. After the reaction was terminated by pouring saturated sodium hydrogen carbonate solution into the reaction mixture, the mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by MPLC to obtain the target compound (450 mg, 40%) as a yellow solid.

MS m/z: 410 [M+H]

Step 5: of tert-butyl(3-(6-cyano-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate manufacturing

The compound (370 mg, 0.904 mmol) prepared in step 4 was dissolved in chloroform (7 mL), and 3-chloroperbenzoic acid (234 mg, 1.36 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After filtration of the reaction mixture through Celite, the separated filtrate was concentrated under reduced pressure to obtain the target compound (370 mg, quant) as a yellow solid without purification.

MS m/z : 426 [M+H]

<Example 1> N-(5-((6-cyano-8-methyl-7-oxo-7,8-dihydroxypyrido[2,3-d]pyrimidin-2-yl)amino) Preparation of -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

Step 1: 2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methyl-7-oxo-7,8-dihydroxypyrido[2,3-d] Preparation of pyrimidine-6-carbonitrile

8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydroxypyrido[2,3-d]pyrimidine-6-carbonitrile (0.119 g, 0.479 mmol) was mixed with toluene (2 mL), 4-fluoro-2-methoxy-5-nitroaniline (0.107 g, 0.575 mmol) was added at room temperature, and then stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound (0.170 g, quant) as a yellow solid without purification.

MS m/z: 371 [M+H]

Step 2: 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-8-methyl-7-oxo-7,8 - Preparation of dihydroxypyrido [2,3-d] pyrimidine-6-carbonitrile

The compound prepared in step 1 (0.170 g, 0.459 mmol) was dissolved in 1,4-dioxene (3 mL), and then N1,N1,N2-trimethylethane-1,2-diamine (0.469 g, 4.590 mmol) After addition, the mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound (0.210 g, quant) as a deep red liquid without purification.

MS m/z: 453 [M+H]

Step 3: 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-8-methyl-7-oxo-7,8- Preparation of dihydroxypyrido[2,3-d]pyrimidine-6-carbonitrile

The compound prepared in step 2 (0.074 g, 0.163 mmol) was dissolved in ethyl acetate (1.5 mL), tin (II) chloride and dihydrate (0.368 g, 1.629 mmol) were added thereto, and then at 60 °C for 5 hours. stirred for a while. Ammonia water was added to the reaction mixture to make PH5, sodium carbonate was added to make PH7, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the target compound (0.069 g, quant) as a deep red liquid.

MS m/z: 423 [M+H]

Step 4: N-(5-((6-cyano-8-methyl-7-oxo-7,8-dihydroxypyrido[2,3-d]pyrimidin-2-yl)amino)-2 Preparation of -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The compound prepared in step 3 (0.063 g, 0.151 mmol) was dissolved in tetrahydrofuran (3 mL) and saturated sodium hydrogen carbonate (3 mL), and then acryloyl chloride (0.018 mL, 0.226 mmol) at 0 °C. After addition, the mixture was stirred at 0 °C for 30 min. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to obtain the target compound (0.028 g, 39%) as an orange solid.

MS (m/z): 477 [m+1].

A method similar to that of Example 1 was carried out to prepare the compound of Examples 3-12.

<Example 2> N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2] Preparation of ,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

Step 1: tert-Butyl(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2, Preparation of 3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

A target compound was prepared in a manner similar to that of Example 1, Step 1.

MS m/z: 611 [M+H]

Step 2: 2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-8-(3-aminophenyl)-7-oxo-7,8-dihydroxy Preparation of pyrido[2,3-d]pyrimidine-6-carbonitrile

The compound prepared in step 1 (0.059 g, 0.097 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL, 12.98 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the target compound (0.050 g, quant) was obtained as a deep red liquid without purification.

MS m/z: 511 [M+H]

Step 3: N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2,3 Preparation of -d]pyrimidin-8(7H)-yl)phenyl)acrylamide

A target compound was prepared by performing a method similar to that of Example 1, Step 4.

MS (m/z): 565 [m+1].

The compounds of Examples 13-21 were prepared in a manner similar to that of Example 2 above.

The compounds of Examples 3-12 were prepared in a manner similar to that of Example 1, the compounds of Examples 13-21 were prepared in a manner similar to Example 2, and the chemical structures of Examples 1-21 are shown in Table 1 In, the compound name, ¹ H NMR, mass, yield and HPLC analysis results are summarized in Table 2 below.

Example chemical structure Example chemical structure One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

- -

Example compound name ¹ H NMR or Mass transference number
(%) analysis
condition,
HPLC
rt(min),
Purity One N-(5-((6-cyano-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2 -(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ9.39 (br s, 2H), 9.30 (br s, 1H), 8.79 (br s, 1H), 8.59 (s, 1H), 7.00 (s, 1H), 6.67- 6.26 (m, 1H), 6.31-6.26 (m, 1H), 5.78 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H), 3.28 (s, 3H), 2.81 (s, 3H), 2.80 (s, 3H), 2.61 (s, 3H)
MS (m/z): 477 [m+1] 39 (B), 1.895, 99% 2 N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2,3-d] Pyrimidin-8(7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ10.35 (s, 1H), 8.82 (br s, 2H), 8.68 (br s, 1H), 7.87-7.86 (m, 1H), 7.63 (br s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.19-7.17 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.54 (br s, 1H), 6.44 (dd, J = 10.8, 16.9) Hz, 1H), 6.25 (dd, J = 1.8, 16.9 Hz, 1H), 5.99-5.98 (m, 1H), 5.76 (dd, J = 1.8, 10.0 Hz, 1H), 3.76 (s, 3H), 3.56 -3.55 (m, 4H), 3.05-2.99 (m, 4H), 2.04 (s, 3H)
MS (m/z): 565 [m+1] 18 (A), 5.574, 100% 3 N-(5-((6-cyano-8-(2-methoxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ9.51 (br s, 2H), 9.20 (br s, 1H), 8.79 (br s, 1H), 8.58 (s, 1H), 8.28 (br s, 1H), 6.97 (s, 1H), 6.63-6.57 (m, 1H), 6.28 (d, J = 16.8 Hz, 1H), 5.79 (d, J = 11.0 Hz, 1H), 4.35 (br s, 2H), 3.82 (s) , 3H), 3.26 (br s, 5H), 3.05 (br s, 4H), 2.77 (br s, 6H), 2.60 (s, 3H)
MS (m/z): 521 [m+1] 20 (B), 1.882, 99% 4 N-(5-((6-cyano-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2 -(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ9.46 (s, 1H), 9.35 (br s, 1H), 9.23 (br s, 1H), 8.80 (br s, 1H), 8.57 (s, 1H), 8.44 ( br s, 1H), 6.97 (s, 1H), 6.64-6.57 (m, 1H), 6.30-6.26 (m, 1H), 5.80-5.77 (m, 1H), 4.23-4.21 (m, 2H), 3.84 (br s, 3H), 3.28-3.27 (m, 4H), 2.79 (s, 3H), 2.78 (s, 3H), 2.61 (s, 3H), 1.11 (br s, 3H)
MS (m/z): 491 [m+1] 51 (B), 1.929, 100% 5 N-(5-((8-benzyl-6-cyano-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2 -(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ9.64 (s, 1H), 9.45 (s, 1H), 9.22 (br s, 1H), 8.80 (br s, 1H), 8.61 (s, 1H), 8.15 (br s, 1H), 7.13 (br s, 3H), 7.01 (br s, 2H), 6.65-6.58 (m, 1H), 6.31-6.26 (m, 1H), 5.80-5.77 (m, 1H), 5.29 ( s, 2H), 3.77 (s, 3H), 3.28-3.25 (m, 4H), 2.76 (s, 3H), 2.75 (s, 3H), 2.60 (s, 3H)
MS (m/z): 553 [m+1] 45 (B), 2.115, 98% 6 N-(5-((6-cyano-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(( 2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ9.44 (br s, 2H), 9.27 (br s, 1H), 8.77 (br s, 1H), 8.53 (s, 1H), 6.99 (s, 1H), 6.66 6.59 (m, 1H), 6.31-6.27 (m, 1H), 5.81-5.78 (m, 1H), 5.65 (br s, 1H), 3.83 (s, 3H), 3.29-3.26 (m, 2H), 2.80 (s, 3H), 2.79 (s, 3H), 2.62 (s, 3H), 1.37 (br s, 6H)
MS (m/z): 505 [m+1] 39 (A), 1.992, 99% 7 N-(5-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(( 2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹ H NMR (400 MHz, MeOD) δ8.78 (s, H), 8.40 (s, H), 8.19 (s, H), 7.01 (s, H), 6.54-6.50 (m, 1H), 5.91-5.88 (m, 2H), 4.00 (s, 3H), 3.53-3.51 (m, 2H), 2.89 (s, 6H), 2.76 (s, 3H), 2.24-2.20 (m, 2H), 1.96-1.87 (m) , 4H), 1.65-1.60 (m, 3H), 1.35-1.31 (m, 2H) MS (m/z): 531 [m+1] 31 (A), 4.785, 94% 8 N-(5-((6-cyano-7-oxo-8-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2 -(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ9.65 (s, 1H), 9.43 (s, 1H), 9.21 (br s, 1H), 8.90 (br s, 1H), 8.73 (s, 1H), 8.12 (br s, 1H), 7.15 (br s, 3H), 7.12 (br s, 2H), 6.65-6.58 (m, 1H), 6.45-6.39 (m, 1H), 5.82-5.78 (m, 1H), 3.73 ( s, 3H), 3.26-3.23 (m, 4H), 2.76 (s, 3H), 2.74 (s, 3H), 2.59 (s, 3H)MS(m/z): 539 [m+1] 28 (A), 4.897, 95% 9 N-(5-((6-cyano-8-(4-methoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino) -2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ9.72 (s, 1H), 9.57 (s, 1H), 9.45 (br s, 1H), 8.97 (br s, 1H), 8.12 (br s, 1H), 7.33 ( br s, 3H), 7.11 (br s, 2H), 6.78-6.74 (m, 1H), 6.43-6.39 (m, 1H), 5.80-5.77 (m, 1H), 3.97 (s, 3H), 3.63 ( s, 3H), 3.34-3.30 (m, 4H), 2.77 (s, 3H), 2.75 (s, 3H), 2.63 (s, 3H)MS(m/z): 569 [m+1] 26 (A), 4.946, 94% 10 N-(5-((6-cyano-8-cyclohexyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(( 2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ9.41 (br s, 2H), 9.34 (br s, 1H), 8.56 (br s, 1H), 8.48 (s, 1H), 7.01 (s, 1H), 6.53 6.49 (m, 1H), 6.31-6.25 (m, 1H), 5.81-5.78 (m, 1H), 5.60 (br s, 1H), 3.98 (s, 3H), 3.43-3.26 (m, 4H), 3.33 -3.26 (m, 2H), 3.12-3.03 (m, 4H), 2.71 (s, 3H), 2.79 (s, 3H), 2.62 (s, 3H), MS (m/z): 545 [m+1 ] 25 (A), 5.257, 93% 11 N-(5-((6-cyano-8-(6-methylpyridin-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ9.89 (s, 1H), 9.67 (s, 1H), 9.58 (br s, 1H), 8.99 (br s, 1H), 8.23 (br s, 1H), 7.47- 7.40 (m, 3H), 7.11 (br s, 2H), 6.32-6.35 (m, 1H), 5.81-5.77 (m, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 3.31-3.27 (m, 4H), 2.83 (s, 3H), 2.77 (s, 3H), 2.72 (s, 3H), 2.59 (s, 3H)MS (m/z): 554 [m+1] 31 (A), 4.925, 94% 12 N-(3-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-5-(4 -Methylpiperazin-1-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, MeOD) δ8.81 (s, 1H), 8.65 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 6.06-5.99 (m) , 3H), 5.84-5.81 (m, 1H), 3.17-3.14 (m, 4H), 2.78-2.74 (m, 4H), 2.31-2.24 (m, 3H), 2.04 (s, 3H), 2.05-1.94 (m, 3H), ), 1.68-1.62 (m, 3H)
MS(m/z): 499 [m+1] 22 (A), 4.675, 92% 13 N-(3-(6-cyano-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8( 7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, MeOD) δ8.80 (s, 1H), 8.54 (s, 1H), 8.21 (d, J = 7.2 Hz 1H), 7.61 (t, J = 7.8 Hz 1H), 7.42 (s, 1H), 7.24 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.9 Hz, 2H), 6.45-6.41 (m, 2H), 5.82 ( dd, J = 2.6, 9.1 Hz, 1H), 3.73-3.67 (m, 2H), 3.63-3.60 (m, 2H), 3.00-2.92 (m, 5H)
MS (m/z): 507 [m+1] 13 (A), 4.618, 95% 14 N-(3-(6-cyano-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d] Pyrimidin-8(7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ10.62 (br s, 1H), 10.38 (s, 1H), 9.64 (br s, 1H), 8.91 (s, 1H), 8.75 (s, 1H), 7.89 (d) , J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.55 (t, J = 8.1 Hz 1H), 7.19 (d, J = 14.8 Hz, 1H), 7.12-7.06 (m, 2H), 6.79 ( t, J = 8.9 Hz, 1H), 6.45 (dd, J = 10.0, 16.9 Hz, 1H), 6.26 (dd, J = 1.9, 16.9 Hz, 1H), 5.79-5.76 (m, 1H), 3.51-3.49 (m, 4H), 3.21-3.17 (m, 2H), 2.93-2.87 (m, 5H)
MS (m/z): 525 [m+1] 87 (A), 4.674, 92% 15 N-(3-(6-cyano-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ10.37 (s, 1H), 9.54 (br s, 1H), 8.83 (br s, 2H), 8.68 (br s, 1H), 7.95-7.94 (m, 1H), 7.55-7.48 (m, 2H), 7.20-7.18 (m, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.52 (br s, 1H), 6.45 (dd, J = 10.0, 16.9 Hz, 1H) ), 6.29-6.25 (m, 1H), 6.00-5.99 (m, 1H), 5.77 (dd, J = 1.8, 10.0 Hz, 1H), 3.76 (s, 3H), 3.29 (br s, 1H), 2.78 (d, J = 4.8 Hz, 6H), 2.67-2.58 (m, 4H), 2.04-2.01 (m, 2H), 1.66-1.64 (m, 2H)
MS (m/z): 565 [m+1] 21 (A), 4.650, 100% 16 N-(3-(6-cyano-2-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido[2,3-d] Pyrimidin-8(7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ10.37 (s, 1H), 9.43 (br s, 1H), 8.85 (br s, 1H), 8.69 (br s, 1H), 7.92 (br s, 1H), 7.52 -7.48 (m, 2H), 7.23-7.21 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.58 (br s, 1H), 6.44 (dd, J = 10.0, 16.9 Hz, 1H) , 6.30-6.25 (m, 1H), 6.03 (br s, 1H), 5.79-5.76 (m, 1H), 3.77 (s, 3H), 3.56 (d, J = 11.3 Hz, 4H), 3.24-3.19 ( m, 2H), 3.11-3.08 (m, 2H), 2.90-2.86 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H)
MS (m/z): 551 [m+1] 19 (A), 4.850, 98% 17 N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d] Pyrimidin-8(7H)-yl)phenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ10.38 (br s, 1H), 8.83-8.78 (m, 2H), 7.88-7.86 (m, 1H), 7.65 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.20-7.18 (m, 1H), 7.05-7.03 (m, 1H), 6.50-6.46 (m, 1H), 6.44-6.42 (m, 1H), 6.28-6.23 (m, 1H), 5.98-5.96 (m, 1H), 5.77 (d, J=7.5 Hz, 1H), 3.76 (br s, 2H), 3.18-3.12 (m, 2H), 2.99 (br s, 3H), 2.26 (s, 3H), 2.03-1.91 (m, 2H), 1.76-1.73 (m, 1H), 1.48-1.43 (m, 1H)MS (m/z): 537 [m+1] 34 (A), 4.831, 99% 18 N-(3-(6-cyano-2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)- 1) Phenyl) acrylamide ¹ H NMR (400 MHz, DMSO) δ10.37 (s, 1H), 8.83-8.80 (m, 2H), 8.68 (br s, 1H), 7.88-7.85 (m, 1H), 7.65 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.21-7.19 (m, 1H), 7.05-7.03 (m, 1H), 6.51 (br s, 1H), 6.48-6.41 (m, 1H), 6.28-6.23 (m, 1H), 5.98-5.96 (m, 1H), 5.77 (d, J=7.5 Hz, 1H), 3.77-3.71 (m, 6H), 3.21-3.02 (m, 1H), 3.01 (br s, 3H), 2.03-1.91 (m, 1H)MS (m/z) : 524 [m+1] 36 (A), 5.442, 98% 19 N-(3-(6-cyano-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide TFA salt; ¹ H NMR (400 MHz, DMSO) δ10.34 (br s, 1H), 9.20 (br s, 1H), 8.85 (s, 1H), 8.70 (s, 1H), 7.88-7.86 (m, 1H), 7.49 -7.47 (m, 2H), 7.44-7.42 (m, 1H), 6.48-6.41 (m, 2H), 6.30-6.26 (m, 1H), 5.95-5.93 (m, 1H), 5.79 (d, J= 7.5 Hz, 1H), 3.73-3.69 (m, 2H), 3.12 (s, 3H), 3.11-2.85 (m, 6H), 2.34 (s, 3H)
MS (m/z): 538 [m+1] 35 (A), 4.725, 98% 20 N-(3-(6-cyano-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3-d]pyri Midin-8(7H)-yl)phenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ10.58 (br s, 2H), 10.37 (br s, 1H), 8.76 (br s, 1H), 8.63 (s, 1H), 7.80-7.78 (m, 1H), 7.71 (s, 1H), 7.56-7.52 (m, 1H), 7.11 (s, 1H), 7.07-7.05 (m, 1H), 6.79 (s, 1H), 6.41-6.35 (m, 1H), 6.21- 6.17 (m, 1H), 5.72-5.69 (m, 1H), 3.86-3.82 (m, 2H), 3.40-3.34 (m, 2H), 3.06 (s, 3H)MS(m/z): 457 [m +1] 25 (A), 6.459, 95% 21 N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7-oxopyrido[2,3-d ]pyrimidin-8(7H)-yl)phenyl)acrylamide ¹ H NMR (400 MHz, DMSO) δ10.36 (br s, 1H), 8.83-8.78 (m, 2H), 7.88-7.86 (m, 1H), 7.65 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.20-7.18 (m, 1H), 7.15-7.13 (m, 1H), 6.60-6.53 (m, 1H), 6.44-6.42 (m, 1H), 6.28-6.23 (m, 1H), 5.98-5.96 (m, 1H), 5.74 (d, J=7.5 Hz, 1H), 3.62 (br s, 2H), 3.18-3.12 (m, 2H), 3.01 (br s, 3H), 2.26 (s, 3H), 2.01-1.92 (m, 2H), 1.65-1.62 (m, 1H), 1.51-1.48 (m, 1H)MS (m/z): 565 [m+1] 21 (A), 4.712, 96%

<Experimental Example 1> Evaluation of EGFR mutation inhibitory activity of the compound represented by Formula 1 according to the present invention

In order to evaluate the EGFR mutation inhibitory activity of the compound according to the present invention, the following experiment was performed to evaluate the inhibitory activity against EGFR T790M/L858R kinase.

Specifically, the substrate was prepared in a basic reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1%). DMSO) and then the cofactor required for the reaction was added. Next, EGFR (T790M/L858R) kinase was added and mixed, and then each of the example compounds was added using Acoustic technology (Echo550; nanoliter range). After standing at room temperature for 20 minutes, ³³ P-ATP (specific activity 10 mCi/ml) was added to initiate the reaction. After reacting at room temperature for 2 hours, spotting was made on P81 exchange paper. After the reaction, kinase activity was detected using the filter-binding method.

_{When the IC 50} value of the measured kinase is less than 10 nM, it is class A, when it is 10 to 100 nM, it is class B, when it exceeds 100 nM, it is classified as class C, and is summarized in Table 3 below.

Example EGFR (T790M/L858R)
IC ₅₀ (uM) Example EGFR (T790M/L858R)
IC ₅₀ (uM) One A 11 A 2 B 12 A 3 A 13 A 4 B 14 A 5 B 15 A 6 B 16 A 7 B 17 A 8 B 18 B 9 B 19 B 10 - 20 B

As shown in Table 3 above,

It was confirmed that the example compounds according to the present invention exhibit excellent inhibitory activity against EGFR (T790M/L858R).

Therefore, the compound represented by Formula 1 according to the present invention can be usefully used for the treatment of diseases related to EGFR mutation, in particular, EGFR (T790M/L858R) activity.

<Experimental Example 2> Kinase inhibitory activity evaluation experiment

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

Specifically, among the example compounds of this alias, for Example 1 selected, the enzyme (kinase) selectivity was measured by requesting DiscoverX, and the experiment was conducted using a ^{scanMAX TM Kinase analysis panel.}

At this time, the concentration of the drug treated with the enzyme was 1 uM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Table 4-7 below.

[Equation 1]

(Example compound - positive control) / (negative control - positive control) × 100

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

kinase Example 1 kinase Example 1 AAK1 90 CAMK2D 79 ABL1(E255K)-phosphorylated 44 CAMK2G 100 ABL1(F317I)-nonphosphorylated 55 CAMK4 92 ABL1(F317I)-phosphorylated 48 CAMKK1 89 ABL1(F317L)-nonphosphorylated 55 CAMKK2 97 ABL1(F317L)-phosphorylated 32 CASK 91 ABL1(H396P)-nonphosphorylated 29 CDC2L1 92 ABL1(H396P)-phosphorylated 74 CDC2L2 94 ABL1(M351T)-phosphorylated 76 CDC2L5 97 ABL1(Q252H)-nonphosphorylated 26 CDK11 100 ABL1(Q252H)-phosphorylated 43 CDK2 100 ABL1(T315I)-nonphosphorylated 74 CDK3 100 ABL1(T315I)-phosphorylated 89 CDK4 76 ABL1(Y253F)-phosphorylated 100 CDK4-cyclinD1 81 ABL1-nonphosphorylated 53 CDK4-cyclinD3 93 ABL1-phosphorylated 72 CDK5 100 ABL2 48 CDK7 90 ACVR1 100 CDK8 98 ACVR1B 82 CDK9 80 ACVR2A 97 CDKL1 91 ACVR2B 100 CDKL2 99 ACVRL1 100 CDKL3 87 ADCK3 98 CDKL5 85 ADCK4 100 CHEK1 99 AKT1 92 CHEK2 95 AKT2 93 CIT 98 AKT3 78 CLK1 78 ALK 80 CLK2 80 ALK (C1156Y) 92 CLK3 97 ALK (L1196M) 85 CLK4 100 AMPK-alpha1 96 CSF1R 71 AMPK-alpha2 100 CSF1R-autoinhibited 6.5 ANKK1 80 CSK 76 ARK5 93 CSNK1A1 93 ASK1 100 CSNK1A1L 95 ASK2 88 CSNK1D 100 AURKA 89 CSNK1E 97 AURKB 84 CSNK1G1 99 AURKC 100 CSNK1G2 100 AXL 96 CSNK1G3 92 BIKE 92 CSNK2A1 18 BLK 13 CSNK2A2 24 BMPR1A 84 CTK 88 BMPR1B 59 DAPK1 75 BMPR2 94 DAPK2 80 BMX 86 DAPK3 60 BRAF 74 DCAMKL1 74 BRAF(V600E) 76 DCAMKL2 96 BRK 79 DCAMKL3 100 BRSK1 87 DDR1 94 BRSK2 94 DDR2 97 BTK 16 DLK 84 BUB1 86 DMPK 81 CAMK1 82 DMPK2 89 CAMK1B 72 DRAK1 86 CAMK1D 86 DRAK2 100 CAMK1G 82 DYRK1A 67 CAMK2A 94 DYRK1B 83 CAMK2B 78 DYRK2 88

kinase Example 1 kinase Example 1 EGFR 1.3 FYN 96 EGFR (E746-A750del) 3.7 GAK 15 EGFR (G719C) 0.6 GCN2(Kin.Dom.2,S808G) 86 EGFR(G719S) 26 GRK1 76 EGFR (L747-E749del, A750P) 0.65 GRK2 99 EGFR (L747-S752del, P753S) 4.2 GRK3 79 EGFR (L747-T751del,Sins) 2.3 GRK4 82 EGFR(L858R) 0 GRK7 87 EGFR(L858R,T790M) 5.3 GSK3A 92 EGFR (L861Q) 2.3 GSK3B 81 EGFR (S752-I759del) 0 HASPIN 100 EGFR(T790M) 3.1 HCK 100 EIF2AK1 84 HIPK1 35 EPHA1 80 HIPK2 40 EPHA2 97 HIPK3 59 EPHA3 100 HIPK4 91 EPHA4 100 HPK1 91 EPHA5 100 HUNK 91 EPHA6 100 ICK 88 EPHA7 93 IGF1R 100 EPHA8 97 IKK-alpha 75 EPHB1 49 IKK-beta 82 EPHB2 93 IKK-epsilon 62 EPHB3 100 INSR 81 EPHB4 100 INSRR 92 EPHB6 95 IRAK1 78 ERBB2 12 IRAK3 100 ERBB3 94 IRAK4 76 ERBB4 1.9 ITK 33 ERK1 100 JH1 domain-catalytic (JAK1) 90 ERK2 93 JH2domain-pseudokinase (JAK1) 99 ERK3 91 JH1 domain-catalytic (JAK2) 81 ERK4 80 JH1 domain-catalytic (JAK3) 3.1 ERK5 89 JNK1 67 ERK8 100 JNK2 100 ERN1 84 JNK3 94 FAK 100 KIT 20 FER 85 KIT(A829P) 54 FES 98 KIT(D816H) 53 FGFR1 93 KIT(D816V) 49 FGFR2 76 KIT(L576P) 4.1 FGFR3 100 KIT(V559D) 5.3 FGFR3 (G697C) 76 KIT(V559D,T670I) 81 FGFR4 100 KIT(V559D,V654A) 96 FGR 100 KIT-autoinhibited 5.8 FLT1 79 LATS1 100 FLT3 85 LATS2 81 FLT3 (D835H) 76 LCK 86 FLT3 (D835V) 44 LIMK1 100 FLT3 (D835Y) 91 LIMK2 83 FLT3 (ITD) 80 LKB1 94 FLT3(ITD,D835V) 84 LOK 98 FLT3(ITD,F691L) 84 LRRK2 100 FLT3(K663Q) 96 LRRK2(G2019S) 88 FLT3 (N841I) 86 LTK 100 FLT3 (R834Q) 91 LYN 96 FLT3-autoinhibited 68 LZK 74 FLT4 89 MAK 97 FRK 59 MAP3K1 89

kinase Example 1 kinase Example 1 MAP3K15 100 NEK9 85 MAP3K2 75 NIK 97 MAP3K3 87 NIM1 69 MAP3K4 100 NLK 13 MAP4K2 89 OSR1 84 MAP4K3 74 p38-alpha 92 MAP4K4 100 p38-beta 81 MAP4K5 100 p38-delta 77 MAPKAPK2 87 p38-gamma 79 MAPKAPK5 87 PAK1 97 MARK1 96 PAK2 70 MARK2 99 PAK3 100 MARK3 100 PAK4 97 MARK4 94 PAK6 87 MAST1 100 PAK7 100 MEK1 80 PCTK1 91 MEK2 87 PCTK2 89 MEK3 95 PCTK3 82 MEK4 93 PDGFRA 64 MEK5 47 PDGFRB 42 MEK6 100 PDPK1 89 MELK 94 PFCDPK1 (P. falciparum) 100 MERTK 98 PFPK5 (P. falciparum) 83 MET 99 PFTAIRE2 76 MET (M1250T) 100 PFTK1 100 MET (Y1235D) 100 PHKG1 98 MINK 92 PHKG2 92 MKK7 85 PIK3C2B 95 MKNK1 87 PIK3C2G 73 MKNK2 76 PIK3CA 98 MLCK 97 PIK3CA(C420R) 83 MLK1 98 PIK3CA (E542K) 77 MLK2 85 PIK3CA (E545A) 92 MLK3 88 PIK3CA (E545K) 87 MRCKA 100 PIK3CA(H1047L) 89 MRCKB 18 PIK3CA(H1047Y) 100 MST1 100 PIK3CA(I800L) 49 MST1R 95 PIK3CA (M1043I) 95 MST2 61 PIK3CA (Q546K) 83 MST3 90 PIK3CB 86 MST4 98 PIK3CD 54 MTOR 65 PIK3CG 100 MUSK 89 PIK4CB 36 MYLK 84 PIKFYVE 91 MYLK2 100 PIM1 88 MYLK4 99 PIM2 89 MYO3A 93 PIM3 98 MYO3B 96 PIP5K1A 70 NDR1 92 PIP5K1C 80 NDR2 89 PIP5K2B 100 NEK1 100 PIP5K2C 58 NEK10 72 PKAC-alpha 76 NEK11 83 PKAC-beta 73 NEK2 91 PKMYT1 11 NEK3 68 PKN1 100 NEK4 92 PKN2 73 NEK5 93 PKNB (M. tuberculosis) 82 NEK6 100 PLK1 72 NEK7 91 PLK2 64

kinase Example 1 kinase Example 1 PLK3 81 SRPK1 93 PLK4 93 SRPK2 97 PRKCD 82 SRPK3 80 PRKCE 97 STK16 82 PRKCH 100 STK33 97 PRKCI 89 STK35 85 PRKCQ 100 STK36 97 PRKD1 94 STK39 58 PRKD2 98 SYK 92 PRKD3 89 TAK1 88 PRKG1 79 TAOK1 86 PRKG2 99 TAOK2 87 PRKR 99 TAOK3 79 PRKX 98 TBK1 87 PRP4 100 TEC 51 PYK2 100 TESK1 87 QSK 80 TGFBR1 89 RAF1 100 TGFBR2 88 RET 99 TIE1 97 RET(M918T) 87 TIE2 86 RET(V804L) 97 TLK1 73 RET(V804M) 91 TLK2 100 RIOK1 100 TNIK 87 RIOK2 85 TNK1 71 RIOK3 100 TNK2 97 RIPK1 89 TNNI3K 100 RIPK2 81 TRKA 100 RIPK4 81 TRKB 99 RIPK5 77 TRKC 100 ROCK1 86 TRPM6 95 ROCK2 79 TSSK1B 91 ROS1 87 TSSK3 85 RPS6KA4(Kin.Dom.1-N-terminal) 81 TTK 80 RPS6KA4(Kin.Dom.2-C-terminal) 0.55 TXK 5.5 RPS6KA5(Kin.Dom.1-N-terminal) 100 TYK2 (JH1 domain-catalytic) 98 RPS6KA5(Kin.Dom.2-C-terminal) 59 TYK2 (JH2domain-pseudokinase) 95 RSK1 (Kin.Dom.1-N-terminal) 87 TYRO3 100 RSK1 (Kin.Dom.2-C-terminal) 61 ULK1 60 RSK2 (Kin.Dom.1-N-terminal) 76 ULK2 99 RSK2 (Kin.Dom.2-C-terminal) 80 ULK3 100 RSK3 (Kin.Dom.1-N-terminal) 92 VEGFR2 52 RSK3 (Kin.Dom.2-C-terminal) 72 VPS34 98 RSK4 (Kin.Dom.1-N-terminal) 80 VRK2 85 RSK4 (Kin.Dom.2-C-terminal) 42 WEE1 100 S6K1 93 WEE2 100 SBK1 82 WNK1 87 SGK 79 WNK2 83 SgK110 100 WNK3 93 SGK2 89 WNK4 87 SGK3 100 YANK1 87 SIK 100 YANK2 100 SIK2 83 YANK3 96 SLK 83 YES 94 SNARK 94 YSK1 100 SNRK 87 YSK4 100 SRC 80 ZAK 86 SRMS 87 ZAP70 75

As shown in Table 4-7 above,

Example 1 compound of the present invention is ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(Q252H)-nonphosphorylated, BLK, BTK, CSF1R-autoinhibited, CSNK2A1, CSNK2A2, EGFR, EGFR(E746-A750del) EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR (L861Q), EGFR (S752-I759del), EGFR (T790M), ERBB2, ERBB4, GAK, ITK, JAK3 (JH1domain-catalytic), KIT, KIT (L576P), KIT (V559D), KIT-autoinhibited, MRCKB, NLK , PKMYT1, RPS6KA4 (Kin.Dom.2-C-terminal), and TXK kinase can be seen to have a value less than 35% of the control percentage.

This indicates that the example compounds of the present invention have inhibitory activity against the enzymes listed above, suggesting that they have useful effects when used in diseases related to the enzymes listed above.

Accordingly, the compound represented by Formula 1 according to the present invention is ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(Q252H)-nonphosphorylated, BLK, BTK, CSF1R-autoinhibited, CSNK2A1, CSNK2A2, EGFR, EGFR ( E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R) ,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), ERBB2, ERBB4, GAK, ITK, JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D), KIT- Autoinhibited, MRCKB, NLK, PKMYT1, RPS6KA4 (Kin.Dom.2-C-terminal), and can be usefully used as a pharmaceutical composition for the treatment or prevention of TXK kinase-related diseases.

<Experimental Example 3> Ba/F3 cell activity evaluation

The following experiment was performed to evaluate the activity of the compound according to the present invention on Ba/F3 cells expressing EGFR mutations.

More specifically, BaF3-parental, EGFR (WT, CrownBio C2009), EGFR (L858R), EGFR (T790M/L858R, CrownBio C2055), EGFR (Del19/T790M), EGFR (Del19/T790M/C797S), and EGFR ( L858R/T790M/C797S) containing 12 concentrations (0.00005 - 10 mM) of compound and DMSO control serially diluted in triplicate after planting ^{at 2 Х 10 3} /100 μl/well in a clear bottom white 96-well plate 0.5 μl/well of the obtained culture solution was added so that the final concentration was 0.0003 - 50 μM, and then _{incubated in a 37° C. CO 2} incubator for 72 hours. After 72 hours, take out the plate treated with the compound, and mix well after treatment with 100 μl/well of CellTiter-Glo® 2.0 Assay (Promega) solution. Mix well at room temperature for about 10 minutes, and measure the fluorescence with a microplate reader. The data were expressed as a percentage in proportion to the treated cells based on the vehicle standard, and GI ₅₀ values were calculated using GraphPad Prism 7.0 (GraphPad software Inc., San Diego). The results are shown in Table 8 below.

In Table 8, A has a GI ₅₀ of 0.1 μM or less, B is more than 0.1 μM to 1 μM or less, and C is more than 1 μM to 100 μM or less.

Example Ba/F3 GI ₅₀ parental EGFR
WT EGFR
L858R EGFR
T790M
/L858R EGFR
Del19
/T790M EGFR
Del19
/T790M
/C797S EGFR
L858R
/T790M
/C797S NPH
Ins SVD
Ins One C - A B A C C - - 2 C A A B C - - C C 3 C - A A B C C - - 4 C - A A A C C - - 5 C A A A A C C A B 6 C A A A A C C B B 7 C A A A B C C B B 8 C A A A A C C A B 9 C A A B B C C B B 10 C A A B B C C B C 11 C C C C C C C C C 12 C C C C C C C C C 13 C - A B B C C - - 14 C A A A B C C B B 15 C A A A B C C B B 16 C A A A A C C B A 17 C A A A A C C B A 18 C A A A A C C B B 19 C A B B C - - C C 20 C B B C C - - C C 21 C C C C C - - C C

As shown in Table 8, it can be seen that in the Ba/F3 cell line, the compounds of the examples of the present invention not only exhibit excellent inhibitory activity in wild-type EGFR, but also exhibit high inhibitory activity against EGFR single, double or triple mutations. In particular, it can be seen that exhibits excellent inhibitory ability against EGFR L858, EGFR T790M / L858, EGFR Del19 / T790M.

Therefore, the compound represented by Formula 1 according to the present invention exhibits high inhibitory ability against EGFR (epidermal growth factor receptor) wild-type or mutant, and thus EGFR Del19, EGFR Del19/T790M, EGFR Del19/T790M/C797S as well as EGFR wild-type , EGFR L858R, EGFR T790M / L858R, and EGFR L858R / T790M / C797S EGFR mutations, in particular, EGFR L858, EGFR T790M / L858, EGFR Del19 / T790M can be usefully used for the treatment of expressed cancer.

Claims (14)

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

(In Formula 1,

is a single bond or a double bond;

R ¹ is hydrogen, linear or branched C _1-10 alkyl, straight or branched C _1-10 alkoxy, straight or branched C _1-10 alkoxyC _1-2 alkyl, C _3-7 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted pyridinyl;
In this case, the substituted benzyl or substituted pyridinyl is substituted with one or more selected from the group consisting _{of straight or branched C 1-6} alkyl and straight or branched C _{1-6 alkoxy,}
The substituted phenyl is straight or branched C _1-6 alkyl, straight or branched C _1-6 alkoxy and

may be substituted with one or more selected from the group consisting of;
R ² is hydrogen or linear or branched C _1-10 alkoxy;
R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ contains hydrogen, halogen or one or more heteroatoms selected from the group consisting of N, O and S is a 3-7 membered heterocycloalkyl, wherein the heterocycloalkyl may be one or more substituted with _{straight-chain or branched C 1-6} ^{alkyl, R 5} is hydrogen or straight-chain or branched C _1-10 alkoxyC _1-2 alkyl;
A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d is independently hydrogen or linear or branched C _1-6 alkyl, wherein said alkyl may be unsubstituted or substituted one or more with amines one or more substituted with _{straight or branched C 1-6 alkyl, or} , R ^a and R ^b or R ^c and R ^d are each taken together with the N atom to which they are attached to form a 3-7 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S wherein the heterocycloalkyl may be substituted with one or more selected from the group consisting _{of straight or branched C 1-6} alkyl, di(straight or branched C _{1-6 alkyl)amino and acetyl;}

When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,
When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

,

or

can form,
When n is 0 and when n is 1 and R ³ is hydrogen, R ¹ is

phenyl substituted with ).
According to claim 1,
R ² is hydrogen or linear or branched C _1-6 alkoxy;
R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ contains hydrogen, halogen or one or more heteroatoms selected from the group consisting of N, O and S is a 3-6 membered heterocycloalkyl, wherein the heterocycloalkyl may be one or more substituted with _{straight-chain or branched C 1-4} ^{alkyl, R 5} is hydrogen or straight-chain or branched C _1-6 alkoxyC _1-2 alkyl;
A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d , wherein R ^a , R ^b , R ^c and R ^d is independently hydrogen or straight-chain or branched C _1-4 alkyl, wherein said alkyl may be unsubstituted or substituted one or more with amines one or more substituted with _{straight-chain or branched C 1-4 alkyl, or} , R ^a and R ^b or R ^c and R ^d are each taken together with the N atom to which they are attached to form a 3-6 membered heterocycloalkyl comprising at least one heteroatom selected from the group consisting of N, O and S wherein the heterocycloalkyl may be substituted with one or more selected from the group consisting _{of straight or branched C 1-4} alkyl, di(straight or branched C _{1-4 alkyl)amino and acetyl;}

When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,
When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

,

or

can form,
When n is 0 and when n is 1 and R ³ is hydrogen, R ¹ is

A compound characterized in that it is phenyl substituted with a compound, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ² is hydrogen or linear or branched C _1-4 alkoxy;
R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ is hydrogen, halogen or 5-6 membered heterocycloalkyl comprising at least one N atom, In this case, the heterocycloalkyl may be one or more substituted with _{C 1-2} ^{alkyl, R 5} is hydrogen or a linear or branched C _1-4 alkoxyC _1-2 alkyl;
A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d ,
In this case, R ^a and R ^b are independently hydrogen or C _1-2 alkyl, wherein the alkyl may be unsubstituted or substituted one or more with an amine substituted with one or more _{straight-chain or branched C 1-2 alkyl, or} , R ^a and R ^b together with the N atom to which they are attached may form a 5-6 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N and O, wherein said heterocycloalkyl is C _1-2 may be substituted with one or more selected from the group consisting of alkyl, dimethylamino and acetyl,
R ^c and R ^d together with the N atom to which they are attached may form a 5-6 membered heterocycloalkyl comprising one or more N atoms, wherein said heterocycloalkyl is substituted with one or more _{C 1-2 alkyl} can be;

When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,
When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

or

can form,
When n is 0 and when n is 1 and R ³ is hydrogen, R ¹ is

A compound characterized in that it is phenyl substituted with a compound, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ² is hydrogen or methoxy;
R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ is hydrogen, F or piperazinyl substituted with methyl, and R ⁵ is hydrogen or methoxyethyl ego;
A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is -NR ^a R ^b or -(C=O)NR ^c R ^d ,
In this case, R ^a and R ^b are independently hydrogen, methyl or ethyl substituted with dimethylamino, or R ^a and R ^b together with the N atom to which they are attached to form piperidinyl, piperazinyl or morpholinyl wherein the piperidinyl or piperazinyl may be substituted with one or more selected from the group consisting of methyl, ethyl, dimethylamino and acetyl,
R ^c and R ^d together with the N atom to which they are attached may form a piperazinyl substituted with methyl;

When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,
When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

or

can form,
When n is 0 and when n is 1 and R ³ is hydrogen, R ¹ is

A compound characterized in that it is phenyl substituted with a compound, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
Wherein R ¹ is hydrogen, methyl, ethyl, methoxyethyl, cyclopentyl, cyclohexyl,

,

,

,

or

ego;

R ² is hydrogen or methoxy;
R ³ is hydrogen or

ego;

n is 0 or 1;

A ¹ is -C(R ⁴ )=, -N= or -N(R ⁵ )-, wherein R ⁴ is hydrogen, F or

, R ⁵ is hydrogen or methoxyethyl;
A ² is =C(R ⁶ )- or -N=, wherein R ⁶ is

,

,

,

,

,

or

ego,

When n is 0, the bonding structure of ^{A 1} and A ^{2 is}

can form,
When n is 1, the bonding structure of ^{A 1} and A ^{2 is}

or

can form,
When n is 0 and when n is 1 and R ³ is hydrogen, R ¹ is

A compound, characterized in that it is a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
A compound, characterized in that it is any one selected from the group of compounds, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1> N-(5-((6-cyano-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<2> N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-6-cyano-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<3> N-(5-((6-cyano-8-(2-methoxyethyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<4> N-(5-((6-cyano-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<5> N-(5-((8-benzyl-6-cyano-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<6> N-(5-((6-cyano-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<7> N-(5-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<8> N-(5-((6-cyano-7-oxo-8-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2- ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<9> N-(5-((6-cyano-8-(4-methoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<10> N-(5-((6-cyano-8-cyclohexyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<11> N-(5-((6-cyano-8-(6-methylpyridin-3-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- 2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;
<12> N-(3-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-5 -(4-methylpiperazin-1-yl)phenyl)acrylamide;
<13> N-(3-(6-cyano-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidine -8(7H)-yl)phenyl)acrylamide;
<14> N-(3-(6-cyano-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<15> N-(3-(6-cyano-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<16> N-(3-(6-cyano-2-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<17> N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<18> N-(3-(6-cyano-2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidine-8( 7H)-yl)phenyl)acrylamide;
<19> N-(3-(6-cyano-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide;
<20> N-(3-(6-cyano-2-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide; and
<21> N-(3-(6-cyano-2-((2-methoxy-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide.
delete A pharmaceutical composition for the prevention or treatment of cancer comprising the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The method of claim 8,
The compound is EGFR (epidermal growth factor receptor) pharmaceutical composition, characterized in that inhibiting wild-type or mutant.
10. The method of claim 9,
The EGFR mutation is at least one selected from the group consisting of EGFR Del19, EGFR Del19/T790M, EGFR Del19/T790M/C797S, EGFR L858R, EGFR T790M/L858R and EGFR L858R/T790M/C797S.
9. The method of claim 8,
The cancer is a pharmaceutical composition, characterized in that associated with protein kinase activity.
12. The method of claim 11,
The protein kinase is AAK1, ABL1 (E255K)-phosphorylated. ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(M351T) (Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVR1B, ACVR2A1B, ACVR2A ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC, AURKB BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF(V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2A, CAMK2A, CAMK2, CAMK2B, K CAMK2, CAMK2B, K CAMK2 , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CLK2, C , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, FRRK2, EG DYK2, DRAK2, DRAK1, DYRK1 -A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R, T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB2, EPHB3 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 (D835H) D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICKK IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-cat alytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P) ), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2(G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK5, MEK4, MAST1, MEK, MEK MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-beta delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFTAIRE2, PFTK1, PHKG1 PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA(C420R), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (E545K), PIK3CA (H1047L), PIK3CA (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CD, PIK3CB, PIK PIK PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M. , PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK2, RIOK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4 (Kin.Dom.1-N-terminal), RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.1-N-terminal) , RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1, N-terminal), RSK1(Kin.Dom.2-C-terminal), RSK2(Kin.Dom.1-N- terminal), RSK2(Kin.Dom.2-C-terminal), RSK3(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.2-C-terminal), RSK4(Kin.Dom.1- N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, ST K39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRPM6, TRKC TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, YANK3, WNK4, YANK A pharmaceutical composition, characterized in that at least one selected from the group consisting of YES, YSK1, YSK4, ZAK and ZAP70.
9. The method of claim 8,
The compound is ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(Q252H)-nonphosphorylated, BLK, BTK, CSF1R-autoinhibited, CSNK2A1, CSNK2A2, EGFR, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR (S752-I759del), EGFR (T790M), ERBB2, ERBB4, GAK, ITK, JAK3 (JH1domain-catalytic), KIT, KIT (L576P), KIT (V559D), KIT-autoinhibited, MRCKB, NLK, PKMYT1, RPS6KA4 ( Kin.Dom.2-C-terminal) and a pharmaceutical composition, characterized in that it exhibits inhibitory activity against one or more kinases selected from the group consisting of TXK.
9. The method of claim 8,
The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, and thymus cancer A pharmaceutical composition, characterized in that at least one selected from the group.