KR102568168B1 - Novel pyrimidine-2,4-diamine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient - Google Patents

Abstract

It relates to a pyrimidine-2,4-diamine 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 pyrimidine-2,4-diamine derivative is effective against EGFR and HER2 mutations Since it exhibits high inhibitory activity, it can be usefully used in the treatment of cancer in which EGFR and HER2 mutations have occurred, and since it exhibits a remarkable synergistic effect when administered in combination, it can also be usefully used in combination therapy.

Description

Novel pyrimidine-2,4-diamine derivatives, preparation method thereof, and pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient {Novel pyrimidine-2,4-diamine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient}

The present invention relates to a pyrimidine-2,4-diamine derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.

The occurrence of cancer is related to various environmental factors including chemicals, radiation, and viruses, and changes in oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. Understanding the mechanism enables a new treatment, targeted chemotherapy.

Targeted therapies are generally made to show their effects by targeting molecules that are characteristic of cancer cells. (matrix), cell cycle regulator, and apoptosis. Currently, there are 'signal transduction pathway inhibitors' and 'angiogenesis inhibitors', including tyrosine kinase inhibitors, that are used as important target therapeutics in the treatment.

Protein tyrosine kinases have been found to play an important role in many malignancies, and in particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the erbB family, has been shown to play an important role in non-small cell lung cancer. It is abnormally active in many epithelial cell tumors, including NSCLC, breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, 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, angiogenesis, and increases cell survival.

Specifically, the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER2, ErbB3, ErbB4), and has an extracelluar ligand-binding domain and a tyrosine kinase domain. It is a transmembrane tyrosine kinase with an intracellular domain including When a ligand binds to a homodimer or heterodimer receptor, intracellular tyrosine kinase is activated, and the signal stimulated by EGFR in this way is phosphatidylinositol 3-kinase (PI3K)/ 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 target for treatment. EGFR TKIs (tyrosine kinase inhibitors) that inhibit EGFR tyrosine kinase activity have 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 mutations are largely divided into sensitizing mutations and resistant mutations, and the deletion of exon 19 and the L858R point mutation in exon 21 are the most important sensitizing mutations, about 85 to 90 %, and exon 19 del mutations are known to have better sensitivity to TKIs. On the other hand, the T790M point mutation in exon 20 is known to be found in more than 50% of acquired resistance patients as the most important resistance mutation (Clin Cancer Res 2006; 12:6494-6501.).

Somatic mutations identified to date include in-frame deletions in exon 19 or insertions in exon 20, as well as point mutations that alter a single nucleic acid residue within an 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 early clinical effects of gefitinib/erlotinib in NSCLC patients with EGFR mutations, most patients eventually develop advanced cancer while receiving therapy with these agents. Early studies of relapsed specimens identified a secondary EGFR mutation, T790M, which renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity (Kobayashi et al NEJM 2005 and Pao et al PLOS Medicine 2005). Subsequent studies demonstrated that EGFR T790M mutations were found in approximately 50% (24/48) of tumors from patients who acquired resistance to gefitinib or erlotinib (Kosaka et al CCR 2006; Balak et al CCR 2006 and Engelman et al Science 2007). These secondary genetic alterations occur in patients treated with kinase inhibitors at locations similar to the 'gatekeeper' residue and its associated secondary resistance allele (eg, T315I in ABL in imatinib-resistant CML).

It has long been known that the EGFR mutation EGFR_del19 or EGFR_L858R is a major cause of non-small cell lung cancer and head and neck cancer, and their therapeutic drugs, Iressa and Tarceva, have been developed and are currently used in clinical practice. However, when these drugs were used in patients, acquired resistance, in which EGFR secondary mutations occur based on the structure of the drug, was observed, and it was also found that this is the main cause of actual drug resistance. When EGFR 1st generation inhibitors are used for an average of about 10 months, acquired resistance, called the T790M mutation located in the gatekeeper of EGFR kinase, occurs, so that EGFR 1st generation inhibitors do not have a drug effect. That is, EGFR_del19_T790M or EGFR_L858R_T790M double mutations occur, preventing the existing therapeutic agents from exhibiting drug efficacy.

Based on these facts, the need for the development of second- and third-generation drugs with excellent efficacy and new structures has emerged.

AZD9291 (Osimertinib, Tagrisso) from AstraZeneca, a multinational pharmaceutical company, is a variety of third-generation drugs that have been shown to be effective against EGFR T790M double mutation in the last 10 years. However, it has been reported that AZD9291 also develops resistance after about 10 months, and the drug efficacy of AZD9291 is lost. In particular, it has been reported that resistance to triple mutations including C797S occurs (Thress et al, Nature Medicine 2015).

Accordingly, there is a need to develop inhibitors that show relatively low inhibition of WT EGFR and at the same time show higher inhibition of specific activated or various resistant mutant forms of EGFR.

The EGFR Tyrosine kinase inhibitors (TKIs), gefitinib, erlotinib, and afatinib, are approved treatments for non-small cell lung cancer with activating mutations in EGFR kinase, but resistance is rapidly developing. However, there is a problem in that the T790M mutation in the ATP site of the receptor frequently occurs. Thus, the recently developed irreversible mutagenesis inhibitor exhibits high activity against the T790M mutation, but its efficacy can be neutralized by acquired mutation of C797, a cysteine residue forming a key covalent bond.

Intracellular Human EGFR2, known as HER2/neu or ErbB2, is a tyrosine kinase receptor belonging to the human epidermal growth factor receptor (HER/EGFR/ERBB) family and is normally involved in signal transduction pathways for cell growth and differentiation induce HER2 shows very high structural similarity with the other three EGFR family members (EGFR, HER3, HER4).

However, unlike other anticancer targets, in the case of HER2 (Human epidermal growth factor 2), the ligand that binds to it is not yet known. It is involved in cell cycle increase, regulation of cell proliferation, and differentiation and survival. In the case of an antibody targeting Her2, an antibody treatment of IgG2 type has been developed and is on the market, and is not antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Its neutralizing activity is the main therapeutic action.

Therefore, while trying to develop a cancer treatment agent that inhibits EGFR multimutation, the pyrimidine-2,4-diamine derivative according to the present invention exhibits relatively low inhibition against nocturnal EGFR, and is effective against EGFR mutation and HER2 mutation. The present invention was completed by finding out that it can be usefully used for the prevention or treatment of cancer by exhibiting high inhibitory activity against cancer.

One object of the present invention is to provide a pyrimidine-2,4-diamine derivative.

Another object of the present invention is to provide a method for preparing a pyrimidine-2,4-diamine derivative.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing a pyrimidine-2,4-diamine derivative as an active ingredient.

Another object of the present invention is to provide a health functional food for preventing or improving cancer containing a pyrimidine-2,4-diamine derivative as an active ingredient.

In order to achieve the above purpose,

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

[Formula 1]

In Formula 1,

n is an integer from 0 to 3;

X is sulfonyl or carbonyl;

R ¹ is hydrogen, halogen, nitrile, unsubstituted or straight or branched C _1-10 alkyl substituted with one or more halogens, carboxyl, or straight or branched C _1-10 alkoxycarbonyl;

R ² is -OR _a or -NR _b1 R _b2 ;

R _a is -(CH ₂ ) _m -NR _b1 R _b2 , where m is an integer from 1 to 3;

R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted straight-chain or branched-chain C _1-10 alkyl, or R _b1 and R _b2 together with the nitrogen to which they are bonded are unsubstituted or substituted 3 to 7 membered hetero Forms a cycloalkyl, wherein the substituent of the substituted straight-chain or branched-chain C _1-10 alkyl may be -NR _c1 R _c2 , and the substituent of the substituted 3-7 membered heterocycloalkyl is -NR _c1 R _c2 or straight-chain or branched-chain C _1-10 alkyl;

R _c1 and R _c2 are each independently hydrogen, straight or branched chain C _1-10 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are attached form an unsubstituted or substituted 3 to 7 membered heterocycloalkyl; , At this time, the substituent of the substituted 3 to 7 membered heterocycloalkyl may be a straight-chain or branched-chain C _1-10 alkyl;

R ³ , R ⁵ and R ⁶ are each independently hydrogen, halogen, straight-chain or branched-chain C _1-10 alkoxy, or unsubstituted or straight-chain or branched-chain C _1-10 alkyl substituted with one or more halogens;

R ⁴ is —NH ₂ , straight or branched chain C _1-10 alkyl, or C _3-7 cycloalkyl;

R ⁷ and R ⁸ are each independently hydrogen or straight or branched chain C _1-10 alkyl;

n is an integer from 0 to 3;

p and q are each independently an integer of 1 to 3;

In addition, as shown in Scheme 1 below, the present invention

Provided is a method for producing a compound represented by Formula 1 of claim 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:

[Scheme 1]

In Scheme 1, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n, p and q are as defined in Formula 1 of claim 1.

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient Provided.

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

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

According to another aspect of the present invention, a pharmaceutical composition containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, or Provides the use of health functional food.

Since the pyrimidine-2,4-diamine derivative of the present invention exhibits high inhibitory activity against EGFR and HER2 mutations, it can be usefully used in the treatment of cancers in which EGFR and HER2 mutations have occurred, and can produce a remarkable synergistic effect when administered in combination. Therefore, it can be usefully used in combination therapy.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

X is sulfonyl or carbonyl;

R ¹ is hydrogen, halogen, nitrile, unsubstituted or straight or branched C _1-10 alkyl substituted with one or more halogens, carboxyl, or straight or branched C _1-10 alkoxycarbonyl;

R ² is -OR _a or -NR _b1 R _b2 ;

R _a is -(CH ₂ ) _m -NR _b1 R _b2 , where m is an integer from 1 to 3;

R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted straight-chain or branched-chain C _1-10 alkyl, or R _b1 and R _b2 together with the nitrogen to which they are bonded are unsubstituted or substituted 3 to 7 membered hetero Forms a cycloalkyl, wherein the substituent of the substituted straight-chain or branched-chain C _1-10 alkyl may be -NR _c1 R _c2 , and the substituent of the substituted 3-7 membered heterocycloalkyl is -NR _c1 R _c2 or straight-chain or branched-chain C _1-10 alkyl;

R _c1 and R _c2 are each independently hydrogen, straight or branched chain C _1-10 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are attached form an unsubstituted or substituted 3 to 7 membered heterocycloalkyl; , At this time, the substituent of the substituted 3 to 7 membered heterocycloalkyl may be a straight-chain or branched-chain C _1-10 alkyl;

R ³ , R ⁵ and R ⁶ are each independently hydrogen, halogen, straight-chain or branched-chain C _1-10 alkoxy, or unsubstituted or straight-chain or branched-chain C _1-10 alkyl substituted with one or more halogens;

R ⁴ is —NH ₂ , straight or branched chain C _1-10 alkyl, or C _3-7 cycloalkyl;

R ⁷ and R ⁸ are each independently hydrogen or straight or branched chain C _1-10 alkyl;

n is an integer from 0 to 3;

p and q are each independently an integer of 1 to 3;

In addition, R ¹ is hydrogen, halogen, straight-chain or branched-chain C _1-3 alkyl unsubstituted or substituted with one or more halogens, or straight-chain or branched-chain C _1-6 alkoxycarbonyl;

R ² is -NR _b1 R _b2 ;

R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted straight or branched chain C _1-3 alkyl, or R _b1 and R _b2 together with the nitrogen to which they are bonded are unsubstituted or substituted 5 to 6 membered hetero Forms a cycloalkyl, wherein the substituent of the substituted straight-chain or branched-chain C _1-3 alkyl may be -NR _c1 R _c2 , and the substituent of the substituted 5- to 6-membered heterocycloalkyl is -NR _c1 R _c2 or straight-chain or branched-chain C _1-3 alkyl;

R _c1 and R _c2 are each independently hydrogen, straight or branched chain C _1-3 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are attached form an unsubstituted or substituted 5 to 6 membered heterocycloalkyl; , At this time, the substituent of the substituted 5- to 6-membered heterocycloalkyl may be straight-chain or branched-chain C _1-3 alkyl;

R ³ and R ⁵ are each independently hydrogen or unsubstituted or straight-chain or branched-chain C _1-3 alkyl substituted with one or more halogens;

R ⁴ is —NH ₂ , straight or branched chain C _1-3 alkyl, or C _4-6 cycloalkyl;

R ⁶ is straight or branched C _1-3 alkoxy;

n may be an integer from 1 to 3.

Further, R ¹ is hydrogen, halogen, unsubstituted or straight-chain or branched-chain C _1-2 alkyl substituted with one or more halogens, or straight-chain or branched-chain C _1-3 alkoxycarbonyl;

R ² is -NR _b1 R _b2 ;

R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted C _1-2 alkyl, or R _bi and R _b2 together with the nitrogen to which they are attached form an unsubstituted or substituted 6-membered heterocycloalkyl; In this case, the substituted C _1-2 alkyl substituent may be -NR _c1 R _c2 , and the substituted 6-membered heterocycloalkyl substituent may be -NR _c1 R _c2 or C _1-2 alkyl;

R _c1 and R _c2 are each independently hydrogen, straight-chain or branched-chain C _1-3 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are attached form an unsubstituted or substituted 6-membered heterocycloalkyl, which In this case, the substituent of the substituted 6-membered heterocycloalkyl may be C _1-2 alkyl;

R ³ and R ⁵ are each independently hydrogen or C _1-2 alkyl;

R ⁴ is C _1-2 alkyl;

R ⁶ is methoxy;

R ⁷ and R ⁸ are each independently hydrogen or C _1-2 alkyl;

n is 1 or 2;

p and q may each independently be an integer of 1 to 3.

In addition, R ¹ is methyl, F, Cl, CF ₃ , or ego;

R ² is , , or ego;

R ³ is hydrogen;

R ⁴ is methyl or ethyl;

R ⁵ is hydrogen;

R ⁶ is methoxy;

R ⁷ is hydrogen;

R ⁸ is hydrogen;

n is 1 or 2;

p and q may each independently be an integer of 1 to 3.

The term "heterocycloalkyl", unless otherwise specified, includes monovalent saturated moieties consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. The two or three rings may include bridged, fused or spiro heterocycloalkyls, for example pyridine, pyrazine, pyrimidine, pyridazine, piperazine, piperi It may be din, pyrazole, oxazole, thiazole, or morpholine.

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

<1> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline-7- 1) pyrimidine-2,4-diamine;

<2> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl group) phonyl) indolin-7-yl) pyrimidine-2,4-diamine;

<3> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline-7- 1) pyrimidine-2,4-diamine;

<4> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1,2, 3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;

<5> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl group) phonyl)-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;

<6> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1,2, 3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;

<7> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N4-(1-(methylsulfonyl group) phonyl) indolin-7-yl) pyrimidine-2,4-diamine;

<8> 5-fluoro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methyl sulfonyl) indolin-7-yl) pyrimidine-2,4-diamine;

<9> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indoline -7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;

<10> Isopropyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-( methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate;

<11> methyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-(methyl sulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate;

<12> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino ) pyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one;

<13> 5-chloro-N4-(1-(ethylsulfonyl)indolin-7-yl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)p peridin-1-yl)phenyl)pyrimidine-2,4-diamine;

<14> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)indolin-1-yl)propan-1-one;

<15> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one;

<16> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one; and

<17> 5-chloro-N2-(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indole Lin-7-yl) pyrimidine-2,4-diamine.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. 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 dioate, 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 from Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube rate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, 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 a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An 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. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is 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, stereoisomers, hydrates, and the like prepared therefrom.

The term "hydrate" refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water 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, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present invention from water or a water-containing solvent.

The term “solvate” refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.

The term “isomer” refers to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but differ structurally or sterically. These isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as 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 provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.

At this time, the cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell Cancer, ovarian epithelial cancer, ovarian germ cell cancer, 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 cancer, bladder cancer, peritoneum Cancer, parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer , duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, choriocarcinoma of pregnancy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid carcinoma, vaginal cancer, spinal cord cancer, blue 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, hematological cancer and thymus At least one selected from the group consisting of cancer, and the cancer may be a cancer expressing mutations in at least one selected from the group consisting of EGFR, HER2, ALK, FAK, FLT3, JAK3, KIT, and PLK4 there is.

In addition, the compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof may inhibit epidermal growth factor receptor (EGFR) mutation, wherein the EGFR mutation is EGFR del19, EGFR T790M, or EGFR mutation. It may be one or more selected from the group consisting of C797S, EGFR L858R and EGFR Ex20 insertion mutations, preferably EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/T790M /C797S, EGFR A763_Y764insFHEA, EGFR V769_D770insASV, and EGFR D770_N771insSVD.

In addition, the compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof may inhibit HER2 mutation, wherein the HER2 mutation is one selected from the group consisting of HER2 A775_G776insYVMA, HER2 G776_delinsVC, etc. may be ideal

In addition, the pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, its stereoisomer or its pharmaceutically acceptable salt as an active ingredient is administered as an individual therapeutic agent or administered in combination with other anticancer agents in use. and can be used.

In addition, the pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient can enhance anticancer effects by administering in combination with an anticancer agent.

The compound represented by Formula 1 of the present invention exhibits a relatively weak EGFR activity inhibitory effect on wild-type EGFR, and selectively exhibits high inhibitory activity against EGFR and HER2 mutants, particularly the triple mutant EGFR del19/T790M/C797S or EGFR L858R. /T790M/C797S, EGFR Ex20 insertion mutation, and HER2 mutation show high inhibitory activity.

When the compound represented by Formula 1 of the present invention is administered alone, it can be seen that the cell viability of the Ba/F3 Del19/T790M/C797S cell line in which the EGFR triple mutation occurred is lower than that of conventional drugs, and when administered in combination with existing drugs. When administered alone, it exhibits significantly reduced cell viability compared to single administration, so even when administered alone, it has excellent ability to kill cancer cells against cell lines caused by EGFR triple mutation, EGFR Ex20 insertion mutation, and HER2 mutation, and can be administered in combination with existing drugs In this case, it can be seen that a significantly increased anticancer effect is exhibited.

Therefore, the compound represented by Formula 1 according to the present invention exhibits higher inhibitory activity against EGFR and HER2 mutations than EGFR wild-type, and in particular, exhibits a remarkably good inhibitory effect against EGFR mutations of EGFR L858R/T790M/C797S, and EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C797S, EGFR L858R, EGFR L858R/T790MS, EGFR L858R/T790M/C797S, EGFR A763_Y764insFHEA, EGFR V769_D770insASV, and EGFR D770_N771insSVD useful for the treatment of cancer in which EGFR mutations such as can be used, and in particular, the inhibitory activity against the triple mutation EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S is remarkably excellent, so EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S, EGFR A763_Y764insFHEA, EGFR V769_D770ins ASV and EGFR D770_N771insSVD can also be usefully used for the treatment of expressed cancer.

In addition, by showing a synergistic effect when administered in combination with existing drugs, it can be usefully used in combination with existing drugs.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, 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, for example, starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.

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 performed 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 in water together with a stabilizer or buffer to prepare a solution or suspension, which is prepared in an ampoule or vial unit dosage form can be manufactured with The composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification accelerators, salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and may contain conventional methods such as mixing and granulation. It can be formulated according to the coating or coating method.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , 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 optionally boric acid such as starch, agar, alginic acid or its sodium salt. release or effervescent mixtures and/or absorbents, colorants, flavors, and sweeteners.

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

The cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, 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 of Barter cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, choriocarcinoma of pregnancy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic schwannoma, The group consisting of 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 thymic cancer It may be one or more selected from, and the cancer may be one in which mutations are expressed for EGFR and HER2.

The compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against EGFR and HER2 mutations, and thus can be added to health functional food such as food and beverage as a health functional food composition for preventing or improving 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 foods or food ingredients, and may be appropriately used according to conventional methods. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). Generally, the amount of the compound in the health food may 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 intake for the purpose of health and hygiene or health control, the 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 components except for containing the compound as an essential component in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional components like conventional beverages. there is. Examples of the aforementioned 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 dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be 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 is various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectins acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, the compound represented by Formula 1 of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages.

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

Another aspect of the present invention is a pharmaceutical composition containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, or a health care product. Use of functional food is provided.

The pharmaceutical composition of the present invention is administered in a “pharmaceutically effective amount”. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level is the type and severity of the subject, age, It may be determined according to factors including gender, activity of drug, sensitivity to drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 1000 mg/kg, 0.01 mg/kg to 100 mg/kg or 0.1 to 20 mg/kg or 0.1 to 500 mg/kg are included. The upper limit of the amount of the pharmaceutical composition of the present invention can be selected and implemented by those skilled in the art within an appropriate range.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

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

[Scheme A]

According to Scheme A above, the compounds of Preparation Examples 1 to 3 were obtained.

<Preparation Example 1> Preparation of 1-(methylsulfonyl)-7-nitroindoline

To a stirred solution of 7-nitroindoline (2.0 g, 1.21 mmol) in DMF was added NaH (0.8 g, 3.6 mmol) and mesyl chloride (4.7 ml, 6.0 mmol) at 0 °C. The resulting mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was quenched with cold water. The precipitated solid was filtered, washed with water and dried to give 1-(methylsulfonyl)-7-nitroindoline (87%) as a pure yellow solid.

¹ H NMR (500 MHz, Chloroform- d ) δ 7.79 (d, J = 8.3 Hz, 1 H), 7.57 - 7.48 (m, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 4.29 ( t, J = 7.8 Hz, 2 H), 3.26 (s, 3 H), 3.22 (t, J = 7.8 Hz, 2 H); LCMS: 243.0 [M+H ⁺ ].

<Preparation Example 2> Preparation of 1-(methylsulfonyl)indolin-7-amine

To a stirred solution of 1-(methylsulfonyl)-7-nitroindoline (2.2 g, 9.0 mmol) in methanol was added 10% Pd/C (0.1 g, 0.9 mmol). The resulting mixture was stirred at room temperature under 1 atm hydrogen gas for 4 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 1-(methylsulfonyl)indolin-7-amine (90%) as a brown solid.

¹ H NMR (400 MHz, Chloroform- d ) δ 7.00 (td, J = 7.8, 2.3 Hz, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 6.61 (dd, J = 8.1, 2.3 Hz , 1 H), 4.60 (s, 2 H), 4.11 (t d, J = 7.8, 2.3 Hz, 2 H), 3.03 (t d, J = 7.6, 2.3 Hz, 2 H), 2.87 (s, 3 H); LCMS: 213.0 [M+H ⁺ ].

<Preparation Example 3> Preparation of N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine

To a stirred solution of 1-(methylsulfonyl)indolin-7-amine (500 mg, 2.35 mmol) in n-BuOH (5 ml) was added diisopropylethylamine (1.3 ml, 7.05 mmol) and 2,4 ,5-Trichloropyrimidine (518 mg, 2.82 mmol) was added at room temperature. The reaction mixture was heated to 90 °C for 14 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained material was filtered and washed with n-BuOH to give N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine as an off-white solid.

¹ H NMR (400 MHz, Chloroform- d ) δ 9.35 (s, 1 H), 8.21 (s, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.42 - 7.26 (m, 2 H) , 7.18 (d, J = 7.5 Hz, 1 H), 4.16 (t d, J = 7.5, 2.2 Hz, 2 H), 3.15 (t, J = 7.7 Hz, 2 H), 2.92 (s, 3 H); LCMS: 359.8 [M+H ⁺ ].

[Scheme B]

According to Scheme B above, the compounds of Preparation Examples 4 and 5 were obtained.

<Preparation Example 4> Preparation of (3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine

To a stirred solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.4 mmol) in DMF (150 ml) was added N,N-dimethylpiperidin-4-amine (7.5 g, 58.4 mmol) and cesium carbonate (3.8 g, 116.8 mmol) were added at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with cold water and stirred for 15 minutes. The precipitated solid was filtered and 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine (14.0 g, 85%) was obtained as a yellow solid under reduced pressure.

¹ H NMR (500 MHz, Chloroform- d ) δ 8.01 (d, J = 9.4 Hz, 1 H), 6.44 (dd, J = 9.4, 2.6 Hz, 1 H), 6.33 (d, J = 2.5 Hz, 1 H) H), 3.97 (s, 3 H), 3.97-3.86 (m, 2 H), 3.03 - 2.94 (m, 2 H), 2.50 - 2.36 (m, 1 H), 2.33 (s, 6 H), 2.04 -1.89 (m, 2 H), 1.68 - 1.51 (m, 2 H); LCMS: 279.0 [M+H ⁺ ].

<Preparation Example 5> Preparation of 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine

To a stirred solution of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine (14.0 g, 50.1 mmol) in methanol (150 ml) 10% Pd/C (1.0 g, 10.0 mmol) was added. The resulting mixture was stirred at room temperature under 1 atm hydrogen gas for 4 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to afford 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (11.2 g, 90%) as a brown solid. obtained.

¹ H NMR (500 MHz, Chloroform- d ) δ 6.65 (d, J = 8.3 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.4, 2.5 Hz, 1 H) H), 3.86 (s, 3 H), 3.57 - 3.50 (m, 4 H), 2.67 - 2.60 (m, 2H), 2.34 (s, 6H), 2.89-2.19 (m, 1 H), 1.96 - 1.90 (m, 2H); LCMS: 249.0 [M+H ⁺ ].

[Scheme C]

According to Scheme C above, the compounds of Preparation Examples 6 and 7 were obtained.

<Preparation Example 6> Preparation of N1-(3-methoxy-4-nitrophenyl)-N1,N2,N2-trimethylethane-1,2-diamine

In the same manner as in Preparation Example 4, N1-(3-methoxy-4-nitrophenyl)-N1,N2,N2-trimethylethane-1,2-diamine (84%) was obtained.

¹ H NMR (500 MHz, Chloroform- d ) δ 8.03 (d, J = 9.3 Hz, 1 H), 6.25 (dd, J = 9.4, 2.6 Hz, 1 H), 6.13 (d, J = 2.6 Hz, 1 H) H), 3.96 (s, 3 H), 3.59 - 3.53 (m, 2 H), 3.11 (s, 3 H), 2.53 (t, J = 7.3 Hz, 2 H), 2.32 (s, 6 H); LCMS: 253.0 [M+H ⁺ ].

<Preparation Example 7> Preparation of N1-(2-(dimethylamino)ethyl)-3-methoxy-N1-methylbenzene-1,4-diamine

In the same manner as in Preparation Example 5, N1-(2-(dimethylamino)ethyl)-3-methoxy-N1-methylbenzene-1,4-diamine (96%) was obtained.

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.23 (d, J = 8.7 Hz, 1 H), 6.61 (d, J = 2.6 Hz, 1 H), 6.52 (dd, J = 8.8, 2.7 Hz, 1 H), 4.02 (s, 3 H), 3.84 (t, J = 7.3 Hz, 2 H), 3.43 - 3.35 (m, 5 H), 3.06 (s, 3 H), 2.98 (s, 6 H) ; LCMS: 223.0 [M+H ⁺ ].

[Scheme D]

According to Scheme D above, the compounds of Preparation Examples 8 to 10 were obtained.

<Preparation Example 8> Preparation of 1-(methylsulfonyl)-8-nitro-1,2,3,4-tetrahydroquinoline

In the same manner as in Preparation Example 1, 1-(methylsulfonyl)-8-nitro-1,2,3,4-tetrahydroquinoline (69%) was obtained.

¹ H NMR (400 MHz, Chloroform- d ) δ 7.80 - 7.73 (m, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.25 (dq, J = 7.4, 3.5, 2.5 Hz, 1 H ), 3.72 (s, 2 H), 3.14 (s, 3 H), 2.95 (td, J = 7.3, 2.2 Hz, 2 H), 2.23 (s, 2 H), 1.43 - 1.34 (m, 2 H) ; LCMS: 257.0 [M+H ⁺ ].

<Preparation Example 9> Preparation of 1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-amine

1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-amine (92%) was obtained by performing the same method as in Preparation Example 2.

¹ H NMR (400 MHz, Chloroform- d ) δ 7.03 (td, J = 7.8, 2.2 Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H), 6.59 (d, J = 7.5 Hz, 1 H) H), 4.44 (s, 2 H), 3.73 (s, 2 H), 2.94 (s, 3 H), 2.83 - 2.71 (m, 2 H), 2.17 - 2.00 (m, 2 H); LCMS: 227.0 [M+H ⁺ ].

<Preparation Example 10> Preparation of N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-8-amine

N- (2,5-dichloropyrimidin-4-yl) -1- (methylsulfonyl) -1,2,3,4-tetrahydroquinolin-8-amine (77 %) was obtained.

¹ H NMR (400 MHz, Chloroform- d ) δ 9.05 (s, 1 H), 8.21 (s, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.41 - 7.29 (m, 1 H) , 7.09 (d, J = 7.7 Hz, 1 H), 3.89 - 3.59 (m, 2 H), 2.97 (s, 3 H), 2.89 (t, J = 7.5 Hz, 2 H), 2.18 (d, J = 9.8 Hz, 2H); LCMS: 374.0 [M+H ⁺ ].

The compound of Preparation Example 11 was obtained according to the following reaction scheme.

<Preparation Example 11> Preparation of N-(2-chloro-5-methylpyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine

In the same manner as in Preparation Example 3, N-(2-chloro-5-methylpyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine (29%) was obtained.

¹ H NMR (500 MHz, Chloroform- d ) δ 8.86 (s, 1 H), 8.16 (dd, J = 8.4, 1.1 Hz, 1 H), 8.02 (s, 1 H), 7.35 - 7.27 (m, 1 H), 7.13 (dq, J = 7.4, 1.1 Hz, 1 H), 4.17 (t, J = 7.5 Hz, 2 H), 3.13 (t, J = 7.5 Hz, 2 H), 2.89 (s, 3 H) ), 2.22 (d, J = 0.9 Hz, 3 H); LCMS: 338.8 [M+H ⁺ ].

The compound of Preparation Example 12 was obtained according to the following reaction scheme.

<Preparation Example 12> Preparation of N-(2-chloro-5-fluoropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine

In the same manner as in Preparation Example 3, N-(2-chloro-5-fluoropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine (82%) was obtained.

¹ H NMR (400 MHz, Chloroform- d ) δ 9.28 (s, 1 H), 8.14 (bs, 2 H), 7.31 (d, J = 12.3 Hz, 1 H), 4.18 (t, J = 7.7 Hz, 2 H), 3.15 (t, J = 7.8 Hz, 2 H), 2.91 (s, 3 H); LCMS: 342.0 [M+H ⁺ ].

The compound of Preparation Example 13 was obtained according to the following reaction scheme.

<Preparation Example 13> Preparation of N-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine

N-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine (24%) was prepared in the same manner as in Preparation Example 3. were obtained and separated using HPLC.

¹ H NMR (400 MHz, Chloroform- d ) δ 9.20 (s, 1 H), 8.44 (cs, 1 H), 7.80 (dd, J = 8.2, 1.1 Hz, 1 H), 7.35 - 7.29 (m, 1 H), 7.22 (dq, J = 7.4, 1.1 Hz, 1 H), 4.13 (t, J = 7.5 Hz, 2 H), 3.17 (t, J = 7.4 Hz, 2 H), 2.94 (s, 3 H) ); LCMS: 394.0 [M+H ²⁺ ].

The compound of Preparation Example 14 was obtained according to the following reaction scheme.

<Preparation Example 14> Preparation of isopropyl 2-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate

In the same manner as in Preparation Example 3, isopropyl 2-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate (84%) was obtained.

¹ H NMR (500 MHz, Chloroform- d ) δ 10.71 (s, 1 H), 8.83 (s, 1 H), 7.94 (dd, J = 8.3, 1.0 Hz, 1 H), 7.31 - 7.27 (m, 2 H), 7.18 (dq, J = 7.4, 1.1 Hz, 1 H), 5.41 - 5.29 (m, 1 H), 4.13 (t, J = 7.4 Hz, 2 H), 3.20 - 3.15 (m, 2 H) , 3.00 (s, 3 H), 1.41 (d, J = 6.3 Hz, 6 H); LCMS: 411.8 [M+H ⁺ ].

The compound of Preparation Example 15 was obtained according to the following reaction scheme.

<Preparation Example 15> Preparation of methyl 2-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate

In the same manner as in Preparation Example 3, methyl 2-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate (88%) was obtained.

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.44 (s, 1H), 8.80 (s, 1H), 7.72 (dd, J = 7.3, 2.1 Hz, 1H), 7.31 - 7.24 (m, 2H), 4.05 (t, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.12 (t, J = 7.4 Hz, 2H), 3.07 (s, 3H); LCMS: 383.1 [M+H ⁺ ].

[Scheme E]

According to Scheme E above, the compounds of Preparation Examples 16 to 18 were obtained.

<Preparation Example 16> Preparation of 1-(7-nitroindolin-1-yl)ethane-1one

In the same manner as in Preparation Example 1, 1-(7-nitroindolin-1-yl)ethan-1-one was obtained.

¹ H NMR (300 MHz, Chloroform-d) δ 7.64 (dd, J = 8.2, 1.1 Hz, 1 H), 7.46 - 7.39 (m, 1 H), 7.15 (t, J = 7.8 Hz, 1 H), 4.25 (t, J = 8.1 Hz, 2 H), 3.23 (t, J = 8.0 Hz, 2 H), 2.27 (s 3 H). LCMS: 207.2 [M+H ⁺ ].

<Preparation Example 17> Preparation of 1-(7-aminoindolin-1-yl)-ethan-1-one

To a stirred solution of 1-(methylsulfonyl)-7-nitroindoline (1.0 g, 4.84 mmol) in 20 mL of THF/H ₂ O (1:1) was added iron powder (1.3 g, 24.24 mmol) at room temperature. mmol) and NH ₄ Cl (1.3 g 24.24 mmol) gave 1-(7-aminoindolin-1-yl)-ethan-1-one as a brown solid (90%).

¹ H NMR (400 MHz, Chloroform-d) δ 6.97 (t, J = 7.6 Hz, 1 H), 6.66 (dt, J = 7.3, 1.1 Hz, 1 H), 6.60 (dd, J = 8.1, 1.0 Hz , 1 H), 4.82 (s, 2 H), 4.07 (t, J = 7.8 Hz, 2 H), 3.07 (t, J = 7.7 Hz, 2 H), 2.33 (s, 3 H). LCMS: 177.8 [M+H+].

<Preparation Example 18> Preparation of 1-(7-((2,5-dichloropyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one

1-(7-aminoindolin-1-yl)-ethan-1-one (1.0 g, 5.67 mmol) was prepared in the same manner as in Preparation Example 3 to obtain 1-(7-((2,5 -dichloropyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one was obtained (80%).

¹ H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1 H), 8.38 (s, 1 H), 7.64 - 7.57 (m, 1 H), 7.22 (t, J = 7.7 Hz, 1 H) , 7.15 (dd, J = 7.3, 1.3 Hz, 1 H), 4.16 (t, J = 7.8 Hz, 2 H), 3.11 (t, J = 7.7 Hz, 2 H), 2.32 (s, 3 H). LCMS: 324.8 [M+H ⁺ ].

[Scheme F]

According to Scheme F above, the compounds of Preparation Examples 19 to 21 were obtained.

<Preparation Example 19> Preparation of 1-(ethylsulfonyl)-7-nitroindoline

In the same manner as in Preparation Example 1, 1-(ethylsulfonyl)-7-nitroindoline was prepared (59%).

¹ H NMR (400 MHz, Chloroform- d ) δ 7.78 (dd, J = 8.3, 1.1 Hz, 1 H), 7.49 (dd, J = 7.4, 1.2 Hz, 1 H), 7.21 (dd, J = 8.2, 1 H) 7.4 Hz, 1 H), 4.28 (t, J = 7.7 Hz, 2 H), 3.42 (q, J = 7.4 Hz, 2 H), 3.21 (tt, J = 7.7, 1.0 Hz, 2 H), 1.52 ( t, J = 7.4 Hz, 3 H). LCMS: 257.0 [M+H ⁺ ].

<Preparation Example 20> Preparation of 1-(ethylsulfonyl)indolin-7-amine

In the same manner as in Preparation Example 17, 1-(ethylsulfonyl)indolin-7-amine was prepared (92%).

¹ H NMR (400 MHz, Chloroform- d ) δ 7.01 - 6.89 (m, 1 H), 6.69 (t, J = 8.2 Hz, 1 H), 6.60 (t, J = 8.7 Hz, 1 H), 4.61 ( s, 2 H), 4.20 - 3.93 (m, 2 H), 3.16 - 2.76 (m, 4 H), 1.50 - 1.20 (m, 3 H). LCMS: 227.0 [M+H ⁺ ].

<Preparation Example 21> Preparation of N-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)indolin-7-amine

In the same manner as in Preparation Example 3, N-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)indolin-7-amine was prepared (71%).

¹ H NMR (500 MHz, Chloroform- d ) δ 9.33 (s, 1 H), 8.21 (s, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 7.33 - 7.24 (m, 2 H) , 7.16 (d, J = 7.4 Hz, 1 H), 4.13 (t, J = 7.4 Hz, 2 H), 3.16 (t, J = 7.5 Hz, 2 H), 3.11 (q, J = 7.4 Hz, 2 H) H), 1.50 - 1.40 (m, 3 H). LCMS: 374.0 [M+2H ⁺ ].

[Scheme G]

According to Scheme G above, the compounds of Preparation Examples 22 to 24 were obtained.

<Preparation Example 22> Preparation of 1-(7-nitroindolin-1-yl)propan-1-one

1-(7-nitroindolin-1-yl)propan-1-one was prepared in the same manner as in Preparation Example 1.

¹ H NMR (500 MHz, DMSO-d6) δ 7.66 - 7.56 (m, 2 H), 7.23 (t, J = 7.8 Hz, 1 H), 4.24 (t, J = 8.1 Hz, 2 H), 3.21 ( t, J = 8.2 Hz, 2 H), 2.54 (dd, J = 8.7, 6.2 Hz, 2 H), 1.05 (td, J = 7.4, 2.5 Hz, 3 H). LCMS: 220.0 [M+H ⁺ ].

<Preparation Example 23> Preparation of 1-(7-aminoindolin-1-yl)propan-1-one

1-(7-aminoindolin-1-yl)propan-1-one was prepared in the same manner as in Preparation Example 2.

¹ H NMR (500 MHz, DMSO-d6) δ 6.86 (t, J = 7.6 Hz, 1 H), 6.61 - 6.50 (m, 7.6 Hz, 2 H), 5.42 (s, 2 H), 4.03 (t, J = 7.8 Hz, 2 H), 2.96 (t, J = 7.9 Hz, 2 H), 2.56 (q, J = 7.5 Hz, 2 H), 1.10 (t, J = 7.4 Hz, 3 H). LCMS: 190.2 [M+H ⁺ ].

<Preparation Example 24> Preparation of 1-(7-((2,5-dichloropyrimidin-4-yl)amino)indolin-1-yl)propan-1-one

1-(7-((2,5-dichloropyrimidin-4-yl)amino)indolin-1-yl)propan-1-one was prepared in the same manner as in Preparation Example 3.

¹ H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H), 4.16 (s, 2 H), 3.12 (s, 2 H), 2.64 (d, J = 7.4 Hz, 2 H) , 1.11 (t, J = 7.4 Hz, 3 H). LCMS: 337.8 [M+H ⁺ ].

[Scheme H]

According to Scheme G above, the compounds of Preparation Examples 25 to 27 were obtained.

<Preparation Example 25> Preparation of 1-(8-nitro-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

In the same manner as in Preparation Example 16 using 8-nitro-3,4-dihydroquinoline, 1-(8-nitro-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one manufactured.

1H NMR (500 MHz, DMSO-d6) δ 7.76 - 7.65 (m, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 1 H), 3.82 (s , 2 H), 2.83 (s, 2 H), 2.19 (d, J = 2.2 Hz, 3 H), 1.98 (s, 2 H). LCMS: 220.4 [M+H ⁺ ].

<Preparation Example 26> Preparation of 1-(8-amino-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

1-(8-amino-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one was prepared in the same manner as in Preparation Example 2.

¹ H NMR (500 MHz, DMSO-d6) δ 6.89 (t, J = 7.6 Hz, 1 H), 6.61 (d, J = 7.9 Hz, 1 H), 6.44 (d, J = 7.3 Hz, 1 H) , 5.12 (s, 2 H), 4.63 - 4.48 (m, 2 H), 2.68 - 2.59 (m, 1 H), 2.58 - 2.53 (m, 1 H), 2.33 - 2.26 (m, 1 H), 2.15 - 2.04 (m, 1H), 1.90 (s, 3 H), 1.61 - 1.49 (m, 1 H). LCMS: 190.2 [M+H ⁺ ].

<Preparation Example 27> Preparation of 1-(8-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

In the same manner as in Preparation Example 3, 1-(8-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethane-1- on was produced.

¹ H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1 H), 8.37 (s, 1 H), 7.52 - 7.08 (m, 3 H), 4.31 - 3.98 (m, 2 H), 3.12 - 2.69 (m, 2 H), 2.20 (d, J = 49.1 Hz, 3 H), and 1.91 - 1.53 (m, 2 H). LCMS: 337.8 [M+H ⁺ ].

[Scheme I]

According to the above Scheme I, the compounds of Preparation Examples 28 to 30 were obtained.

<Preparation Example 28> Preparation of 1-(8-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

1-(8-nitro-3,4-dihydroquinolin-1(2H)-yl)propan-1-one was prepared in the same manner as in Preparation Example 1.

¹ H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J = 8.1 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 3.83 (bs, 2 H), 2.82 (s, 2 H), 2.54 (s, 2 H), 2.12 - 1.79 (m, 2 H), 1.01 (t, J = 7.5 Hz, 3 H). LCMS: 234.4 [M+H ⁺ ].

<Preparation Example 29> Preparation of 1-(8-amino-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

1-(8-amino-3,4-dihydroquinolin-1(2H)-yl)propan-1-one was prepared in the same manner as in Preparation Example 2.

¹ H NMR (500 MHz, DMSO-d6) δ 6.89 (t, J = 7.7 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 6.44 (d, J = 7.5 Hz, 1 H) , 5.10 (s, 2 H), 4.68 - 4.55 (m, 2 H), 2.70 - 2.59 (m, 1 H), 2.54 (d, J = 4.9 Hz, 1 H), 2.41 (dq, J = 15.4, 7.6 Hz, 1 H), 2.24 (q, J = 12.2, 11.0 Hz, 1 H), 2.10 (s, 1 H), 2.02 (dt, J = 15.9, 7.6 Hz, 1 H), 1.53 (s, 1 H) H), 1.09 (t, J = 7.5 Hz, 1 H), 0.90 (t, J = 7.5 Hz, 3 H). LCMS: 204.4 [M+H ⁺ ].

<Preparation Example 30> Preparation of 1-(8-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

In the same manner as in Preparation Example 3, 1-(8-((2,5-dichloropyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1- on was produced.

¹ H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1 H), 8.36 (s, 1 H), 7.44 (s, 1 H), 7.33 - 7.09 (m, 2 H), 4.17 (d, J = 78.3 Hz, 2 H), 3.28 (s, 1 H), 2.83 (s, 1 H), 2.74 (s, 1 H), 2.58 (s, 1 H), 2.33 - 1.52 (m, 2 H) , 1.05 (s, 2 H), 0.83 (s, 1 H). LCMS: 351.8 [M+H ⁺ ].

The compound of Example 1 was obtained according to the following reaction scheme.

<Example 1> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline- Preparation of 7-yl) pyrimidine-2,4-diamine

N-(2,5-dichloropyrimidin-4-yl)-1-(methylsulfonyl)indolin-7-amine (100 mg, 0.27 mmol) in 1 N TFA in n-BuOH (3 ml) To the stirred solution was added 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (81.3 mg, 0.27 mmol) at room temperature. The resulting mixture was heated to 90° C. for 14 hours. The reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO ₃ solution followed by water, brine, dried over MgSO ₄ and evaporated under reduced pressure. The obtained material was purified using column chromatography (5-10% methanol in DCM as eluent) to yield 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl as a white solid. )-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine (49%).

¹ H NMR (400 MHz, Chloroform- d ) δ 8.95 (s, 1 H), 8.14 - 8.03 (m, 2 H), 8.04 - 7.98 (m, 1 H), 7.36 - 7.24 (m, 3 H), 7.15 (dd, J = 7.4, 1.2 Hz, 1 H), 6.54 (d, J = 2.6 Hz, 1 H), 6.43 (dd, J = 8.8, 2.6 Hz, 1 H), 4.17 (t, J = 7.5 Hz, 2 H), 3.87 (s, 3 H), 3.66 (d, J = 11.9 Hz, 2 H), 3.16 (t, J = 7.5 Hz, 2 H), 2.94 (s, 3 H), 2.72 ( td, J = 12.3, 2.4 Hz, 2 H), 2.64 - 2.40 (m, 6 H), 2.08 (d, J = 12.3 Hz, 2 H), 1.79 (qd, J = 12.1, 4.1 Hz, 2 H) ; LCMS: 572.8 [M+H ⁺ ].

The compound of Example 2 was obtained according to the following reaction scheme.

<Example 2> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-( Preparation of methylsulfonyl) indolin-7-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4- Obtained (1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine (54%).

¹ H NMR (400 MHz, Chloroform- d ) δ 8.94 (s, 1 H), 8.10 - 7.99 (m, 3 H), 7.33 - 7.23 (m, 3 H), 7.17 - 7.12 (m, 1 H), 6.54 (d, J = 2.5 Hz, 1 H), 6.42 (dd, J = 8.8, 2.5 Hz, 1 H), 4.17 (t, J = 7.5 Hz, 2 H), 3.87 (s, 3 H), 3.65 (d, J = 12.1 Hz, 2 H), 3.15 (t, J = 7.5 Hz, 2 H), 2.94 (s, 3 H), 2.87 - 2.57 (m, 9 H), 2.47 (m, 1 H) , 2.41 (s, 3 H), 1.99 (d, J = 12.1 Hz, 2 H), 1.82 - 1.67 (m, 2 H); LCMS: 627.9 [M+H ⁺ ].

The compound of Example 3 was obtained according to the following reaction scheme.

<Example 3> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline- Preparation of 7-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl) )indolin-7-yl)pyrimidine-2,4-diamine (43%).

¹ H NMR (400 MHz, Chloroform- d ) δ 8.93 (s, 1 H), 8.08 - 8.02 (m, 2 H), 7.97 (d, J = 8.9 Hz, 1 H ), 7.28 - 7.24 (m, 1 H), 7.18 (s, 1 H), 7.15 - 7.10 (m, 1 H), 6.39 (d, J = 2.6 Hz, 1 H), 6.26 (dd, J = 8.9, 2.7 Hz, 1 H), 4.17 (t, J = 7.5 Hz, 2 H), 3.88 (s, 3 H), 3.53 (t, J = 7.5 Hz, 2 H), 3.15 (t, J = 7.4 Hz, 2 H), 2.96 (s, 3 H), 2.94 (s, 3 H), 2.68 - 2.60 (m, 2 H), 2.44 (s, 6 H); LCMS: 546.8 [M+H ⁺ ].

The compound of Example 4 was obtained according to the following reaction scheme.

<Example 4> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1, Preparation of 2,3,4-tetrahydroquinolin-8-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl) )-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine (55%) was obtained.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1 H), 8.06 (s, 1 H), 7.99 (d, J = 8.9 Hz, 1 H), 7.93 (dd, J = 8.2, 1.4 Hz, 1 H), 7.33 - 7.28 (m, 3 H), 7.10 - 7.05 (m, 1 H), 6.54 (d, J = 2.6 Hz, 1 H), 6.39 (dd, J = 8.9, 2.6 Hz, 1 H), 3.86 (s, 3 H), 3.76 - 3.60 (m, 4 H), 3.02 (s, 3 H), 2.89 (t, J = 7.2 Hz, 2 H), 2.71 (td, J = 12.2 , 2.4 Hz, 2 H), 2.50 - 2.37 (m, 6 H), 2.24 - 2.11 (m, 2 H), 2.03 (d, J = 12.5 Hz, 2 H), 1.75 (qd, J = 12.1, 3.9 Hz, 2H); LCMS: 586.9 [M+H ⁺ ].

The compound of Example 5 was obtained according to the following reaction scheme.

<Example 5> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)phenyl)-N4-(1-(methylsulfonyl)-1,2 Preparation of ,3,4-tetrahydroquinolin-8-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)phenyl)-N4-(1-(methylsulfonyl) This gave -1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine (49%).

¹ H NMR (400 MHz, Chloroform- d ) δ 8.46 (s, 1 H), 8.05 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.93 (dd, J = 8.2, 1.4 Hz , 1 H), 7.34 - 7.29 (m, 2 H), 7.08 (dd, J = 7.4, 1.4 Hz, 1 H), 6.53 (d, J = 2.6 Hz, 1 H), 6.38 (dd, J = 8.9 , 2.5 Hz, 1 H), 3.86 (s, 3 H), 3.75 - 3.60 (m, 4 H), 3.02 (s, 3 H), 2.89 (t, J = 7.2 Hz, 2 H), 2.84 - 2.52 (m, 11 H), 2.39 (s, 3 H), 2.23 - 2.11 (m, 2 H), 1.99 (d, J = 12.4 Hz, 2 H), 1.74 (dd, J = 12.0, 3.9 Hz, 2 H); LCMS: 641.0 [M+H ⁺ ].

The compound of Example 6 was obtained according to the following reaction scheme.

<Example 6> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1, Preparation of 2,3,4-tetrahydroquinolin-8-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl) )-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine (34%) was obtained.

¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 (s, 1 H), 8.05 (s, 1 H), 7.97 (dd, J = 8.2, 1.4 Hz, 1 H), 7.92 (d, J = 8.9 Hz , 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.19 (s, 1 H), 7.06 (dd, J = 7.5, 1.4 Hz, 1 H), 6.40 (d, J = 2.6 Hz, 1 H), 6.23 (dd, J = 8.9, 2.6 Hz, 1 H), 3.88 (s, 3 H), 3.77 - 3.64 (bs, 2 H), 3.62 - 3.51 (bs, 2 H), 3.02 (s , 3 H), 2.96 (s, 3 H), 2.89 (t, J = 7.1 Hz, 2 H), 2.69 (s, 2 H), 2.48 (s, 6 H), 2.23 - 2.12 (m, 2 H) ); LCMS: 561.0 [M+H ⁺ ].

The compound of Example 7 was obtained according to the following reaction scheme.

<Example 7> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N4-(1-( Preparation of methylsulfonyl) indolin-7-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N4- Obtained (1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine (54%).

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 7.76 (d, J = 8.0 Hz, 1 H), 7.67 (s, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.37 - 7.32 (m, 1 H), 7.29 (t, J = 7.7 Hz, 1 H), 6.83 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 8.8, 2.5 Hz, 1 H), 4.12 (t , J = 7.6 Hz, 2 H), 3.88 (s, 3 H), 3.83 (d, J = 2.5 Hz, 2 H) 3.27 - 3.06 (m, 6 H), 2.96 (m, 6 H), 2.88 ( s, 3 H), 2.57 - 2.52 (m, 5 H) 2.21 (s, 3 H), 2.14 (d, J = 12.6 Hz, 2 H), 1.91 - 1.71 (m, 2 H); LCMS: 606.9 [M+H ⁺ ].

The compound of Example 8 was obtained according to the following reaction scheme.

<Example 8> 5-Fluoro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-N4-(1-(methyl) Preparation of sulfonyl) indolin-7-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-fluoro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-N4-( Obtained 1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine (45%).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.92 (d, J = 2.5 Hz, 1 H), 8.06 (d, J = 3.3 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H) ), 7.69 (s, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.22 - 7.12 (m, 2 H), 6.61 (d, J = 2.5 Hz, 1 H), 6.42 (dd, J = 8.8, 2.5 Hz, 1 H), 4.07 (t, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 3.68 (d, J = 12.1 Hz, 2 H), 3.12 (t, J = 7.5 Hz, 2 H), 3.05 (s, 3 H), 2.64 (td, J = 12.2, 2.4 Hz, 2 H), 2.57 - 2.52 (m, 4 H), 2.46 - 2.27 (m, 4 H) 2.20 (s, 3 H), 1.86 (d, J = 12.5 Hz, 2 H), 1.52 (dt, J = 13.3, 9.6 Hz, 2 H); LCMS: 610.8 [M+H ⁺ ].

The compound of Example 9 was obtained according to the following reaction scheme.

<Example 9> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl) Preparation of indolin-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-( Obtained methylsulfonyl)indolin-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (48%).

¹ H NMR (400 MHz, Methanol- d ₄ ) δ 8.35 (s, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 7.9 Hz, 1 H), 7.37 (dd , J = 7.4, 1.4 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 6.99 (d, J = 2.5 Hz, 1 H), 6.72 (dd, J = 8.8, 2.5 Hz, 1 H), 4.10 (t, J = 7.6 Hz, 2 H), 3.93 (s, 3 H), 3.82 (d, J = 12.5 Hz, 2 H), 3.45 - 3.33 (m, 3 H), 3.26 (d , J = 12.0 Hz, 3 H), 3.24 - 3.08 (m, 6 H), 2.98 (s, 3 H), 2.92 (s, 3 H), 2.57 - 2.52 (m, 4 H), 2.20 (d, J = 13.0 Hz, 2 H), 2.06 - 1.89 (m, 2 H); LCMS: 661.0 [M+H ⁺ ].

The compound of Example 10 was obtained according to the following reaction scheme.

<Example 10> Isopropyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1 Preparation of -(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate

In the same manner as in Example 1, isopropyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4 Obtained -((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate (52%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, 1 H), 8.60 (d, J = 9.5 Hz, 2 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.16 - 6.93 (m, 2 H), 6.62 (d, J = 2.5 Hz, 1 H), 6.43 (dd, J = 8.9, 2.5 Hz, 1 H), 5.18 - 5.06 (m, 1 H), 4.00 (t, J = 7.1 Hz, 2 H), 3.75 (s, 5 H), 3.12 - 3.01 (m, 5 H), 2.76 - 2.62 (m, 2 H), 2.57 - 2.52 (m, 4 H), 2.42 - 2.23 ( m, 5 H), 2.15 (s, 3 H), 1.91 - 1.80 (m, 2 H), 1.58 - 1.45 (m, 2 H), 1.32 (d, J = 6.2 Hz, 6 H); LCMS: 679.0 [M+H ⁺ ].

The compound of Example 11 was obtained according to the following reaction scheme.

<Example 11> Methyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1- Preparation of (methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate

In the same manner as in Example 1, methyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4- Obtained ((1-(methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate (44%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1 H), 8.62 (d, J = 10.4 Hz, 2 H), 7.87 (s, 1 H), 7.31 (d, J = 8.6 Hz , 1 H), 7.12 - 6.93 (m, 2 H), 6.61 (d, J = 2.5 Hz, 1 H), 6.50 - 6.38 (m, 1 H), 4.00 (t, J = 7.2 Hz, 2 H) , 3.82 (s, 3 H), 3.78 - 3.68 (m, 5 H), 3.13 - 3.02 (m, 5 H), 2.69 (t, J = 11.7 Hz, 2 H), 2.57 - 2.52 (m, 4 H) ), 2.41 - 2.24 (m, 5 H), 2.15 (s, 3 H), 1.86 (d, J = 12.2 Hz, 2 H), 1.64 - 1.42 (m, 2 H); LCMS: 651.0 [M+H ⁺ ].

The compound of Example 12 was obtained according to the following reaction scheme.

<Example 12> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl Preparation of )amino) pyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one

In the same manner as in Example 1, 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one.

¹ H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1 H), 8.03 (s, 1 H), 7.74 - 7.63 (m, 2 H), 7.54 (d, J = 8.7 Hz, 1 H) , 7.13 (t, J = 7.7 Hz, 1 H), 7.06 (d, J = 7.2 Hz, 1 H), 6.58 (d, J = 2.5 Hz, 1 H), 6.37 (dd, J = 8.8, 2.5 Hz) , 1 H), 4.13 (t, J = 7.7 Hz, 2 H), 3.77 (s, 3 H), 3.67 (d, J = 12.2 Hz, 2 H), 3.07 (t, J = 7.7 Hz, 2 H) ), 2.63 (t, J = 11.9 Hz, 2 H), 2.31 (s, 8 H), 2.14 (s, 3 H), 1.84 (d, J = 12.3 Hz, 2 H), 1.51 (tt, J = 12.7, 6.4 Hz, 2H).

The compound of Example 13 was obtained according to the following reaction scheme.

<Example 13> 5-chloro-N4-(1-(ethylsulfonyl)indolin-7-yl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl) Preparation of )piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

In the same manner as in Example 1, 5-chloro-N4-(1-(ethylsulfonyl)indolin-7-yl)-N2-(2-methoxy-4-(4-(4-methylpiperazine) -1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine was obtained.

¹ H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1 H), 8.08 (s, 1 H), 7.86 (s, 1 H), 7.82 (t, J = 4.7 Hz, 1 H), 7.44 (d, J = 8.7 Hz, 1 H), 7.19 - 7.10 (m, 2 H), 6.59 (d, J = 2.4 Hz, 1 H), 6.38 (dd, J = 8.7, 2.4 Hz, 1 H), 4.03 (t, J = 7.4 Hz, 2 H), 3.76 (s, 3 H), 3.68 (d, J = 12.3 Hz, 2 H), 3.27 (t, J = 7.3 Hz, 2 H), 3.09 (t , J = 7.4 Hz, 2 H), 2.64 (t, J = 11.7 Hz, 2 H), 2.49 (s, 5 H) 2.30 (t, J = 11.6 Hz, 4 H), 2.15 (s, 3 H) , 1.84 (d, J = 11.8 Hz, 2 H), 1.51 (tt, J = 13.6, 6.9 Hz, 2 H), 1.20 (t, J = 7.3 Hz, 3 H).

The compound of Example 14 was obtained according to the following reaction scheme.

<Example 14> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl Preparation of )amino)pyrimidin-4-yl)amino)indolin-1-yl)propan-1-one

In the same manner as in Example 1, 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)indolin-1-yl)propan-1-one was prepared.

1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1 H), 8.31 (s, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.72 (s, 1 H), 7.43 (d, J = 7.3 Hz, 1 H), 7.38 (d, J = 7.5 Hz, 1 H), 6.89 (d, J = 2.7 Hz, 1 H), 6.70 (dd, J = 8.7, 2.8 Hz, 1 H), 4.45 (t, J = 7.9 Hz, 2 H), 4.10 (s, 3 H), 3.95 (d, J = 12.3 Hz, 2 H), 3.41 (t, J = 7.8 Hz, 2 H), 3.05 - 2.97 (m, 2 H), 2.93 (q, J = 7.3 Hz, 2 H), 2.85 (d, J = 4.7 Hz, 4 H), 2.68 (t , J = 4.8 Hz, 4 H), 2.55 (s, 3 H) 2.17 (d, J = 11.8 Hz, 2 H), 1.93 - 1.80 (m, 2 H), 1.74 (q, J = 6.9 Hz, 1 H), 1.65 (q, J = 7.4 Hz, 1 H), 1.47 (t, J = 7.3 Hz, 3 H).

The compound of Example 15 was obtained according to the following reaction scheme.

<Example 15> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl Preparation of )amino)pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one

In the same manner as in Example 1, 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one was prepared.

¹ H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.43 (s, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.57 (d, J = 2.6 Hz, 1 H), 6.34 (d, J = 8.4 Hz, 1 H), 3.79 (s, 3H), 3.64 (d, J = 12.1 Hz, 2 H), 2.81 - 2.62 (m, 4 H), 2.57 - 2.52 (m, 4 H), 2.51 - 2.42 ( m, 4 H), 2.39 - 2.26 (m, 5 H), 2.18 (s, 5 H), 1.95 (s, 2 H), 1.86 (d, J = 12.9 Hz, 2 H), 1.63 - 1.46 (m , 2H).

The compound of Example 16 was obtained according to the following reaction scheme.

<Example 16> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl Preparation of )amino)pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one

In the same manner as in Example 1, 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one was prepared.

¹ H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 7.7 Hz, 1 H), 7.92 (s, 1 H), 7.64 - 7.57 (m, 1 H), 7.55 - 7.48 (m, 1 H), 7.40 (d, J = 9.1 Hz, 1 H), 7.24 - 7.13 (m, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 6.55 (d, J = 8.6 Hz, 1 H) ), 6.32 (d, J = 8.9 Hz, 1 H), 3.78 (s, 3 H), 3.62 (s, 2 H), 2.68 (t, J = 11.1 Hz, 4 H), 2.37 - 2.26 (m, 6 H), 2.17 (s, 3 H), 1.92 (s, 2 H), 1.85 (d, J = 11.7 Hz, 2 H), 1.54 (t, J = 11.6 Hz, 2 H), 1.13 - 0.98 ( m, 3 H).

The compound of Example 17 was obtained according to the following reaction scheme.

<Example 17> 5-chloro-N2-(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl) ) Preparation of indolin-7-yl) pyrimidine-2,4-diamine

In the same manner as in Example 1, the intermediate compound tert-butyl 4-(1-(4-((5-chloro-4-((1-(methylsulfonyl)indolin-7-yl)amino)pyridine Prepared midin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. Then, the target compound 5-chloro-N2-(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl) was obtained by deprotection using 4N HCl. Phenyl)-N4-(1-(methylsulfonyl)indolin-7-yl)pyrimidine-2,4-diamine was prepared.

¹ H NMR (500 MHz, Methanol-d4) δ 8.10 (s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 6.88 (s, 1 H), 6.67 (d, J = 8.7 Hz, 1 H), 4.13 (t, J = 7.6 Hz) , 2 H), 3.94 - 3.84 (m, 5H), 3.56 (d, J = 5.1 Hz, 4 H), 3.50 (s, 4 H), 3.37 (m, 1 H), 3.20 (t, J = 7.5 Hz, 2 H), 3.09 (t, J = 12.5 Hz, 2 H), 2.98 (s, 3 H), 2.28 (d, J = 12.3 Hz, 2 H), 2.05 - 1.95 (m, 2 H).

Table 1 below summarizes the structural formulas of the prepared ring compounds in Examples 1-17.

Example chemical structure Example chemical structure One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

<Experimental Example 1> Measurement of inhibitory ability of the compound represented by Formula 1 according to the present invention against wild-type EGFR and EGFR mutation

In order to confirm the inhibitory ability of the compound represented by Formula 1 according to the present invention against various EGFR mutations according to the present invention, the following experiments were performed. The results are shown in Table 2 below.

The activity of the EGFR mutant enzyme for the compound of the present invention was measured using the HTRF system sold by Cisbio as follows. For the EGFR del19/T790M mutant enzyme, a recombinant protein provided by Carna Biosciences was purchased and used, and for the EGFR del19/T790M/C797S mutant enzyme, a protein provided by SignalChem was purchased and used as an enzyme source.

The composition of the assay buffer used for activity measurement was 50 mM Tris-HCl pH 7.5, 100 mM NaCl, 7.5 mM MgCl ₂ , 3 mM KCl, 0.01% Tween 20, 0.1% BSA, and 1 mM DTT. Here, an enzyme reaction was performed using a peptide substrate labeled with 50 mM ATP and 0.5 mM biotin. Analysis of the compound's inhibitory effect on EGFR activity was performed according to the following analysis reaction recipe.

Component 1: 4 ml of EGFR mutant enzyme

Component 2: 2 ml of compound solution

Component 3: 4 ml ATP and biotin-labeled peptide

The enzymatic reaction starts by mixing component 1 and component 2 first and then adding component 3. After reacting for 2 hours at 37 ° C, 10 ml of a measurement solution consisting of streptavidin-XL665 and europium-labeled anti-phosphotyrosine antibody provided by Cisbio is added to the enzyme reaction solution and reacted at room temperature for 1 hour. Finally, using Perkin-Elmer's Envision equipment, the ratio of the fluorescence values at 615 nm and 665 nm is obtained to quantitatively measure the enzyme activity and confirm the inhibitory ability of the compound. Measurement values measured at 7 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of compound inhibitory ability, were calculated.

Example EGFR del19/T790M IC ₅₀ (μM) EGFR del19/T790M/C797S IC ₅₀ (μM) One <0.001 <0.001 2 <0.001 <0.001 3 <0.001 <0.001 4 <0.001 <0.001 5 <0.001 <0.001 6 0.001 <0.001 7 <0.001 <0.001 8 <0.001 <0.001 9 <0.001 <0.001 10 0.06 0.05 11 0.002 0.005 12 <0.001 <0.001 13 <0.001 <0.001 14 0.091 0.050 15 0.073 0.056 16 0.170 0.150 17 <0.001 <0.001

As shown in Table 2 above,

It can be seen that the compounds of the examples of the present invention exhibit high inhibitory activity against EGFR del19/T790M and EGFR del19/T790M/C797S, which are EGFR double and triple mutants.

Therefore, the compound represented by Formula 1 of the present invention has an excellent effect of inhibiting EGFR del19/T790M and EGFR del19/T790M/C797S, which are double and triple mutations of EGFR, and thus is useful for the treatment of cancer, a disease associated with EGFR mutation. It can be used, and in particular, it can be usefully used for the treatment of cancer in which EGFR del19/T790M/C797S is expressed.

<Experimental Example 2> Measurement of inhibitory ability of the compound represented by Formula 1 according to the present invention against EGFR mutation in Ba/F3 cell line

In order to confirm the ability of the compound represented by Formula 1 according to the present invention to inhibit EGFR mutation in the Ba/F3 cell line, the following experiment was performed. The results are shown in Table 3 below.

The activity of the mutant Ba/F3 EGFR cell line for the compound of the present invention was measured using the CellTiter-Glo system sold by Promega, as follows. CellTiter-Glo assay is a method to check cell viability by measuring ATP present in cells in cell culture. Ba/F3 EGFR del19, Ba/F3 EGFR del19/T790M, and Ba/F3 del19/T790M/C797S mutant cell lines were purchased from Crown Bioscience and used. Ba/F3 EGFR del19, Ba/F3 EGFR del19/T790M, and Ba/F3 del19/T790M/C797S mutant cell lines were cultured in RPMI containing 10% FBS and 1% penicillin-streptomycin by adding 1 ug of puromycine at 37°C and 5% CO ₂ cultured in an incubator.

EGFR inhibitory effect of the compound was analyzed according to the following analysis reaction recipe.

2500 cells/ 90ul was cultured by passage in a 96 well cell culture plate, and after 24 hours, the compound represented by Formula 1 was treated with 0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 (μM). After reacting for 72 hours, the plate treated with the compound was left at room temperature for 30 minutes, then 100 μl of the reagent was further treated and shaken at room temperature for 10 minutes. Finally, the ratio of the fluorescence value at 570 nm is obtained and quantitatively measured using equipment, and the inhibitory ability of the compound is confirmed. Measurement values measured at 8 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of compound inhibitory ability, were calculated.

Example Ba/F3 EGFR del19
IC ₅₀ (μM) Ba/F3 EGFR del19/T790M
IC ₅₀ (μM) Ba/F3 EGFR del19/T790M/C797S
IC ₅₀ (μM) One <0.030 <0.030 <0.100 2 <0.030 <0.100 <0.100 3 <0.100 <0.100 >0.100 4 <0.030 <0.030 <0.030 5 <0.030 <0.030 <0.030 6 <0.100 <0.100 >0.100 7 <0.030 <0.100 >0.100 8 <0.100 >0.100 >0.100 9 <0.030 <0.030 >0.100 10 >0.100 >0.100 >0.100 11 <0.100 >0.100 >0.100 12 <0.100 >0.100 >0.100 13 <0.100 >0.100 >0.100 14 <0.100 >0.100 >0.100 15 >0.100 >0.100 >0.100 16 >0.100 >0.100 >0.100 17 <0.100 <0.100 >0.100

As shown in Table 3,

It was confirmed that the exemplary compounds according to the present invention exhibit high inhibitory activity against various EGFR mutations including the triple mutation EGFR del19/T790M/C797S.

<Experimental Example 3> Measurement of inhibitory ability of the compound represented by Formula 1 according to the present invention against EGFR mutation in Ba/F3 cell line 2

In order to confirm the ability of the compound represented by Formula 1 according to the present invention to inhibit EGFR mutation in the Ba/F3 cell line, the following experiments were additionally performed. The results are shown in Table 4 below.

The activity of the mutant Ba/F3 EGFR cell line for the compound of the present invention was measured using the CellTiter-Glo system sold by Promega, as follows. CellTiter-Glo assay is a method to check cell viability by measuring ATP present in cells in cell culture. Ba/F3 EGFR L858R, Ba/F3 EGFR L858R/T790M, and Ba/F3 EGFR L858R/T790M/C797S mutant cell lines were used. Ba/F3 EGFR L858R, Ba/F3 EGFR L858R/T790M, and Ba/F3 EGFR L858R/T790M/C797S mutant cell lines were cultured in RPMI containing 10% FBS and 1% penicillin-streptomycin with 1 μg of puromycine added to them at 37°C, 5% Cultured in a CO ₂ incubator.

EGFR inhibitory effect of the compound was analyzed according to the following analysis reaction recipe.

2500 cells/ 90ul was cultured by passage in a 96 well cell culture plate, and after 24 hours, the compound represented by Formula 1 was treated with 0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 (μM). After reacting for 72 hours, the plate treated with the compound was left at room temperature for 30 minutes, then 100 μl of the reagent was further treated and shaken at room temperature for 10 minutes. Finally, the ratio of the fluorescence value at 570 nm is obtained and quantitatively measured using equipment, and the inhibitory ability of the compound is confirmed. Measurement values measured at 8 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of compound inhibitory ability, were calculated.

Example Ba/F3 EGFR L858R
IC ₅₀ (μM) Ba/F3 EGFR L858R/T790M
IC ₅₀ (μM) Ba/F3 EGFR L858R/T790M/C797S
IC ₅₀ (μM) One <0.030 <0.030 <0.100 2 <0.030 <0.030 <0.100 3 >0.100 >0.100 na 4 <0.100 <0.100 na 5 <0.030 <0.030 na 6 >0.100 <0.100 na 7 <0.030 <0.100 >0.100 8 <0.030 <0.100 >0.100 9 <0.100 <0.030 >0.100 10 <0.100 >0.100 >0.100 11 <0.100 <0.100 >0.100 12 >0.100 >0.100 >0.100 13 >0.100 >0.100 >0.100 14 >0.100 >0.100 >0.100 15 >0.100 >0.100 >0.100 16 >0.100 >0.100 >0.100 17 <0.100 >0.100 >0.100

As shown in Table 4,

It was confirmed that the example compounds according to the present invention exhibit high inhibitory activity against various EGFR mutations including the triple mutation Ba/F3 EGFR L858R/T790M/C797S.

Therefore, since the compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against EGFR mutations, EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C797S, EGFR L858R, EGFR L858R/T790MS, EGFR L858R/ It can be usefully used for the treatment of cancer in which EGFR mutations such as T790M/C797S are expressed, and in particular, the inhibitory activity against the triple mutation EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S is remarkably excellent, so EGFR del19/T790M /C797S or EGFR L858R/T790M/C797S can also be usefully used for the treatment of cancer.

In addition, by showing a synergistic effect when administered in combination with existing drugs, it can be usefully used in combination with existing drugs.

<Experimental Example 4> Measurement of inhibitory ability of the compound represented by Formula 1 according to the present invention against EGFR Ex20 insertion mutant enzyme

In order to confirm the inhibitory ability of the compound represented by Formula 1 according to the present invention against the EGFR Ex20 insertion mutant enzyme, the following experiment was performed. The results are shown in Table 5 below.

The activity of the EGFR mutant enzyme for the compound of the present invention was measured using the HTRF system sold by Cisbio as follows. As the EGFR mutant enzyme, the EGFR A763_Y764insFHEA enzyme was purchased and used as a recombinant protein provided by SignalChem.

The composition of the assay buffer used for activity measurement was 50 mM Tris-HCl pH 7.5, 100 mM NaCl, 7.5 mM MgCl ₂ , 3 mM KCl, 0.01% Tween 20, 0.1% BSA, and 1 mM DTT. Here, an enzyme reaction was performed using a peptide substrate labeled with 50 mM ATP and 0.5 mM biotin. Analysis of the compound's inhibitory effect on EGFR activity was performed according to the following analysis reaction recipe.

Component 1: 4 uL of EGFR mutant enzyme

Component 2: 2 uL of compound solution

Component 3: 4 uL ATP and biotin-labeled peptide

The enzymatic reaction starts by mixing component 1 and component 2 first and then adding component 3. After reacting for 2 hours at 37℃, 10 mL of a measurement solution consisting of streptavidin-XL665 and europium-labeled anti-phosphotyrosine antibody provided by Cisbio is added to the enzyme reaction solution and reacted at room temperature for 1 hour. Finally, using Perkin-Elmer's Envision equipment, the ratio of the fluorescence values at 615 nm and 665 nm is obtained to quantitatively measure the enzyme activity and confirm the inhibitory ability of the compound. Measurement values measured at 7 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of compound inhibitory ability, were calculated.

Example EGFR A763_Y764insFHEA IC ₅₀ (μM) 2 0.0017 5 0.011 12 0.178 13 0.091 14 > 0.1 15 > 0.1 16 > 0.1 17 0.020

As shown in Table 5,

It was confirmed that the Example compounds according to the present invention exhibit high inhibitory activity against the EGFR A763_Y764insFHEA mutation, which is an EGFR Ex20 insertion mutation.

<Experimental Example 5> Measurement of Ba/F3 EGFR Ex20 insertion mutant cell growth inhibition ability of the compound represented by Formula 1 according to the present invention

In order to confirm the ability of the compound represented by Formula 1 according to the present invention to inhibit the growth of Ba/F3 EGFR Ex20 insertion mutant cells, the following experiment was performed. The results are shown in Table 6 below.

The activity of the compound of the present invention against the mutant cell line of Ba/F3 EGFR V769_D770insASV was measured using the CellTiter-Glo system sold by Promega as follows. CellTiter-Glo assay is a method to check cell viability by measuring ATP present in cells in cell culture. The Ba/F3 EGFR V769_D770insASV mutant cell line was purchased and used from Crown Bioscience. The Ba/F3 EGFR V769_D770insASV mutant cell line was cultured in RPMI containing 10% FBS and 1% penicillin-streptomycin with 1ug/ml of puromycine added to it in a 37°C, 5% CO ₂ incubator.

Analysis of the compound's ability to inhibit EGFR mutant cell growth was performed according to the following analysis reaction recipe.

1000 cells/ 100 μL was subcultured in a 96 well cell culture plate and cultured, and after 24 hours, the compound represented by Formula 1 was treated with 0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 (μM). After reacting for 72 hours, the plate treated with the compound was left at room temperature for 30 minutes, and then 100 μL of the reagent was further treated and shaken at room temperature for 10 minutes. Finally, using the equipment, the ratio of fluorescence values at 570 nm is obtained and quantitatively measured, and the cell growth inhibitory ability of the compound is confirmed. Measurement values measured at 8 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of the compound's ability to inhibit cell growth, were calculated.

Example Ba/F3 EGFR V769_D770insASV IC ₅₀ (μM) 2 0.21 5 0.36 12 >0.100 13 >0.100 14 >0.100 15 >0.100 16 >0.100 17 >0.100

As shown in Table 6,

It was confirmed that the Example compounds according to the present invention exhibit high inhibitory activity against the growth of Ba/F3 EGFR V769_D770insASV mutant cells.

<Experimental Example 6> Measurement of inhibitory ability of the compound represented by Formula 1 according to the present invention against HER2 mutation

In order to confirm the ability of the compound represented by Formula 1 according to the present invention to inhibit HER2 mutation, the following experiment was performed. The results are shown in Table 7 below.

The activity of the HER mutant enzyme for the compound of the present invention was measured using the HTRF system sold by Cisbio as follows. As the HER2 mutant enzyme, the HER2 A775_G776insYVMA mutant enzyme was purchased and used as a recombinant protein provided by Carna Biosciences.

The composition of the assay buffer used for activity measurement was 50 mM Tris-HCl pH 7.5, 100 mM NaCl, 7.5 mM MgCl ₂ , 3 mM KCl, 0.01% Tween 20, 0.1% BSA, and 1 mM DTT. Here, an enzyme reaction was performed using a peptide substrate labeled with 50 mM ATP and 0.5 mM biotin. Analysis of the activity inhibitory effect of the compound on the HER2 A775_G776insYVMA mutation was performed according to the following analysis reaction recipe.

Component 1: 4 uL of HER2 A775_G776insYVMA mutant enzyme

Component 2: 2 uL of compound solution

Component 3: 4 uL ATP and biotin-labeled peptide

The enzymatic reaction starts by mixing component 1 and component 2 first and then adding component 3. After reacting for 2 hours at 37℃, 10 mL of a measurement solution consisting of streptavidin-XL665 and europium-labeled anti-phosphotyrosine antibody provided by Cisbio is added to the enzyme reaction solution and reacted at room temperature for 1 hour. Finally, using Perkin-Elmer's Envision equipment, the ratio of the fluorescence values at 615 nm and 665 nm is obtained to quantitatively measure the enzyme activity and confirm the inhibitory ability of the compound. Measurement values measured at 7 compound concentrations were analyzed using the Prism program (Version 5.01, Graphpad Software, Inc.), and IC ₅₀ values, which are indicators of compound inhibitory ability, were calculated.

Example HER2 A775_G776insYVMA IC ₅₀ (μM) 2 0.001 5 0.003 12 0.025 13 0.026 14 > 0.1 15 0.589 16 > 0.1 17 0.004

As shown in Table 7,

It was confirmed that the Example compounds according to the present invention exhibit high inhibitory activity against the HER2 A775_G776insYVMA mutation. Therefore, since the compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against EGFR mutations, EGFR del19/T790M, EGFR del19/T790M/C797S and EGFR A763_Y764insFHEA, Ba/F3 EGFR del19, Ba/F3 EGFR del19 /T790M, Ba/F3 EGFR del19/T790M/C797S, Ba/F3 EGFR L858R, Ba/F3 EGFR L858R/T790M, Ba/F3 EGFR L858R/T790M/C797S, Ba/F3 EGFR A763_Y764insFHEA, Ba/F3 EGFR V769_D770insASV and Ba /F3 EGFR D770_N771insSVD can be usefully used for the treatment of cancers in which EGFR mutations are expressed.

In addition, since the compound represented by Formula 1 according to the present invention exhibits high inhibitory activity against HER2 mutations, it is also useful for the treatment of cancers in which HER2 mutations such as HER2 A775_G776insYVMA, Ba/F3 HER2 A775_G776insYVMA, and Ba/F3 HER2 G776_delinsVC are expressed. can be used

From the above results, it can be seen that the pyrimidine-2,4-diamine derivative compound according to the present invention can effectively inhibit EGFR and HER2 mutations, and thus can be usefully used as a pharmaceutical composition for preventing or treating cancer. .

Claims (12)

A compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
X is sulfonyl or carbonyl;
R ¹ is hydrogen, halogen, nitrile, unsubstituted or straight or branched C _1-10 alkyl substituted with one or more halogens, carboxyl, or straight or branched C _1-10 alkoxycarbonyl;
R ² is -NR _b1 R _b2 ;
R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted straight-chain or branched-chain C _1-10 alkyl, or R _b1 and R _b2 together with the nitrogen to which they are bonded represent an unsubstituted or substituted nitrogen atom of 1 to 2 Forms a 3 to 7-membered heterocycloalkyl containing 2, and at this time, the substituent of the substituted straight-chain or branched-chain C _1-10 alkyl may be -NR _c1 R _c2 , and is a substituted 3 to 7-membered heterocycloalkyl. Substituents of alkyl may be -NR _c1 R _c2 or straight-chain or branched-chain C _1-10 alkyl;
R _c1 and R _c2 are each independently hydrogen, straight or branched chain C _1-10 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are bonded are 3 to 2 containing 1 to 2 unsubstituted or substituted nitrogen atoms. form a 7-membered heterocycloalkyl, wherein the substituent of the substituted 3 to 7-membered heterocycloalkyl may be straight-chain or branched-chain C _1-10 alkyl;
R ³ and R ⁵ are each independently hydrogen, halogen, straight-chain or branched-chain C _1-10 alkoxy, or unsubstituted or straight-chain or branched-chain C _1-10 alkyl substituted with one or more halogens;
R ⁴ is straight or branched C _1-10 alkyl;
R ⁶ is straight or branched C _1-10 alkoxy;
R ⁷ and R ⁸ are each independently hydrogen or straight or branched chain C _1-10 alkyl;
n is 1 or 2;
p and q are each independently an integer of 1 to 3;
According to claim 1,
R ¹ is hydrogen, halogen, straight or branched C _1-3 alkyl unsubstituted or substituted with one or more halogens, or straight or branched C _1-3 alkoxycarbonyl;
R ² is -NR _b1 R _b2 ;
R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted straight-chain or branched-chain C _1-3 alkyl, or R _b1 and R _b2 together with the nitrogen to which they are bonded contain one unsubstituted or substituted nitrogen atom Forms a 5- to 6-membered heterocycloalkyl, and at this time, the substituent of the substituted straight-chain or branched-chain C _1-3 alkyl may be -NR _c1 R _c2 , and the substituted 5 to 6-membered heterocycloalkyl The substituent may be -NR _c1 R _c2 or straight or branched chain C _1-3 alkyl;
R _c1 and R _c2 are each independently hydrogen, straight-chain or branched-chain C _1-3 alkyl, or R _c1 and R _c2 are 5 to 6 containing 1 to 2 unsubstituted or substituted nitrogen atoms with the nitrogen to which they are bonded. form a heterocycloalkyl of atoms, wherein the substituent of the substituted 5 to 6 membered heterocycloalkyl may be straight-chain or branched-chain C _1-3 alkyl;
R ³ and R ⁵ are each independently hydrogen or unsubstituted or straight-chain or branched-chain C _1-3 alkyl substituted with one or more halogens;
R ⁴ is straight-chain or branched-chain C _1-3 alkyl;
R ⁶ is straight or branched C _1-3 alkoxy;
Characterized in that n is 1 or 2,
A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ¹ is hydrogen, halogen, C _1-2 alkyl unsubstituted or substituted with one or more halogens, or C _1-3 alkoxycarbonyl;
R ² is -NR _b1 R _b2 ;
R _b1 and R _b2 are each independently hydrogen, unsubstituted or substituted C _1-2 alkyl, or R _b1 and R _b2 are 6-membered atoms containing one unsubstituted or substituted nitrogen atom together with the nitrogen to which they are bonded. Forms heterocycloalkyl, wherein the substituent of substituted C _1-2 alkyl may be -NR _c1 R _c2 , and the substituent of substituted 6-membered heterocycloalkyl is -NR _c1 R _c2 or C _1-2 can be alkyl;
R _c1 and R _c2 are each independently hydrogen, C _1-2 alkyl, or R _c1 and R _c2 together with the nitrogen to which they are attached form a 6-membered heterocycloalkyl containing two unsubstituted or substituted nitrogen atoms. And, at this time, the substituent of the substituted 6-membered heterocycloalkyl may be C _1-2 alkyl;
R ³ and R ⁵ are each independently hydrogen or C _1-2 alkyl;
R ⁴ is C _1-2 alkyl;
R ⁶ is methoxy;
R ⁷ and R ⁸ are each independently hydrogen or C _1-2 alkyl;
Characterized in that n is 1 or 2,
A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ¹ is methyl, F, Cl, CF ₃ , or ego;
R ² is , , or ego;
R ³ is hydrogen;
R ⁴ is methyl or ethyl;
R ⁵ is hydrogen;
R ⁶ is methoxy;
R7 is hydrogen;
R8 is hydrogen;
Characterized in that n is 1 or 2,
A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula 1,
Characterized in that it is any one compound selected from the group of compounds below,
A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
<1> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline-7- 1) pyrimidine-2,4-diamine;
<2> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl group) phonyl) indolin-7-yl) pyrimidine-2,4-diamine;
<3> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)indoline-7- 1) pyrimidine-2,4-diamine;
<4> 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1,2, 3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;
<5> 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl group) phonyl)-1,2,3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;
<6> 5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-N4-(1-(methylsulfonyl)-1,2, 3,4-tetrahydroquinolin-8-yl)pyrimidine-2,4-diamine;
<7> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methyl-N4-(1-(methylsulfonyl group) phonyl) indolin-7-yl) pyrimidine-2,4-diamine;
<8> 5-fluoro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methyl sulfonyl) indolin-7-yl) pyrimidine-2,4-diamine;
<9> N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indoline -7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;
<10> Isopropyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-( methylsulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate;
<11> methyl 2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-((1-(methyl sulfonyl)indolin-7-yl)amino)pyrimidine-5-carboxylate;
<12> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino ) pyrimidin-4-yl)amino)indolin-1-yl)ethan-1-one;
<13> 5-chloro-N4-(1-(ethylsulfonyl)indolin-7-yl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)p peridin-1-yl)phenyl)pyrimidine-2,4-diamine;
<14> 1-(7-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)indolin-1-yl)propan-1-one;
<15> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one;
<16> 1-(8-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)propan-1-one; and
<17> 5-chloro-N2-(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N4-(1-(methylsulfonyl)indole Lin-7-yl) pyrimidine-2,4-diamine.
As shown in Scheme 1 below,
A method for producing a compound represented by Formula 1 of claim 1, comprising the step of preparing a compound represented by Formula 1 by reacting a compound represented by Formula 2 with a compound represented by Formula 3:
[Scheme 1]

In Scheme 1, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n, p and q are as defined in Formula 1 of claim 1.
A pharmaceutical composition for preventing or treating cancer containing 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.
The pharmaceutical composition according to claim 7, wherein the compound inhibits at least one of EGFR (epidermal growth factor receptor) and HER2 mutations.
According to claim 8,
the EGFR mutation is at least one selected from the group consisting of EGFR A763_Y764insFHEA, EGFR V769_D770insASV, and EGFR D770_N771insSVD as EGFR del19, EGFR T790M, EGFR C797S, EGFR L858R, and EGFR Ex20 insertion mutations;
The pharmaceutical composition, characterized in that the HER2 mutation is at least one selected from the group consisting of HER2 A775_G776insYVMA, HER2 G776_delinsVC, and the like.
According to claim 7,
The cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, 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 of Barter cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, choriocarcinoma of pregnancy, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic schwannoma, The group consisting of 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 thymic cancer A pharmaceutical composition, characterized in that at least one member selected from.
According to claim 7,
The pharmaceutical composition, characterized in that the compound inhibits epidermal growth factor receptor (EGFR) mutation and HER2 mutation.
According to claim 7,
The pharmaceutical composition is a pharmaceutical composition, characterized in that to enhance the anti-cancer effect by co-administration with an anti-cancer agent.