EA041822B1 - N2,N4-DIPHENYLPYRIMIDINE-2,4-DIAMINE DERIVATIVE, METHOD FOR ITS PRODUCTION AND PHARMACEUTICAL COMPOSITION CONTAINING IT AS AN ACTIVE INGREDIENT FOR PREVENTION AND TREATMENT OF CANCER - Google Patents

Description

Field of invention

The present invention relates to a N,N-diphenylpyrimidine-2,4-diamine derivative, a method for producing the same, and a pharmaceutical composition for the prevention or treatment of cancer containing it as an active ingredient.

State of the art

The occurrence of cancer is associated with a number of environmental factors, including chemicals, radiation, virus and changes in oncogenes, tumor suppressor genes, genes associated with apoptosis and DNA repair, and the like. Recently, the molecular mechanism of cancer has become clear, and thus makes available targeted anti-cancer therapy, which is a novel therapy.

Targeted therapeutic agents obtained in the usual way, show the effect by targeting molecules that are characteristic of cancer cells. Molecular targets are genes associated with cell signal transduction pathway, angiogenesis, cell matrix, cell cycle regulator, apoptosis, and the like. An important target therapeutic agent used in current therapy are signal transduction pathway inhibitors, including tyrosine kinase inhibitors and angiogenesis inhibitors, and the like.

Protein tyrosine kinase has been found to play an important role in a number of malignant tumors. In particular, the epidermal growth factor receptor (EGFR), which is a receptor tyrosine kinase of the ErbB family, is known to be abnormally upregulated in a number of epithelial cell tumors, including non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, colorectal cancer, rectal adenocarcinoma, head and neck cancer, stomach cancer and prostate cancer; and activation of said EGFR tyrosine kinase causes persistent cell proliferation, invasion of surrounding tissues, distant metastasis and angiogenesis, and increases cell survival.

In particular, EGFR, which is one of the tyrosine kinase receptors of the ErbB family (EGFR, HER-2, ErbB-3 and ErbB-4), is a transmembrane tyrosine kinase that has an extracellular ligand-binding domain and an intracellular domain including a tyrosine kinase domain. If the ligand binds to a receptor that forms a homodimer or heterodimer, tyrosine kinase in the cell is activated, and the signal stimulated by EGFR as such activates the phosphatidylinositol-3 kinase (PI3K)/AKT/mTOR, RAS/RAF/MAPK and JAK/STAT signal transduction pathway ( Nat Rev Cancer 2007; 7:169-81).

In particular, EGFR is overexpressed in at least half of non-small cell lung cancer (NSCLC), and thus there have been a number of studies in which EGFR is the target of therapy. EGFR TGIs (tyrosine kinase inhibitors) have been developed that inhibit EGFR tyrosine kinase activity and representative drugs include gefitinib (TRESS™), erlotinib (TARCEVA™), lapatinib (TYKERB™, TYVER™).

On the other hand, an activating EGFR mutation was reported in 2004 to correlate with 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).

In particular, it is known that the above EGFR mutation is largely classified into sensitizing mutation and stable mutation, and exon 19 deletion and exon 21 point mutation L858R are the most important sensitizing mutations and account for 85 to 90% of sensitizing mutation, and exon deletion mutation 19 is more sensitizing for TKI. On the other hand, the T790M exon 20 point mutation is known to be the most important resistant mutation and is found in at least 50% of patients with acquired resistance (Clin Cancer Res 2006; 12:6494-6501).

Somatic mutations identified to date include an in-frame deletion in exon 19 or an insertion in exon 20, and a point mutation in which one nucleic acid residue is modified in the expressed protein (e.g., L858R, G719S, G719C, G719A, L861Q) (Fukuoka et al JCO 2003; Kris et al JAMA 2003 and Shepherd et al NEJM 2004).

Despite the early clinical effect of gefitinib/erlotinib in patients with EGFR-mutated NSCLC, most patients develop advanced cancer at the end, despite the fact that these patients receive therapy with these drugs. An early study of these samples identified a secondary EGFR mutation, T790M, which rendered gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity (Kobayashi et al. NEJM 2005 and Pao et al. PLOS Medicine 2005). In a subsequent study, the EGFR T790M mutation was found to be found in approximately 50% (24/48) of tumors derived from patients who had become resistant to gefitinib or erlotinib (Kosaka et al. CCR 2006; Balak et al. CCR 2006 and Engelman et al Science 2007). The secondary genetic modification is induced at a position similar to the pylorus residue and the secondary resistance allele associated with it in patients treated with a kinase inhibitor (eg, T315I in ABL for imatinib-resistant chronic myelogenous leukemia).

EGFR_del19 or EGFR_L858R, which is an EGFR mutation, is known to be the main

- 1 041822 cause of non-small cell lung cancer and head and neck cancer, and IRESSA and TARCEVA, which are therapeutic drugs against cancer, have been developed and are currently being used in clinical trials. However, when such drugs were administered to cancer patients, acquired resistance was observed caused by a secondary mutation in EGFR based on the structure of the drug. In addition, it has been found that this is in fact the main cause of drug resistance. If first-generation EGFR inhibitors have been used for an average of about ten months, acquired resistance, which is a T790M mutation located in the EGFR kinase gatekeeper gene, occurs with the prevention of first-generation EGFR inhibitors from eliciting a drug effect. That is, a double mutation of EGFR_del19_T790M or EGFR_L858R_T790M occurs to prevent conventional therapeutic agents from eliciting a drug effect.

Based on these facts, it is extremely important to develop second and third generation drugs with excellent drug effect and novel structure.

Over the past five years, various new third-generation drug candidates showing an effect on the EGFR T790M double mutation have been developed and clinical trials are underway. AZD9291, developed by the international pharmaceutical company AstraZeneca, is the most promising drug. However, after about ten months, another resistance to AZD9291 has been reported, with the loss of drug effect of AZD9291. In particular, it has been reported that resistance caused by a triple mutation, including C797S, has emerged (Thress et al., Nature Medicine 2015).

Thus, there is a need to develop an inhibitor that exhibits higher inhibition of the specific activating or resistance mutant EGFR while exhibiting relatively low inhibition of wild-type EGFR.

Thus, while the present inventors have been trying to develop an anti-cancer therapeutic agent that inhibits EGFR multiple mutation, the present inventors have found that the X2,K4-diphenylpyrimidine-2,4-diamine derivative of the present invention shows relatively low inhibition of wild-type EGFR and thus, EGFR can be effectively used to prevent or treat cancer. Based on the above results, the present invention has been completed.

Detailed description of the invention

Technical task.

The object of the present invention is to provide an N2,N4-diphenyl-pyrimidine-2,4-diamine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of an N2,N4 diphenylpyrimidine-2,4-diamine derivative.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, containing an N2,N4-diphenylpyrimidine-2,4-diamine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a therapeutic functional food composition for the prevention or alleviation of cancer, comprising an N2,N4 diphenylpyrimidine-2,4-diamine derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Solution to the problem.

In order to accomplish the above objects, the present invention provides the compound represented by the formula (1)

in which R ¹ represents CH3 or NH2;

R ² is hydrogen, halogen, methoxy or methyl, unsubstituted or substituted with one or more halogens;

R3 is hydrogen, halogen, or straight or branched C _1-6 alkyl;

R ⁴ is straight or branched C _1-6 alkyl and na.Su

A ^y is an unsubstituted or substituted 5-7 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, where the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of

- 2 041822 of straight or branched C _1-3 alkyl, straight or branched hydroxyC _1-3 alkyl, acetyl, amine, unsubstituted or substituted with one or more straight or branched C _1-3 alkyl, and unsubstituted or substituted piperidinyl or piperazinyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of straight or branched C _1-3 alkyl, straight or branched hydroxyC _1-3 alkyl, acetyl and straight or branched C _1-5 alkoxycarbonyl, its optical an isomer or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for producing a compound represented by formula (1), comprising the step of reacting a compound represented by formula 2 and a compound represented by formula 3 to obtain a compound represented by formula 1 as shown in Reaction Scheme 1.

Reaction Scheme 1

where R ¹ , R ² , R ³ , R ⁴ and have the meanings as given for formula (1) above; And

X is a halogen.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by formula (1), its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

In addition, the present invention provides a therapeutic functional food product for the prevention or alleviation of cancer, containing the compound represented by formula (1), its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

In addition, the present invention provides a method for preventing or treating cancer, comprising the step of administering a pharmaceutical composition or a therapeutic functional food composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

In addition, the present invention provides the use of a pharmaceutical composition or a therapeutic functional food composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer.

The positive effect of the invention

The N2,N4-diphenylpyrimidine-2,4-diamine derivative of the present invention shows a relatively weak inhibitory effect on EGFR activity against wild-type EGFR, high inhibitory ability on EGFR mutation, and high inhibitory ability even on FLT3 and FLT3 mutation, and thus , can be effectively used to treat cancer with EGFR mutation or cancer with FLT3 or its mutation, and the derivative shows a synergistic effect at the time of combination administration, and thus can be effectively used for treatment of combined administration.

Brief description of the drawings

Fig. 1 is a graph showing relative cell viability during administration of brigatinib in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by sigmaplot t-test (**P<0.001, *P>0.01)).

Fig. 2 is a graph showing relative cell viability during administration of the compound of Example 10 in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by sigmaplot t-test (**P<0.001, *P>0.01)).

Fig. 3 is a graph showing relative cell viability during administration of the compound of Example 11 in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by sigmaplot t-test (**P<0.001, *P>0.01)).

Fig. 4 is a graph showing relative cell viability during administration of cetuximab alone to the Ba/F3 Del19/T790M/C797S cell line alone (calculated by sigmaplot t-test (**P<0.001, *P>0.01)).

Fig. 5 shows subsignaling activity during administration of brigatinib alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

Fig. 6 shows subsignaling activity during administration of Example 10 alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

Fig. 7 shows subsignaling activity during administration of the compound of Example 11 alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

- 3 041822

The best embodiment of the invention

The present invention is described in more detail below.

The present invention provides a compound represented by formula (1)

where R ¹ represents CH3 or NH2;

R ² is hydrogen, halogen, methoxy or methyl, unsubstituted or substituted with one or more halogens;

R ³ is hydrogen, halogen, or straight or branched C ₁ . ₆ alkyl;

R ⁴ is straight or branched C ₁ _ ₆ alkyl and > HetCy]

^Άy is an unsubstituted or substituted 5-7 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, where the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of straight or branched Aralkyl, straight or branched hydroxyC _1-3 alkyl, acetyl, amine, unsubstituted or substituted with one or more straight or branched Aralkyl, and unsubstituted or substituted piperidinyl or piperazinyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents, selected from the group consisting of straight or branched C ₁ . ₃ alkyl, straight or branched hydroxyC1. ₃ alkyl, acetyl and straight or branched C ₁ . ₅ alkoxycarbonyl, its optical isomer, or a pharmaceutically acceptable salt thereof.

R ¹ may be CH3. R ¹ may be NH2.

R ² may be hydrogen, F, Cl, Br, methoxy or methyl, unsubstituted or substituted with one or more fluorine atoms;

^R3

^R4

^R2

^R3

R ⁴ may be hydrogen, F, Cl or straight or branched C _1-3 alkyl and may be hydrogen straight or branched C _1-3 alkyl.

may be hydrogen, Cl, Br, methyl, CF3 or methoxy;

may be hydrogen or methyl; and may be hydrogen, methyl.

(HetCy)

C ^y is an unsubstituted or substituted 5- or 6-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, where the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl, hydroxymethyl, hydroxyethyl, acetyl, amine, unsubstituted or substituted with one or more methyl, and unsubstituted or substituted piperidinyl or piperazinyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl , hydroxymethyl, hydroxyethyl, acetyl and tert-butoxycarbonyl.

(Het Cy) g ^{4 y} is an unsubstituted or substituted 5- or 6-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, where the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group , consisting of methyl, hydroxyethyl, acetyl, -NH2, -K(CH ₃ ) ₂ , and unsubstituted or substituted piperidinyl or piperazinyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl , acetyl and tert-butoxycarbonyl.

ιΆ And? ²

V ⁷ is where A ¹ is CH or N and A ² is NH,

O, CH-R ⁵ , or NR ⁵ , provided that if A ¹ is CH, then A ² is not CH-R ⁵ , where R ⁵ is independently hydrogen, methyl, hydroxyethyl, acetyl, -NH2, -N(CH ₃ )2, A or and R ⁶ independently may be hydrogen, methyl, hydroxyethyl, acetyl or t-butoxycarbonyl.

or

Represents

R ⁶ hydrogen, methyl, hydroxyethyl, acetyl, -NH2, -N(CH ₃ )2,

O ^v where R ⁵ is independently l ⁶

N , or ^N and R ⁶ independently may be hydrogen, methyl, hydroxyethyl, acetyl or t-butoxycarbonyl.

Represents

hydrogen, methyl, hydroxyethyl, acetyl, -NH ₂ , -N(CH ₃ ) ₂ ,

represent in-

Represents where R ⁵ is independently -NH(CH ₃ ) or

R ^c and R ^d are independently hydrogen, and R ⁶ may be methyl.

Examples of the compound represented by formula (1) according to the present invention include the following compounds:

<1> N(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide;

<2> N(2-((5-chloro-2-((2-methoxy-5-methyl-4-(piperidin-4yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<3> N(2-((5-bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide;

<4> N(2-((5-methoxy-2-((2-methoxyL-(piperidin-4-yl)phenyl)amino)pyrimidin4-yl)amino)phenyl)methanesulfonamide;

-5 041822 <5> N-(2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide ;

<6> 4-(4-((5-Chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperide in;

<7> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine;

<8> N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4ylamino)phenyl)methanesulphonamide;

<9> N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide;

<10> N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide;

<11> X-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<12> N-(2-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<13>X-(2-((5-chloro-2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide ;

<14> N-(2-((5-chloro-2-((4-(G-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-2methoxyphenyl)amino)pyrimidine-4 -yl)amino)phenyl)methanesulfonamide;

<15>H-(2-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;

- 6 041822 <16> N-(2-((2-((4-([ 1,4'-bipiperidin] -4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino)phenyl )methanesulfonamide;

<17> T4-(2-((5-chloro-2-((2-methoxy-4-(G-methyl-[1,4'-bipiperidin]-4yl)phenyl)amino)pyrimidin-4-yl) amino)phenyl)methanesulfonamide;

<18> X-(2-((2-((4-(G-acetyl-[1,4'-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino) phenyl)methanesulfonamide;

< 19> ? amino)phenyl)methanesulfonamide;

<20> tert-Butyl 4-(1-(4-((5-chloro-4-((2(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperidin-4-yl)piperazine -1 -carboxylate;

<21> X-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1 -yl)piperidin-1 yl)phenyl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide;

<22> T4-(2-((5-chloro-2-((4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl)2-methoxyphenyl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide;

<23>M-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide;

<24> N-(2-((2-((4-(4-(l-acetylpiperidin-4-yl)piperazin-1-yl)-2methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino) phenyl)methanesulfonamide;

<25>X-(2-((5-chloro-2-((2-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1yl)phenyl)amino)pyrimidin-4-yl) amino)phenyl)methanesulfonamide;

<26> tert-Butyl 4-(4-(4-((5-chloro-4-((2-7 041822 (methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperazin-1 - yl) piperidine-1-carboxylate;

<27> M-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-yl)piperazin-1yl)phenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide;

<28> M-(2-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<29> 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperazine;

<30> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperazine;

<31> M-(2-((2-((2-methoxy-4-(piperazin-4-yl)phenyl)amino)-5(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<32> M-(2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide;

<3 3 > N-(2-((5-x lor-2-((4-(4-((3 R, 5 S)-3,5 -d imethylpiperazin-1 -yl)piperidin-1 yl) -2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<34> M-(2-((5-chloro-2-((2-methoxy-4-(4-morpholinopiperidin-1yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<3 5> N-(2-((5-x lor-2-((2-methoxy-4-(4-(p-irrolide in-1-yl)piperidin-1 yl)phenyl)amino)pyrimidine- 4-yl)amino)phenyl)methanesulfonamide;

<36> (M-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)sulfamoyl) carbamate;

- 8 041822 <3 7> (N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1 -yl)piperidin-1 yl)phenyl)amino) pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate;

<38> X-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<39> X-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperidin-4-yl)acetamide;

<40> X-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

<41>X-(2-((5-chloro-2-((4-(4-((2-hydroxyethyl)amino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide;

<42> X-(2-((5-chloro-2-((2-methoxy-4-(4-((2-methoxyethyl)amino)piperidin-1yl)phenyl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide; and <43> X-(2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)amino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide.

The compound represented by formula (1) according to 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 useful as a salt. The acid addition salt is prepared from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, non-toxic organic acids such as aliphatic mono- and dicarboxylate, phenyl-substituted alkanoate, hydroxyalkanoate and alkanedioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, organic acids such as acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid acid, tartaric acid, fumaric acid and the like. Types of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate , heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate , toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalate-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be obtained by a conventional method, and for example, it can be obtained by dissolving a derivative of formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, adding an organic acid or an inorganic acid , filtering the resulting precipitate and drying, or it can be obtained by distilling the solvent and acid in excess under reduced pressure, then drying and crystallizing in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal or alkaline earth metal salt is prepared, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering off the salt of the undissolved compound, evaporating the filtrate, and drying. In this case, the corresponding sodium, potassium or calcium salt is pharmaceutically acceptable for the preparation of the metal salt. In addition, the corresponding salt is obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

In addition, the present invention includes all compounds represented by formula (1) and their pharmaceutically acceptable salt, as well as solvate, optical isomer, hydrate and the like, which can be obtained from them.

- 9 041822

In addition, the present invention provides a method for producing a compound represented by formula (1), comprising the step of reacting a compound represented by formula 2 and a compound represented by formula 3 to obtain a compound represented by formula 1 as shown in Reaction Scheme 1.

Reaction Scheme 1

h (Het.Cyj where \ has the meanings as defined for formula (1) in claim 1; and

X is a halogen.

Next, the production method represented by Reaction Scheme 1 above will be described in detail.

In the method for producing a compound of the present invention represented by the reaction scheme 1 above, step 1 is a step of reacting a compound represented by formula 2 and a compound represented by formula 3 to obtain a compound represented by formula (1). Specifically, this is the step of reacting a halogen of the compound represented by formula 2 and a primary amine of the compound represented by formula 3 to form a compound represented by formula (1).

The reaction in Reaction Scheme 1 above is not limited as long as the reaction condition is a condition under which an amine bond can be formed by binding a halogen and an amine.

In the present invention, acidic conditions are used, and the acid used in the present invention is, but is not limited to, hydrochloric acid.

In addition, as in the production method according to Reaction Scheme 2 below, the sulfonamide may be introduced before the halogen-amine coupling reaction in Reaction Scheme 1, or the sulfonamide may be introduced after the halogen-amine coupling reaction without introducing the sulfonamide.

Solvents available in Reaction Scheme 1 above include, but are not specifically limited to, lower alcohols including isopropanol, methanol, ethanol, propanol, and butanol; tetrahydrofuran (THF); dioxane; ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, acetonitrile, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate , propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, acetonitrile and the like, which can be used alone or in combination. The lower alcohol solvent is used in the present invention, but is not limited thereto.

In addition, the compound represented by formula (1) according to the present invention, where R ¹ is NH ₂ , can be obtained by a production method comprising the step of reacting the compound represented by formula 4 and the compound represented by formula 3 to obtain the compound represented by formula 5 (step 1);

a step of reducing the compound represented by formula 5 obtained in step 1 above by a reduction reaction to obtain a compound represented by formula 6 (step 2);

a step of reacting a compound represented by formula 6 obtained in step 2 above with a compound represented by formula 7 to obtain a compound represented by formula 8 (step 3); and a step of reacting the compound represented by formula 8 obtained in Step 3 above to obtain a compound represented by formula (1) (Step 4) as shown in Reaction Scheme 2:

Reaction Scheme 2

where R ² , R ³ , R ⁴ and have the meanings as presented for formula 1 above; X is a halogen and

- 10 041822

PG is an amine protecting group selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB ), 3,4-dimethoxybenzyl (DMPM), pmethoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

Next, the production method represented by Reaction Scheme 2 above will be described in more detail.

In the production method represented by the reaction scheme 2 above according to the present invention, step 1 above is a step of reacting a compound represented by formula 4 and a compound represented by formula 3 to obtain a compound represented by formula 5. Specifically, it is a step of reacting a halogen compound , represented by formula 2, and the primary amine of the compound represented by formula 3, to form the compound represented by formula 5.

The reaction of Step 1 above is not particularly limited as long as the reaction condition is a condition under which an amine bond can be formed by binding a halogen and an amine.

In the present invention, acidic conditions are used, and the acid used in the present invention is, but is not limited to, hydrochloric acid.

Solvents available in Step 1 above include, but are not specifically limited to, lower alcohols including isopropanol, methanol, ethanol, propanol, and butanol; tetrahydrofuran (THF); dioxane; ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, acetonitrile, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methane sulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, acetonitrile and the like, which may be used alone or in combination. The lower alcohol solvent is used in the present invention, but is not limited thereto.

In the production method represented by Reaction Scheme 2 above according to the present invention, Step 2 above is a step of reducing the compound represented by Formula 5 obtained in Step 1 above by a reduction reaction to obtain a compound represented by Formula 6. Specifically, this is a step of reducing a nitro group of a compound represented by formula 5 to a primary amine by a reduction reaction to form a compound represented by formula 6.

The reduction reaction can be carried out in a well-known manner.

In the preparation method represented by the reaction scheme 2 above according to the present invention, step 3 above is a step of reacting the compound represented by formula 6 obtained in step 2 above with the compound represented by formula 7 to obtain the compound represented by formula 8. Specifically, this is a step of reacting the primary amine of the compound represented by formula 6 with chlorine of tert-butyl chlorosulfonylcarbamate represented by formula 7 to form a compound represented by formula 8 in which a sulfonyl group has been introduced.

In this case, the compound represented by formula 7 above can be used either by purchase as a commercially available product or by preparation by a publicly known method.

In the present invention, it is obtained using chlorosulfonyl isocyanate and tert-butanol, but without limitation thereto.

Solvents available in Step 3 above include, but are not specifically limited to, lower alcohols including isopropanol, methanol, ethanol, propanol, and butanol; tetrahydrofuran (THF); dioxane; ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, water, acetonitrile, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate , methane sulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, acetonitrile and the like, which can be used alone or in combination.

In the production method represented by the reaction scheme 2 above according to the present invention, step 4 above is a step of reacting the compound represented by formula 8 obtained in step 3 above to obtain the compound represented by formula (1). Specifically, this is the step of removing the protecting amine group attached to the amino group of the sulfonyl in the compound represented by formula 8 to obtain the compound represented by formula (1).

The deprotection reaction can be carried out using conventional deprotection reaction conditions.

In the present invention, acidic conditions are used, and hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like can be used as the acid.

In addition, the solvents available in the above reaction are tetrahydrofuran, dioxane, dichloromethane, ether solvents such as 1,2-dimethoxyethane and the like; aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; alcohol solvents such as methanol, ethanol and the like; dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, water and the like, which can be used alone or in combination.

In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by formula (1), its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

In this case, the cancer is one or more selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mushroom mycosis, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, embryonic ovarian carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, cholangiocarcinoma, colorectal cancer, chronic myeloid leukemia, chronic lymphatic leukemia, retinoblastoma, choroidal melanoma, ampulla of vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, cancer of the nasal cavity and near the nasal cavity, non-small cell lung cancer, cancer of the tongue, astrocytoma, small cell lung cancer, childhood head cancer brain, childhood lymphoma, childhood leukemia, small bowel cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, malignant tumor without identified primary focus, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, uterine choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer , salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyoblastoma, laryngeal cancer, pleural cancer, hematologic malignancy, and thymus cancer, and the cancer may be a cancer with a mutation expressed on one or more selected from the group consisting of EGFR, ALK, FAK, FLT3, JAK3, KIT and PLK4.

In this case, the EGFR mutation may be one or more selected from the group consisting of EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C797S, EGFR L858R, EGFR L858R/T790MS and EGFR L858R/T790M/C797S.

In this case, the FLT3 mutation may be one or more selected from the group consisting of FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L ), FLT3(K663Q), FLT3(N841I) and FLT3(R834Q).

A pharmaceutical composition for the prevention or treatment of cancer, containing a compound represented by formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, can be used either by administration as a single therapeutic agent or by administration in combination with another used anticancer agent. .

A pharmaceutical composition for preventing or treating cancer containing a compound represented by formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient can enhance an anti-cancer effect by being administered in combination with an anti-cancer agent.

The compound represented by formula (1) according to the present invention shows a relatively weak inhibitory effect on EGFR activity against wild-type EGFR, a selectively high inhibitory ability against EGFR mutation, and in particular a high inhibitory ability against EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S which is a triple mutation (see Experimental Example 1 and Table 4).

The compound represented by formula (1) according to the present invention shows selectively high inhibitory ability against EGFR mutation in the Ba/F3 cell line, and in particular high inhibitory ability against EGFR del19, which is a single mutation (see Experimental Example 2 and Table . 5).

The compound represented by the formula (1) according to the present invention shows a selectively excellent inhibitory ability against a cancer-related kinase, in particular FLT3 kinase, which is a kinase associated with hematological malignancies, and a high inhibitory ability against wild-type FLT3, and also FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), which are mutated forms (see experimental

- 12 041822 example 3 and table. 6).

It can be seen that the compound represented by formula (1) according to the present invention exhibits lower cell viability in the EGFR triple mutation Ba/F3 Del19/T790M/C797S cell line when administered alone than the conventional drug, and exhibits markedly reduced cell viability when administered in combination with a standard drug than when administered alone, and thus exhibits superior cancer cell apoptosis capability in a triple EGFR mutant cell line even when administered alone, and also exhibits a markedly enhanced anti-cancer effect when administered in combination with standard drug. In particular, it can be seen that the compound represented by formula (1) according to the present invention shows that cell viability is reduced by at least 20% than when brigatinib, which is a commonly used drug, is administered in combination with a standard drug, and thus demonstrates a higher antitumor effect than brigatinib (See Experimental Example 4 and FIGS. 1-4).

It can be seen that the compound represented by formula (1) according to the present invention shows a concentration-dependent activity in pERK, pAKT, pS6, which shows an EGFR subsignal, even when administered alone, and also shows a higher activity when administered in combination with a standard drug. means. In particular, it can be seen that the compound represented by the formula (1) according to the present invention shows a higher activity than when brigatinib, which is a commonly used drug, is administered in combination with a standard drug, and thus shows a better anti-cancer effect. effect than brigatinib (see Experimental Example 4 and Figures 5-7).

Therefore, the compound represented by the formula (1) according to the present invention shows a high inhibitory ability against EGFR mutation, and thus can be effectively used for the treatment of cancer with EGFR mutation, such as EGFR del19, EGFR del19/T790M, EGFR del19 /T790M/C797S, EGFR L858R, EGFR L858R/T790MS, EGFR L858R/T790M/C797S and the like, in particular, the compound represented by the formula (1) according to the present invention shows a markedly higher inhibitory ability against EGFR cdel19/T790M/C797S or EGFR L858R/T790M/C797S, which is a triple mutation and thus can be effectively used for cancer treatment with EGFR del19/T790M/C797S or EGFRL858R/T790M/C797S.

In addition, the compound represented by formula (1) according to the present invention shows high inhibitory ability against FLT3 and its mutation, such as FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3 (ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), or FLT3(R834Q), and thus can be effectively used to treat cancer associated with FLT3 activity or a mutated form of FLT3, in particular hematological malignancy.

In addition, the compound represented by formula (1) according to the present invention shows a synergistic effect when administered in combination with a conventional drug, and thus can be effectively used when administered in combination with a conventional drug.

The compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral formulations in clinical use. It is prepared using diluents or adjuvants such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants and the like, which are commonly used in the formulation. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid compositions are prepared by mixing at least one or more adjuvants, for example starch, calcium carbonate, sucrose or lactose, gelatin and the like, with one or more compounds. Moreover, in addition to simple auxiliary agents, lubricating agents such as magnesium stearate, talc and the like are also used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, syrups, and the like. In addition to simple diluents such as water and liquid paraffin, which are commonly used, various adjuvants such as wetting agents, sweetening agents, flavoring agents, preservatives, and the like may be included. Compositions for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used as non-aqueous solvents, suspending solvents.

The pharmaceutical composition containing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is carried out by infusion methods, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

- 13 041822

In this case, to formulate formulations for parenteral administration, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to prepare a solution or suspension, and it can be prepared in an ampoule or unit dosage vial. The composition may be sterilized and/or contain preservatives, stabilizers, wetting agents or emulsifying accelerators, adjuvants such as salts and/or buffers for adjusting osmotic pressure and the like, and other therapeutically useful substances, and may be formulated in accordance with the usual method mixing, granulation or coating method.

Compositions for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, powders, and the like. These formulations contain, in addition to the active ingredient, diluents (eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and glidants (eg silica, talc, stearic acid and a magnesium or calcium salt and/or polyethylene glycol ). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and the like, and may contain, when appropriate, disintegrants such as starch, agar, alginic acid or its sodium salt and the like, or effervescent mixtures and/or absorbents, colors, flavors and sweeteners.

In addition, the present invention provides a therapeutic functional food product for the prevention or alleviation of cancer, containing the compound represented by formula (1), its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

The cancer is one or more selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, fetal ovarian carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, cholangiocarcinoma, colorectal cancer, chronic myeloid leukemia, chronic lymphatic leukemia, retinoblastoma , choroidal melanoma, cancer of the ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, cancer of the nasal cavity and near the nasal cavity, non-small cell lung cancer, cancer of the tongue, astrocytoma, small cell lung cancer, childhood brain cancer, pediatric ocular lymphoma, childhood leukemia, small bowel cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, soft tissue cancer, bone cancer, lymphoma cancer, mesothelioma cancer, melanoma cancer, cancer eye, vulvar cancer, ureteral cancer, urethral cancer, malignant tumor without identified primary focus, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, uterine choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary cancer glands, Kaposi's sarcoma, Paget's disease, tonsillar cancer ka, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyoblastoma, laryngeal cancer, pleural cancer and thymus cancer; and more preferably, the cancer may be a cancer with a mutation in one or more selected from the group consisting of EGFR, ALK, FAK, FLT3, JAK3, KIT and PLK4.

The compound represented by formula (1) according to the present invention shows a high EGFR mutation inhibitory ability, and thus can be added to therapeutic functional foods such as foods, beverages and the like, as a therapeutic functional food composition for preventing or alleviating cancer, in particular cancer with an EGFR mutation.

The compound represented by the formula (1) of the present invention may be added to foodstuffs as such, or may be used with other foodstuffs or food ingredients, and may be appropriately used in accordance with conventional methods. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of its use (prevention or improvement). Typically, the amount of the compound in medicinal foods may be added in an amount of 0.1 to 90 parts by weight. from the total amount of food. However, the amount may be less than the above range in the case of long-term use for health and hygiene or health regulation, and the active ingredient may also be used in an amount exceeding the above range because there are no safety concerns.

In addition, the therapeutic functional food composition of the present invention may contain, in addition to the above compound as a main ingredient,

- 14 041822 in the indicated ratio, other ingredients that are not specifically limited. The therapeutic functional food composition of the present invention may contain various flavors or natural carbohydrates and the like as additional ingredients, as in conventional beverages. Examples of the aforementioned natural carbohydrates are conventional sugars such as monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol, erythritol and the like. As flavors, in addition to those described above, natural flavors (thaumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, and the like) and synthetic flavors (saccharin, aspartame, and the like) can be effectively used. The natural carbohydrate content is usually 1 to 20 g per 100 g of the composition according to the present invention, preferably 5 to 12 g.

In addition, the compound represented by the formula (1) according to the present invention may contain, in addition to those described above, various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors and the like, colors and enhancers (cheese , chocolate and the like), pectic acids and their salts, alginic acids and their salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, gas generating agents used in carbonated beverages, and the like. In addition, the compound represented by the formula (1) according to the present invention may contain fruit pulp for producing natural fruit juice as well as fruit juice drink and vegetable drink.

Further, the present invention provides a method for preventing or treating cancer, comprising the step of administering a pharmaceutical composition or a therapeutic functional food composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

In addition, the present invention provides the use of a pharmaceutical composition or a therapeutic functional food composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer.

Embodiments of the invention

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

However, the following examples and experimental examples are only illustrations of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

Compounds of Examples 1 and 2 were prepared according to Reaction Example 1 below.

Reaction example 1

where R ³ =H indicates the compound of example 1 and R ³ =CH ₃ indicates the compound of example 2.

Example 1 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

N-(2-Aminophenyl)methanesulfonamide (18.6 mg, 0.1 mmol), 2,4,5-trichloropyrimidine (14 µl, 0.12 mmol), and DIPEA (diisopropylethylamine, 38 µl, 0.22 mmol) were mixed with isopropyl alcohol (1 ml) . The above reaction mixture was stirred overnight at 60°C. The above mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ /EtOAc, 5:1) to give N-(2-((2,5-dichloro-pyrimidin-4yl)amino)phenyl)methanesulfonamide (15 mg, white solid) with a yield of 42%.

1H NMR (300 MHz, CDCl3) δ 8.38 (br s, 1H), 8.24 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.46-7.37 (m, 2H), 7.31-7.29 (m , 1H), 6.56 (s, 1H), 3.08 (s, 3H); LC-MS calculated C _h HioC12N402S 332.0, found 333.0 (M+H+).

Step 2: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

To n-butanol (1 ml) of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (5.0 mg, 0.015 mmol) and tert-butyl 4-(4-amino-3- to methoxyphenyl)piperidine-1-carboxylate (5.0 mg, 0.016 mmol) was added a solution of dioxane (0.15 mL, 0.012 mmol) and 0.08 N HCl. The above reaction mixture was stirred overnight at 95°C. The above mixture was concentrated under reduced pressure, and

- 15 041822 the residue was purified by preparative HPLC to give N-(2-((5-chloro-2-((2-methoxy-4(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl )methanesulfonamide (2.2 mg, white solid) in 30% yield.

1H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.63-7.60 (m, 1H), 7.54-7.52 (m, 1H), 7.41-7.36 ( m, 2H), 6.93 (s, 1H), 6.70 (d, J=7.5 Hz, 1H), 3.90 (s, 3H), 3.53 (d, J=12.6 Hz, 2H), 3.18-3.13 (m, 2H ), 2.96 (s, 3H), 2.93-2.88 (m, 1H), 2.11-2.08 (m, 2H), 1.95-1.88 (m, 2H); LC-MS calculated C23H27CMO3S 502.2, found 503.2 (M+H+).

Example 2 Preparation of N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) methanesulfonamide.

In the same manner as described in Example 1 above, N-(2-((5-chloro-2-((2-methoxy5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4 -yl)amino)phenyl)methanesulfonamide (28 mg, 30%).

1H NMR (300 MHz, CD3OD) δ 8.16 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.57 (dd, J=7.8, 1.5 Hz, 1H), 7.43 (td, J=7.8, 1.5Hz, 1H), 7.36(td, J=7.8,1.5Hz, 1H), 7.32(s, 1H), 6.91(s, 1H), 3.89(s, 3H), 3.55(d, J=12.6Hz, 2H), 3.27-3.14 (m, 3H), 2.97 (s, 3H), 2.16 (s, 3H), 2.00-1.97 (m, 4H); LC-MS calculated C24H29CMO3S 516.2, found 516.8 (M+H+).

The compound of Example 3 was prepared according to Reaction Example 2 below.

Reaction example 2

Example 3 Preparation of N-(2-((5-bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, N-(2-((5bromo-2-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (25 mg, 30%) was prepared.

1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 8.03 (dd, J=8.3, 1.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.31-7.26 (m, 1H), 6.57 ( s, 1H), 3.08 (s, 3H); LC-MS calculated CuH _w BrClN4O2S 375.9, found 376.9 (M+H+).

Step 2: Preparation of N-(2-((5-bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((5bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide (13 mg, 37%).

1H NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.42 (dd, J=7.8, 1.3 Hz, 1H), 7.33-7.21 (m, 3H) , 6.85 (s, 1H), 6.61 (d, J=7.9 Hz, 1H), 3.77 (s, 3H), 3.43 (d, J=12.7 Hz, 2H), 3.08-3.01 (m, 2H), 2.86 ( s, 3H), 2.83-2.77 (m, 1H), 1.99-1.80 (m, 4H); LC-MS calculated C23^B^6O3S 546.1, found 546.7 (M+H+).

The compound of Example 4 was prepared according to Reaction Example 3 below.

Reaction Example 3

Example 4 Preparation of N-(2-((5-methoxy-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin4-yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2-chloro-5-methoxypyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, N-(2-((2-χλορ5-methoxypyrimidin-4-yl)amino)phenyl)methanesulfonamide (6 mg, 8%) was prepared.

1H NMR (300 MHz, CDCl ₃ ) δ 7.98-7.95 (m, 2H), 7.79 (s, 1H), 7.45 (dd, J=7.9, 0.8 Hz, 1H), 7.38 (td, J=7.4, 1.0 Hz , 1H), 6.67 (s, 1H), 4.02 (s, 3H), 3.08 (s, 3H); LC-MS calculated C ₁₂ H ₁₃ ClN ₄ O ₃ S 328.0, found 328.9 (M+H+).

Step 2: Preparation of N-(2-((5-methoxy-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((5-methoxy2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide (5.5 mg, 58%).

1H NMR (300 MHz, CD3OD) δ 7.87-7.84 (m, 1H), 7.53 (s, 1H), 7.51-7.45 (m, 2H), 7.39-7.34 (m, 2H), 6.98 (d, J=1.5 Hz, 1H), 6.78 (dd, J=8.3, 1.5 Hz, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.55-3.51 (m, 2H), 3.20-3.11 (m, 2H) , 2.97 (s, 3H), 2.94-2.90 (m, 1H), 2.21-1.90 (m, 4H); LC-MS calculated C24H30N6O4S 498.2, found 498.8 (M+H+).

- 16 041822

The compound of Example 5 was prepared according to Reaction Example 4 below. Reaction example 4

Example 5 Preparation of N-(2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, N-(2-((2-chloro5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (199 mg, 18%) was prepared.

1H NMR (300 MHz, CDC13) δ 8.47 (s, 1H), 8.23 (br s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.46-7.28 (m, 3H), 6.27 (br s, 1H), 3.05 (s, 3H); LC-MS calculated C12H10CIF3N4O2S 366.0, found 366.8 (M+H+).

Step 2: Preparation of N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((2-((2-methoxy4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)amino)phenyl)methanesulfonamide (15 mg, 31%).

1H NMR (300 MHz, CD3OD) δ 8.38 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.48 (dd, J=7.8, 1.8 Hz, 1H), 7.42-7.29 (m, 3H) , 6.89 (s, 1H), 6.60 (br s, 1H), 3.83 (s, 3H), 3.49 (dd, J=10.2, 3.3 Hz, 2H), 3.11 (td, J=12.9, 3.3 Hz, 2H) , 2.89-2.85 (m, 4H), 2.04-1.81 (m, 4H); LC-MS calculated C ₂₄ H ₂₇ F ₃ N ₆ O ₃ S 536.2, found 536.8 (M+H+).

The compound of Example 6 was prepared according to Reaction Example 5 below.

Reaction Example 5

Example 6 Preparation of 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine.

Step 1. Preparation of tert-butyl 4-(4-((5-chloro-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperidine-1-carboxylate.

To n-butanol (10 ml) of 2,5-dichloro-N-(2-nitrophenyl)pyrimidin-4-amine (1.0 g, 3.5 mmol) and tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1- carboxylate (1.1 g, 3.5 mmol) was added a solution of 1,4dioxane (0.7 ml, 2.8 mmol) and 4 N HCl. The above reaction mixture was stirred overnight at 95°C. The above reactant was concentrated under reduced pressure. To the residual solution, concentrated under reduced pressure, was added CH2Cl2 (10 ml) and di-tert-butyl dicarbonate (1.2 g, 5.3 mmol) and Et ₃ N (0.98 ml, 7.0 mmol) were added at 0°C and stirred overnight at ambient temperature. The above mixture was diluted with methylene chloride (200 ml), washed with saturated aqueous NaHCO ₃ (100 ml), and then washed with water (100 ml). The above organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo to give tert-butyl 4-(4-((5-chloro-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine -1 carboxylate (1.0 g) in 57% yield.

1H NMR (300 MHz, CDC13) δ 10.61 (s, 1H), 8.95 (d, J=8.5 Hz, 1H), 8.29 (dd, J=8.4, 1.4 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 7.67-7.61 (m, 1H), 7.50 (s, 1H), 7.22-7.17 (m, 1H), 6.81-6.77 (m, 2H), 4.31-4.25 (m , 2H), 3.92 (s, 3H), 2.83 (t, J=12.2 Hz, 2H), 2.65 (dt, J=12.1, 3.4 Hz, 1H), 1.88-1.84 (m, 2H), 1.72-7.62 ( m, 2H), 1.51 (s, 9H); LC-MS calculated C ₂₇ H ₃₁ ClN ₆ O ₅ 554.2, found 555.0 (M+H+).

Step 2. Preparation of tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5-chloropyrimidin-2-yl)amino)-3methoxyphenyl)piperidine-1-carboxylate.

tert-Butyl 4-(4-((5-chloro-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (1.4 g, 2.4 mmol), prepared in step 1 above, iron powder (0.68 g, 12 mmol) and NH4C1 (0.65 g, 12 mmol) were added to THF/H2O (1:1, 24 ml). The above reaction mixture was stirred for 1 hour at 60°C. After completion of the reaction, the above reaction mixture was filtered through celite and concentrated in vacuo. The above residue was washed with water and filtered to give tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5-chloropyrimidin-2- 17 041822 yl)amino)-3-methoxyphenyl)piperidine-1- carboxylate (0.50 g) with a yield of 53% without a separate purification process.

LC-MS calculated C ₂₇ H ₃₃ ClN ₆ O ₃ 524.2, found 525.0 (M+H+).

Step 3. Preparation of tert-butyl 4-(4-((4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino)-5-chloropyrimidin-2-yl)amino)-3 -methoxyphenyl)piperidine-1-carboxylate.

To an anhydrous solution of methylene chloride (1 mL) and chlorosulfonyl isocyanate (8.7 μL, 0.1 mmol) was added dropwise an anhydrous solution of methylene chloride (1 mL) and tert-butanol (9.5 μL, 0.1 mmol) at 0°C. The above mixture was stirred for 30 min at 0°C, and Et ₃ N (16 μl, 0.11 mmol) was added and stirred for 30 min at 0°C. The above reaction solution was added slowly at 0°C to a solution of methylene chloride (1 ml) and tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5chloropyrimidin-2-yl)amino)-3-methoxyphenyl )piperidine-1-carboxylate (26 mg, 0.05 mmol) obtained in step 2 above. The above mixture was stirred for 3 hours at ambient temperature. The above reaction mixture was diluted with methylene chloride (20 ml) and washed with water (10 ml). The above organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (CH ₂ Cl ₂ /EtOAc, 5:1) to give tert-butyl 4-(4-((4-((2-((N-(tert-butoxycarbonyl)sulfamoyl) amino)phenyl)amino)5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (17 mg, white solid) in 49% yield.

¹ H NMR (300 MHz, (CD ₃ ) ₂ SO) δ 8.13 (s, 1H), 7.97-7.92 (m, 1H), 7.89-7.85 (m, 1H), 7.71 (d, J=7.8 Hz, 1H ), 7.26-7.13 (m, 3H), 6.88 (s, 1H), 6.67 (d, J=8.3 Hz, 1H), 4.08 (d, J=12.3 Hz, 2H), 3.80 (s, 3H), 2.86 -2.72 (m, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=12.3Hz, 2H), 1.57-1.46 (m, 2H), 1.42 (s, 9H), 1.39 (s, 9H ); LC-MS calculated C32H42QN7O7S 703.3, found 704.8 (M+H+).

Step 4. Preparation of 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine.

CH ₂ C1 ₂ /trifluoroacetic acid (1:1, 1 ml) tert-butyl 4-(4-((4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino)-5-chloropyrimidine -2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (4 mg, 0.006 mmol) obtained in step 3 above was stirred for 2 h at ambient temperature. To the above reaction mixture was added 1,4-dioxane (10 μl) 4 N HCl. The above reaction mixture was concentrated in vacuo to give 4-(4-((5chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine (4.2 mg, solid white) with a quantitative yield.

1H NMR (300 MHz, CD3OD) δ 8.13 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.39-7.27 (m, 2H), 6.98 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 3.53 (d, J=12.3 Hz, 2H), 3.16 (t, J=12.0 Hz, 2H), 2.94 (m, 1H), 2.12 (m, 2H), 2.02-1.91 (m, 2H); LC-MS calculated C ₂₂ H ₂₆ ClN ₇ O ₃ S 503.2, found 503.8 (M+H+).

The compound of Example 7 was prepared according to Reaction Example 6 below.

Reaction example 6

Example 7 Preparation of 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine.

Step 1. Preparation of tert-butyl 4-(4-((5-bromo-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperidine-1-carboxylate.

In the same manner as described in Step 1 of Example 6 above, tert-butyl 4(4-((5-bromo-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl was prepared. )piperidine-1-carboxylate (68 mg, 58%).

1H NMR (300 MHz, CDCl ₃ ) δ 10.52 (s, 1H), 8.90 (d, J=8.7 Hz, 1H), 8.29 (s, 1H), 8.26 (dd, J=8.4, 1.0 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.78-6.76 (m, 2H ), 4.27 (d, J=11.2 Hz, 2H), 3.91 (s, 3H), 2.82 (t, J=12.3 Hz, 2H), 2.68-2.60 (m, 1H), 1.85 (d, J=12.3 Hz , 2H), 1.71-1.57 (m, 2H), 1.50 (s, 9H); LC-MS calculated CwH^BrNA 598.2, found 599.7 (M+H+).

Step 2. Preparation of tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5-bromopyrimidin-2-yl)amino)-3methoxyphenyl)piperidine-1-carboxylate.

In the same manner as described in Step 2 of Example 6 above, tert-butyl 4(4-((4-((2-aminophenyl)amino)-5-bromopyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperidine-1-carboxylate (60 mg, 94%).

LC-MS calculated C ₂₇ H ₃₃ BrN ₆ O ₃ 568.2, found 569.8 (M+H+).

- 18 041822

Step 3. Preparation of tert-butyl 4-(4-((5-bromo-4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino)pyrimidin-2-yl)amino)- 3-methoxyphenyl)piperidine-1-carboxylate.

In the same manner as described in step 3 of Example 6 above, tert-butyl 4(4-((5-bromo-4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino )pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine-1-carboxylate (30 mg, 70%).

'H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.83 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.22 (d, J=13.0 Hz, 2H), 3.87 (s, 3H), 2.89-2.86 (m, 2H), 2.70-2.65 (m, 1H), 1.81 (d, J=12.3 Hz, 2H), 1.63-1.57 (m , 2H), 1.50 (s, 9H), 1.49 (s, 9H); LC-MS calculated C ₃₂ H ₄₂ BrN ₇ O ₇ S 747.2, found 749.6 (M+H+).

Step 4. Preparation of 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidine.

In the same manner as described in Step 4 of Example 6 above, 4-(4-((5-bromo4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperidine (24 mg, quantitative yield).

1H NMR (300 MHz, CD3OD) δ 8.21 (s, 1H), 7.85-7.83 (m, 1H), 7.53-7.27 (m, 5H), 6.99 (s, 1H), 6.80-6.78 (m, 1H), 3.89 (s, 3H), 3.54 (d, J=12.3 Hz, 2H), 3.21-3.12 (m, 2H), 2.99-2.90 (m, 1H), 2.10 (d, J=13.4 Hz, 2H), 2.02 -1.87 (m, 2H); LC-MS calculated C22^Br^O3S 547.1, found 547.7 (M+H+).

The compound of Example 8 was prepared according to Reaction Example 7 below.

Reaction Example 7

Example 8 Preparation of N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4ylamino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, K-(2-((2-chloro5-methylpyrimidin-4-yl)amino)phenyl)methanesulfonamide was prepared in 26% yield.

'H NMR (300 MHz, CDCI3) δ 9.37 (s, 1H), 8.62 (s, 1H), 8.21 (sd, J=0.9 Hz, 1H), 7.64-7.60 (m, 1H), 7.497.45 (m , 1H), 7.32-7.24 (m, 2H), 2.97 (s, 3H), 2.17 (sd, J=0.9 Hz, 1H); LC-MS calculated C ₁₂ H ₁₃ ClN ₄ O ₂ S 312.0, found 312.9 (M+H+).

Step 2: Preparation of N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4ylamino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((2-((2methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4-ylamino )phenyl)methanesulfonamide in 65% yield.

'H NMR (300 MHz, CD ₃ OD) δ 9.54 (br s, 1H), 9.49 (br s, 1H), 9.26 (sd, J=3.6 Hz, 1H), 8.75 (br s, 1H), 8.58 ( br s, 1H), 7.89 (s, 1H), 7.54 (dd, J=8.4, 3.3 Hz, 1H), 7.45 (dd, J=8.4, 3.0 Hz, 1H), 7.41-7.35 (m, 1H), 7.327.23 (m, 2H), 6.88 (s, 1H), 6.52 (sd, J=5.7 Hz, 1H), 3.80 (s, 3H), 3.38 (d, J=12.6 Hz, 2H), 3.05-2.76 (m, 6H), 2.18 (s, 3H), 1.92-1.75 (m, 4H); LC-MS calculated C24H30N6O3S 482.2, found 483.0 (M+H+).

The compound of Example 9 was prepared according to Reaction Example 8 below.

Reaction example 8

Example 9 Preparation of X-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, N-(2-((2chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (white solid) was prepared in 47% yield.

'H NMR (300 MHz, CDCI3) δ 9.28 (s, 1H), 9.13 (s, 1H), 8.12 (d, J=6.0 Hz, 1H), 7.56-7.44 (m, 2H), 7.297.23 (m , 2H), 6.67 (d, J=5.7 Hz, 1H), 2.97 (s, 3H); LC-MS calculated C11H11CIN4O2S 298.0, found 298.9 (M+H+).

Step 2: Preparation of N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((2-((2methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl )methanesulfonamide in 65% yield.

'H NMR (300 MHz, CD3OD) δ '0.27 (s, 1H), 9.74 (s, 'H), 9.26 (s, 1H), 8.78 (d, J=10.8 Hz, 1H), 8.59 (d,

- 19 041822

J=10.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.54-7.46 (m, 3H), 7.36-7.21 (m, 2H), 6.93 (s, 1H), 6.66 (d, J =8.1 Hz,

1H), 6.47 (br s, 1H), 3.82 (s, 3H), 3.39 (d, J=12.6 Hz, 2H), 3.06-2.95 (m, 5H), 2.87-2.79 (m, 1H), 1.95- 1.78(m,

4H); LC-MS calculated C ₂₃ H ₂₈ N ₆ O ₃ S 468.2, found 469.0 (M+H+).

The compound of Example 10 was prepared according to Reaction Example 9 below.

Reaction Example 9

Example 10 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, Ν-(2-((5-χπορ-2-((2methoxy-4-(4-(4-methylpiperazin-1-yl))piperidin-1 - yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (51.3 mg, 57%).

1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.74 (dd, J=7.4, 2.2 Hz, 1H), 7.53 (dd, J=7.4, 2.1 Hz, 1H), 7.48 (d, J= 8.7 Hz, 1H), 7.43 (td, J=7.4, 1.9 Hz, 1H), 7.36 (td, J=7.5, 1.9 Hz, 1H), 6.92 (sd, J=2.5 Hz, 1H), 6.67 (dd, J=8.9, 2.5 Hz, 1H), 3.88 (s, 3H), 3.82 (d, J=12.4 Hz, 2H), 3.43 (br s, 4H), 3.24-3.04 (m, 7H), 2.96 ( s, 3H), 2.92 (s, 3H), 2.19 (d, J=12.7, 2H), 1.99-1.86 (m, 2H); LC-MS calculated C ₂₈ H ₃₇ ClN ₈ O ₃ S 600.2, found 601.0 (M+H+).

The compound of Example 11 was prepared according to Reaction Example 10 below.

Reaction example 10

Example 11 Preparation of N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl) methanesulfonamide.

Step 1. Preparation of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine.

Reaction tube containing DMF (30 ml) of a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5.00 g, 29.22 mmol), N,N-dimethylpiperidin-4-amine (6.53 g, 35.06 mmol), and K ₂ CO ₃ (6.06 g, 43.83 mmol) was capped with Teflon and the above reaction mixture was stirred for 2 h at 90°C. The above mixture was concentrated under reduced pressure. The above reaction mixture was diluted with ethyl acetate (300 ml), washed with water (100 ml), and then washed with brine (100 ml). The residue was purified by silica gel flash column chromatography (CH ₂ Cl ₂ /MeOH, 9:1) to give 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidine-4-amine (9.73 g, solid pale yellow) with a yield of 99%.

1H NMR (300 MHz, CDCl3) δ 7.99 (d, J=9.4 Hz, 1H), 6.42 (dd, J=9.4, 2.6 Hz, 1H), 6.31 (sd, J=2.5 Hz, 1H), 3.94 (s , 3H), 3.92 (d, J=13.0 Hz, 2H), 2.97 (td, J=12.3, 2.8 Hz, 2H), 2.43-2.339 (m, 1H), 2.30 (s, 6H), 1.95 (d , J=13.0 Hz, 2H), 1.58 (qd, J=11.9, 4.0 Hz, 2H); LC-MS calculated C ₁₄ H ₂₁ N ₃ O ₃ 279.2, found 280.0 (M+H+).

Step 2: Preparation of 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine.

In the same manner as described in step 2 of Example 6 above, 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (8.50 mg, 96%) was prepared.

LC-MS calculated C ₁₄ H ₂₄ N ₃ O 249.2, found 250.0 (M+H+).

Step 3: Preparation of N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl) methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, Ν-(2-((5-χλορ2-((4-(4-(dimethylamino))piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidine was prepared -4-yl)amino)phenyl)methanesulfonamide (46.7 mg, 57%).

1H NMR (300 MHz, CD3OD) δ 8.04 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52 (dd, J=7.5, 2.0 Hz, 1H), 7.42-7.32 (m, 2H) , 7.25 (d, J=8.7, 1H), 6.70 (sd, J=2.5Hz 1H), 6.50 (d, J=8.7Hz, 1H), 3.90 (d, J=12.8Hz, 2H), 3.84 (s , 3H), 3.44-3.34 (m, 1H), 2.97 (s, 3H), 2.92-2.82 (m, 8H), 2.25 (d, J=12.1 Hz, 1H), 1.93-1.79 (m, 2H); LC-MS calculated C ₂₅ H ₃₂ ClN ₇ O ₃ S 545.2, found 546.0 (M+H+).

The compound of Example 12 was prepared according to Reaction Example 11 below.

- 20 041822

Reaction example 11

G · «« ' ' OO ί .

- J 1 HH' N ' stage * stage 2 ^C! s

H _S M H>N and ' .

About ^W th

- ⁿ o

Example 12 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

Stage 1. Obtaining 2-methoxy-4-(1-methylpiperidin-4-yl)aniline.

To a suspension of tetrahydrofuran (18 ml) and lithium tetrahydroaluminate (619.3 mg, 16.3 mmol) was added tetrahydrofuran (18 ml) 0°C. The above reaction tube was capped with Teflon, and the above reaction mixture was stirred for 6 hours at 90°C. The above reaction mixture was cooled, Na ₂ SO ₄ 10H ₂ O (3 g) was slowly added and it was stirred for 30 min at ambient temperature. The above mixture was filtered and washed with dichloromethane. The above organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo to give 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (319.4 mg, brown solid) in 89% yield.

1H NMR (300 MHz, CD3OD) δ 6.68-6.64 (m, 3H), 3.82 (s, 3H), 2.98-2.92 (m, 2H), 2.43-2.34 (m, 1H), 2.31 (s, 3H), 2.07-1.98 (m, 2H), 1.82-1.77 (m, 4H); LC-MS calculated Q3H20N2O 220.2, found 221.1 (m+H ⁺ ).

Step 2: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((5-χλορ2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4 -yl)amino)phenyl)methanesulfonamide (55.1 mg, 71%).

1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.75 (dd, J=7.4, 2.2 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.41-7.31 (m, 2H) , 6.92 (sd, J=1.8Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 3.87 (s, 3H), 3.63 (d, J=12.2Hz 1H), 3.15 (td, J=12.1 , 3.1 Hz, 2H), 2.94 (s, 3H), 2.93 (s, 3H), 2.89-2.82 (m, 1H), 2.11 (d, J=14.2 Hz, 2H), 2.03-1.89 (m, 2H) ; LC-MS calculated C ₂₄ H ₂₉ ClN ₆ O ₃ S 516.2, found 516.9 (M+H+).

The compound of Example 13 was prepared according to Reaction Example 12 below.

Reaction example 12

Example 13 Preparation of N-(2-((5-chloro-2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide.

Step 1: Preparation of 2-(4-(4-amino-3-methoxyphenyl)piperidin-1-yl)ethyl acetate.

CH ₂ C1 ₂ /trifluoroacetic acid (1:1, 1 ml) tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate 30 (300 mg, 0.98 mmol) was stirred for 2 h at ambient temperature. The above reactant was concentrated under reduced pressure. To an acetonitrile solution (10 mL) of the above residue was added 2-bromoethyl acetate (140 µL, 1.22 mmol) and potassium carbonate (1.00 g, 7.83 mmol) over 4 h at 95°C. The above mixture was concentrated under reduced pressure. The above reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (50 ml). The residue was purified by silica gel flash column chromatography (CH ₂ C1 ₂ /MeOH, 9:1) to give 2-(4-(4-amino-3-methoxyphenyl)piperidin-1-yl)ethyl acetate (125.8 mg, oil pale -yellow) with a yield of 44%.

1H NMR (300 MHz, CDCl ₃ ) δ 6.66 (m, 3H), 4.23 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 3.68 (br s, 2H), 3.04 (dt, J= 11.3, 2.8 Hz, 2H), 2.67 (t, J=6.0 Hz, 2H), 2.40 (tt, J=10.3, 5.1 Hz, 1H), 2.20-2.10 (m, 2H), 2.08 (s, 3H), 1.841.75 (m, 4H); LC-MS calculated C ₁₆ H ₂₄ N ₂ O ₃ 292.2, found 293.0 (M+H+).

Step 2: Preparation of N-(2-((5-chloro-2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((5-χλορ2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2-methoxyphenyl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide (74 mg, 61%).

1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.74 (dd, J=7.5, 2.0 Hz, 1H), 7.54-7.49 (m, 2H), 7.42-7.31 (m, 2H), 6.93 ( sd, J=1.8 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 3.94-3.91 (m, 2H), 3.87 (s, 3H), 3.74 (d, J=12.5 Hz, 2H), 3.30-3.28 (m, 2H), 3.16 (td, J=12.6, 3.6 Hz, 2H), 2.94 (s, 3H), 2.92-2.86 (m, 1H), 2.14-1.97 (m, 4H); LC-MS calculated C ₂₅ H ₃ iC1N ₆ O ₄ S 546.2, found 547.4 (M+H+).

The compound of Example 14 was prepared according to Reaction Example 13 below.

- 21 041822

Reaction example 13

Example 14 Preparation of N-(2-((5-chloro-2-((4-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-2methoxyphenyl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of tert-butyl 4-(4-(3-methoxy-4-nitrophenyl)-3,6-dihydropyridin-1(2H)yl)piperidine-1-carboxylate.

4-(3-Methoxy-4-nitrophenyl)-1,2,3,6-tetrahydropyridine (1.29 g, 5.51 mmol), 1-boc-4-piperidone (2.19 g, 11.01 mmol), 1 M dichloromethane solution (170 μl, 17.62 mmol) of acetic acid and 1,2dichloroethane (20 ml) of triethylamine (730 μl, 5.23 mmol) were stirred for 1 h at ambient temperature, and then sodium triacetoxyborohydride (1.75 g, 8.26 mmol) was added. The above reaction mixture was stirred overnight at ambient temperature. The above mixture was diluted with methylene chloride (200 ml), washed with saturated aqueous NaHCO ₃ (100 ml) and then washed with water (100 ml). The above organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (CH ₂ Cl ₂ /MeOH, 9:1) to give tert-butyl 4-(4-(3-methoxy- 4-nitrophenyl)-3,6dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (1.11 g, pale brown solid) in 50% yield.

LC-MS calculated C ₂₂ H ₃₁ N ₃ O ₅ 417.2, found 418.0 (M+H+).

Step 2: Preparation of 2-(4-(4-(4-amino-3-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl)piperidin1-yl)ethyl acetate.

In the same manner as described in step 2 of Example 13 above, 2-(4-(4-(4amino-3-methoxyphenyl)-3,6-dihydropyridin-1(2H)-yl)piperidin-1-yl) was prepared ethyl acetate (536.6 mg, 50%).

LC-MS calculated C ₂₁ H ₂₉ N ₃ O ₅ , 403.2, found 404.1 (M+H+).

Step 3: Preparation of 2-(4-(4-amino-3-methoxyphenyl)-[1,4'-bipiperidin]-1'-yl)ethyl acetate.

To a methanolic solution (10 ml) of 2-(4-(4-(4-amino-3-methoxyphenyl)-3,6-dihydropyridin-1(2H)yl)piperidin-1-yl)ethyl acetate (536.6 mg, 1.33 mmol ) was added 10% Pd/C (palladium on activated carbon, 141.5 mg, 1.33 mmol). The above reaction mixture was stirred overnight under a hydrogen atmosphere. The filtrate, filtered through celite, was concentrated under reduced pressure to give 2-(4-(4-amino-3-methoxyphenyl)-[1,4'-bipiperidin]-1'-yl)ethyl acetate (399.9 mg, brown gum) with a yield of 80% without a separate purification process.

LC-MS calculated C ₂₁ H ₃₃ N ₃ O ₃ 375.3, found 376.2 (M+H+).

Step 4: Preparation of N-(2-((5-chloro-2-((4-(1'-(2-hydroxyethyl)-[1,4'-bipiperidin]-4-yl)-2methoxyphenyl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, Ν-(2-((5-χλορ2-((4-( 1'-(2-hydroxyethyl)-[1,4'-bipiperidine]-4 -yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (3.4 mg, 4%).

1H NMR (300 MHz, CD3OD) δ 8.13 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.53 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (d, J=8.2 Hz , 1H), 7.43-7.32 (m, 2H), 6.94 (s, 1H), 6.70 (d, J=8.4 Hz, 1H), 3.93-3.84 (m, 7H), 3.72 (d, J=11.7 Hz, 2H), 3.62-3.54 (m, 1H), 3.24-3.13 (m, 4H), 2.94-2.86 (m, 4H), 2.48 (d, J=13.0 Hz, 2H), 2.22-2.06 (m, 7H) ; LCMS calculated C ₃₀ H ₄₀ ClN ₇ O ₄ S 629.3, found 630.0 (M+H+).

The compound of Example 15 was prepared according to Reaction Example 14 below.

Reaction Example 14

Example 15 Preparation of N-(2-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

To a solution of dichloromethane (2 ml) of N-(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (40 mg, 0.07 mmol) triethylamine (20

- 22 041822 µl, 0.14 mmol) and acetic anhydride (10 µl, 0.07 mmol) at 0°C. The above reaction mixture was stirred for 2 hours at ambient temperature. The above mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N-(2-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4 -yl)amino)phenyl)methanesulfonamide (12.7 mg, white solid) in 34% yield.

1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.51 (dd, J=7.7, 1.9 Hz, 1H), 7.43-7.32 (m, 3H) , 6.94 (s, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.68 (d, J=13.2 Hz, 1H), 4.05 (d, J=13.6 Hz, 1H), 3.86 (s, 3H) , 3.24 (t, J=12.1 Hz 1H), 2.95 (s, 3H), 2.87-2.66 (m, 2H), 2.15 (s, 3H), 1.88 (t, J=13.7 Hz, 2H), 1.76-1.51 (m, 2H); LCMS calculated C ₂₅ H ₂₉ ClN ₆ O ₄ S 544.2, found 545.0 (M+H+).

Examples 16-18 were prepared according to Reaction Example 15 below.

Reaction Example 15 where R ⁶ =H indicates the compound of example 16, R ⁶ =CH ₃ indicates the compound of example 17 and R ⁶ =Ac indicates the compound of example 18.

Example 16 Preparation of N-(2-((2-((4-([1,4'-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide .

No.(2-((5-Chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (24.4 mg, 0.04 mmol), 1-boc-4-piperidone (16.9 mg, 0.08 mmol), 1 M dichloromethane solution (120 µl, 0.12 mmol) acetic acid, and 1,2-dichloroethane (1 ml) triethylamine (10 µl, 0.04 mmol) were stirred for 1 h at ambient temperature, and then a solution of sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) was added. The above reaction mixture was stirred overnight at ambient temperature. The above mixture was concentrated under reduced pressure, CH ₂ C1 ₂ /trifluoroacetic acid (1:1, 1 ml) was added and it was stirred for 2 h at ambient temperature. The above reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give N-(2-((2-((4-([1,4'-bipiperidin]-4-yl)-2methoxyphenyl)amino)-5- chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (9.4 mg, red solid) in 51% yield.

1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.78-7.74 (m, 1H), 7.53-7.47 (m, 1H), 7.42-7.36 (m, 2H), 7.32 (d, J=8.1 Hz, 1H), 7.12 (sd, J=1.6Hz, 1H), 6.99 (dd, J=8.2, 1.6Hz, 1H), 4.39 (d, J=13.4Hz, 1H), 3.98 (s, 3H), 3.89-3.78 (m, 1H), 3.74-3.58 (m, 1H), 3.52 (d, J=13.0 Hz, 2H), 3.21 (t, J=13.0 Hz, 2H), 3.10 (t, J=13.6 Hz , 1H), 3.03 (s, 3H), 2.23 (d, J=13.5 Hz, 2H), 2.08-1.97 (m, 4H), 1.84-1.71 (m, 2H); LC-MS calculated C28H36CIN7O3S 585.2, found 586.0 (M+H+).

Example 17 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(1'-methyl-[1,4'-bipiperidin]-4-yl)phenyl)amino)pyrimidin- 4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in step 1 of Example 16 above, N-(2-((5chloro-2-((2-methoxy-4-(1'-methyl-[1,4'-bipiperidine]-4 -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (73.3 mg, 88%).

1H NMR (300 MHz, CD3OD) δ 8.13 (s, 1H), 7.72 (dd, J=7.8, 1.7 Hz, 1H), 7.52 (dd, J=7.8, 1.7 Hz, 1H), 7.45 (d, J= 8.2 Hz, 1H), 7.40 (td, J=7.6, 1.8 Hz, 1H), 7.34 (td, J=7.7, 1.7 Hz, 1H), 6.94 (sd, J=1.8 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 3.87 (s, 3H), 3.72 (d, J=11.9 Hz, 4H), 3.66-3.53 (m, 1H), 3.27-3.09 (m, 4H), 2.94 (s, 3H ), 2.92 (s, 3H), 2.91-2.84 (m, 1H), 2.47 (d, J=13.4 Hz, 2H), 2.24-2.06 (m, 6H); LC-MS calculated C ₂₉ H ₃₈ ClN ₇ O ₃ S 599.2, found 600.0 (M+H+).

Example 18 Preparation of N-(2-((2-((4-(1'-acetyl-[1,4'-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5chloropyrimidin-4-yl) amino)phenyl)methanesulfonamide.

In the same manner as described in step 1 of Example 16 above, the preparation of N-(2-((2-((4(G-acetyl-[1,4'-bipiperidin]-4-yl)-2-methoxyphenyl) was carried out amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (40.2 mg, 46%).

1Н NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), 7.75 (dd, J=7.2, 2.3 Hz, 1H), 7.55-7.50 (m, 2H), 7.41-7.32 (m, 2H), 6.91 ( s, 1H), 6.68 (d, J=9.5 Hz, 1H), 4.74 (d, J=13.6 Hz, 1H), 4.13 (d, J=13.9 Hz, 1H), 3.87 (s, 3H), 3.67 ( d, J=12.1 Hz, 2H), 3.57-3.49 (m, 1H), 3.21 (t, J=12.9 Hz, 3H), 2.94 (s, 3H), 2.92-2.85 (m, 1H), 2.68 (t , J=12.7 Hz, 1H), 2.24-2.17 (m, 7H), 2.08-1.92 (m, 2H), 1.85-1.61 (m, 2H); LC-MS calculated C ₃₀ H ₃₈ ClN ₇ O ₄ S 627.2, found 628.0 (M+H+).

- 23 041822

Examples 19-22 were prepared according to Reaction Example 16 below. Reaction example 16

where in the compound obtained after step 5, R ⁶ =Ac indicates the compound of example 19 and R ⁶ =Boc indicates the compound of example 20, and the compound obtained after step 6 is the compound of example 21, and the compound obtained after step 7 is the compound of Example 22.

Example 19 Preparation of N-(2-((2-((4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl )amino)phenyl)methanesulfonamide.

Stage 1. Preparation of 8-(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane.

While stirring a solution of DMF (75 mL) and 4-fluoro-2-methoxy-1-nitrobenzene (5 g, 29.21 mmol) at ambient temperature, 1,4-dioxa-8-azaspiro[4.5]decane (5.0 g, 35.0 mmol) and potassium carbonate (8.0 g, 58.0 mmol) was added. The above reaction mixture was stirred overnight at ambient temperature. The above reaction mixture was quenched with cold water and stirred for 15 minutes. The precipitated solid was filtered off and dried to give 8(3-methoxy-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (8.0 g, 94%) as a yellow solid.

'H NMR (300 MHz, CDCl3) δ 8.01 (d, J=9.3 Hz, 1H), 6.45 (dd, J=9.4, 2.6 Hz, 1H), 6.35 (d, J=2.5 Hz, 1H), 4.02 ( s, 4H), 3.96 (s, 3H), 3.72–3.46 (m, 4H), 2.24–1.72 (m, 4H).

Stage 2. Obtaining 2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline.

10% Pd/C (palladium on activated carbon, 36 mg, 0.33 mmol) in an argon atmosphere. The above reaction mixture was stirred for 3 hours at ambient temperature under a hydrogen gas pressure of 1 atm. The above reaction mixture was filtered through Celite and concentrated under reduced pressure to give 2-methoxy-4-(1,4-dioxa-8azaspiro[4.5]decan-8-yl)aniline (800 mg, 90%) as a brown solid .

¹ H NMR (300 MHz, CDCl3) δ 6.67-6.50 (m, 3H), 4.02 (s, 4H), 3.87 (br s, 3H), 3.22 (br s, 4H), 1.95 (br s, 4H).

Step 3. Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8yl)phenyl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide.

To a mixture of n-butanol (5 ml) and N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (200 mg, 0.60 mmol) and 2-methoxy-4-(1,4 -dioxa-8-azaspiro[4.5]decan-8-yl)aniline (158 mg, 0.60 mmol) was added a solution of n-butanol (3.75 ml, 0.30 mmol) and 0.08 N HCl or TFA (trifluoroacetic acid). The above reaction tube was closed with a Teflon-coated cap, and the reaction mixtures were stirred overnight at 95°C. The above mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give N-(2-((5-chloro-2-((2-methoxy-4-(1,4dioxa-8-azaspiro[4.5]decan-8 -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (150 mg, 40%) as a white solid.

Step 4: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-oxopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

While stirring a solution of methanol (2 ml) and N-(2-((5-chloro-2-((2-methoxy-4-(1,4-dioxa-8azaspiro[4.5]decan-8-yl)phenyl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide (150 mg, 0.267 mmol), 6 N HCl (2 mL) was added at ambient temperature. The above reaction mixture was heated at 60° C. for 3 hours. The above reaction mixture was cooled at ambient temperature and the volatile substance was removed under reduced pressure. Received unrefined

- 24 041822 the product was diluted with water, made basic (pH ~8) with 5 N NaOH aqueous solution, and then extracted with dichloromethane. The above organic layer was extracted, washed with water and brine, then dried over Na ₂ SO ₄ , and evaporated under reduced pressure to give N-(2-((5-chloro-2-((2-methoxy-4-(4oxo-piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (100 mg, 72%) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.88-7.65 (m, 3H), 7.64-7.45 (m, 1H), 7.43-7.31 (m, 2H), 6.56 (d, J =2.6 Hz, 1H), 6.39 (dd, J=8.8, 2.5 Hz, 1H), 3.86 (s, 3H), 3.54 (t, J=6.2 Hz, 4H), 2.96 (s, 3H), 2.61 (t , J=6.0 Hz, 4H).

Step 5: Preparation of N-(2-((2-((4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl )amino)phenyl)methanesulfonamide.

After stirring N-(2-((2-((4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino )phenyl)methanesulfonamide (60 mg, 0.11 mmol), 1-acetylpiperazine (28 mg, 0.17 mmol), 1 M solution (220 μl, 0.17 mmol) of dichloromethane and acetic acid, and 1,2-dichloroethane solution (1 ml) of triethylamine (50 μL, 0.34 mmol) for 1 h at ambient temperature, sodium triacetoxyborohydride (49 mg, 0.23 mmol) was added. The above reaction mixture was stirred overnight at ambient temperature. The above mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-(2-((2-((4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)5-chloropyrimidin-4 -yl)amino)phenyl)methanesulfonamide (35 mg, white solid) in 48% yield.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.79-7.75 (m, 1H), 7.72 (dd, J=7.2, 2.3 Hz, 1H), 7.56-7.52 (m, 2H), 7.38-7.32 (m, 3H), 6.51 (br s, 1H), 6.33 (d, J=8.9 Hz, 1H), 3.85 (s, 3H), 3.69-3.61 (m, 4H), 2.93 (s, 3H ), 2.71 (t, J=11.7 Hz, 4H), 2.13 (br s, 3H), 2.03 (s, 4H), 1.80 (bs, 4H); LC-MS calculated C ₂₉ H ₃₇ ClN ₈ O ₄ S 628.23, found 627.0 (MH ⁺ ).

Example 20 Preparation of tert-butyl 4-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-4 -yl)piperazine-1-carboxylate.

In the same manner as described in step 5 of Example 19 above, tert-butyl 4-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino))pyrimidin-2-yl )amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (52 mg, 63%).

A NMR (300 MHz, CDCl ,) δ 8.09 (s, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.72-7.66 (m, 1H), 7.57-7.52 (m, 1H), 7.48 ( s, 1H), 7.38-7.31 (m, 2H), 7.26 (s, 1H), 6.50 (br s, 1H), 6.33 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 3.69- 3.54 (m, 6H), 2.92 (s, 3H), 2.77-2.62 (m, 6H), 2.07-1.99 (m, 3H), 1.83-1.74 (m, 2H), 1.49 (s, 9H); LC-MS calculated C ₃₂ H ₄₃ ClN ₈ O ₅ S 686.28, found 685.0 (MH ⁺ ).

Example 21 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1yl)phenyl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide.

To a mixture of dichloromethane (1 ml) and tert-butyl 4-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl )piperidin-4-yl)piperazine-1-carboxylate (20 mg, 0.03 mmol) dioxane solution (0.014 ml, 0.06 mmol) and 4 N HCl were added at 0°C. The above reaction mixture was heated at ambient temperature and stirred for 2 hours. The above reaction mixture was concentrated under reduced pressure to give N-(2-((5-chloro-2-((2methoxy-4-(4-(piperazine-1 -yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (20 mg, white solid) in 88% yield.

¹ H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.52-7.44 (m, 2H), 7.45-7.40 (m, 1H), 7.16 (br s, 1H), 6.85 (br s, 1H), 3.94-3.88 (m, 5H), 3.70-3.66 (m, 8H), 3.50-3.38 (m, 2H), 3.00 (s, 3H), 2.51-2.40 (m, 2H), 2.34-2.18 (m, 2H); LC-MS calculated C ₂₇ H ₃₅ ClN ₈ O ₃ S 586.22, found 585.1 (M-H ⁺ ).

Example 22 Preparation of N-(2-((5-chloro-2-((4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl)2-methoxyphenyl)amino) pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

While stirring a solution of DMF (1 ml) and N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1yl)piperidin-1-yl)phenyl)amino)pyrimidin- 4-yl)amino)phenyl)methanesulfonamide (30 mg, 0.05 mmol), DIPEA (diisopropylethylamine) (0.017 ml, 0.1 mmol) and 2-iodoethanol (10.9 mg, 0.06 mmol) were added at ambient temperature. The above reaction mixture was heated at 80°C for 30 min under MW (microwaves). The above reaction mixture was concentrated and purified by HPLC to give N-(2-((5-chloro-2-((4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl) 2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (20.1 mg, 70%) as a white solid.

¹ NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), 7.76 (dd, J=7.4, 2.1 Hz, 1H), 7.58-7.53 (m, 1H), 7.49-7.37 (m, 3H), 6.91 ( d, J=2.6 Hz, 1H), 6.66 (dd, J=8.8, 2.5 Hz, 1H), 3.92-3.80 (m, 7H), 3.50 (br s, 4H), 3.31-3.25 (m, 4H), 3.12-3.16 (m, 4H), 2.99 (s, 3H), 2.23 (d, J=12.4 Hz, 2H), 1.99-1.87 (m, 2H); LC-MS calculated C ₂₉ H ₃₉ ClN ₈ O ₄ S 630.25, found 629.1 (MH ⁺ ).

Examples 23 and 27 were prepared according to Reaction Example 17 below.

- 25 041822

Reaction example 17

where the compound obtained after performing step 1 is the compound of example 23, and in the compound obtained after performing step 2, R ⁶ =Ac means the compound of example 24, R ⁶ =Me means the compound of example 25 and R ⁶ =Boc means the compound of example 26 and the compound obtained after step 3 is the compound of Example 27.

Example 23 Preparation of N(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

To a mixture of n-butanol (1 ml) and N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide 2 (100 mg, 0.30 mmol) and tert-butyl 4-(4-amino -3-methoxyphenyl)piperazine-1-carboxylate (92.2 mg, 0.30 mmol) was added an n-butanol solution (3.75 ml, 0.30 mmol) of 0.08 N HCl or TFA (trifluoroacetic acid). The above reaction tube was closed with a Teflon-coated cap, and the reaction mixtures were stirred overnight at 95°C. The above mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give Ν-(2-((5-χλορ-2-((2methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide (150 mg, 82%) as a white solid.

¹ H NMR (500 MHz, CD3OD) δ 8.09 (s, 1H), 7.82-7.77 (m, 1H), 7.54 (dd, J=7.9, 1.7 Hz, 1H), 7.44-7.31 (m, 3H), 6.74 (d, J=2.5 Hz, 1H), 6.50 (s, 1H), 3.87 (s, 3H), 3.45 (m, 4H), 3.41 (m, 4H), 2.98 (s, 3H).

Example 24 Preparation of N-(2-((2-((4-(4-(1-acetylpiperidin-4-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl )amino)phenyl)methanesulfonamide.

In the same manner as described in step 4 of Example 19 above, N-(2-((2-((4(4-(1-acetylpiperidin-4-yl)piperazin-1-yl)-2-methoxyphenyl) was prepared amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (60 mg, 64%).

1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.75-7.68 (m, 1H), 7.60 (s, 1H), 7.577.50 (m, 1H), 7.37-7.31 (m, 2H), 6.49 (d, J=2.5 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.29-3.18 (br s, 4H), 3.16-3.40 (m, 2H), 2.94 (s, 3H), 2.90-2.81 (br s, 4H), 2.66-2.52 (m, 2H), 2.13 (s, 3H), 1.99-1.95 (m , 2H), 1.59–1.47 (s, 2H); LC-MS calculated C29H37QN8O4S 628.23, found 627.0 (MH ⁺ ).

Example 25 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide.

In the same manner as described in Step 4 of Example 19 above, N-(2-((5-χλορ-2-((2methoxy-4-(4-(1-methylpiperidin-4-yl))piperazin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (29.6 mg, 33%).

¹ H NMR (500 MHz, CD ₃ OD) δ 8.08 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.53 (dd, J=7.7, 1.8 Hz, 1H), 7.40-7.33 (m , 3H), 6.73 (d, J=2.5 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 3.87 (s, 3H), 3.75 (d, J=12.8 Hz, 2H), 3.62-3.45 (m, 8H), 3.20-3.12 (m, 2H), 2.98 (s, 3H), 2.95 (s, 3H), 2.56-2.47 (d, J=13.4 Hz, 2H), 2.20-2.10 (m, 2H ); LC-MS calculated C2 ₈ H37ClN ₈ O3S 600.24, found 599.0 (MH ⁺ ).

Example 26 Preparation of tert-butyl 4-(4-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin2-yl)amino)-3-methoxyphenyl)piperazin-1-yl )piperidine-1-carboxylate.

In the same manner as described in Step 4 of Example 19 above, tert-butyl 4-(4-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino))pyrimidin-2-yl )amino)-3-methoxyphenyl)piperazin-1-yl)piperidine-1-carboxylate (16.0 mg, 17%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.56-7.51 (m, 2H), 7.38- 7.31 (m, 2H), 6.49 (d, J=2.5 Hz, 1H), 6.32 (d, J=9.2 Hz, 1H), 4.23 (br s, 2H), 3.84 (s, 3H), 3.29 (br s , 4H), 2.94 (br s, 7H), 2.83–2.67 (m, 4H), 2.08–2.98 (m, 2H), 1.49 (s, 9H); LC-MS calculated C ₃₂ H ₄₃ ClN ₈ O ₅ S 686.28, found 684.9 (MH ⁺ ).

Example 27 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-yl)piperazin-1yl)phenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide.

In the same manner as described in Example 21 above, N-(2-((5-chloro-2-((2-methoxy-4-(4(piperidin-4-yl)piperazin-1-yl)phenyl) was prepared )amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (16 mg, 95%).

1H NMR (300 MHz, CD3OD) δ 8.09 (s, 1H), 7.75 (br s, 1H), 7.55 (br s, J=7.9, 1.6 Hz, 1H), 7.48-7.35 (m, 2H), 7.29 ( d, J=8.8 Hz, 1H), 6.77 (s, 1H), 6.54 (br s, 1H), 4.04-3.90 (m, 2H), 3.88 (s, 3H), 3.84-3.69 (m, 4H), 3.66-3.58 (m, 2H), 3.44-3.34 (m, 2H), 3.27-3.11 (m, 3H), 3.00 (s, 3H), 2.55 (d, J=13.3 Hz, 2H), 2.29-2.00 ( m, 2H); LC-MS calculated C27H35ClN8O3S 586.22, found 585.0 (MH ⁺ ).

- 26 041822

Example 28 was prepared according to Reaction Example 18 below. Reaction example 18

Example 28 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((5-χλορ-2-((2methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-4 -yl)amino)phenyl)methanesulfonamide (15.0 mg, 19%).

1H NMR (300 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.51 (m, 2H), 7.38-7.32 (m, 2H), 6.48 (d, J=2.5 Hz, 1H), 6.35-6.28 (m, 1H), 3.85 (s, 3H), 3.34-3.26 (m, 4H), 3.02-2.86 (m, 7H ), 2.59 (s, 3H); LC-MS calculated C ₂₃ H ₂₈ ClN ₇ O ₃ S 517.17, found 515.9 (MH ⁺ ).

The compound of Example 29 was prepared according to Reaction Example 19 below.

Reaction example 19

Example 29 Preparation of 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperazine.

Step 1. Preparation of tert-butyl 4-(4-((5-chloro-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in Step 1 of Example 6 above, tert-butyl 4(4-((5-chloro-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl was prepared. )piperazine-1-carboxylate (1.35 g, 69%).

1H NMR (300 MHz, CDCl3) δ 10.61 (s, 1H), 8.95 (dd, J=8.7, 1.3 Hz, 1H), 8.26 (dd, J=8.5, 1.6 Hz, 1H), 8.19 (s, 1H) , 8.02 (d, J=8.7Hz, 1H), 7.60 (td, J=8.6, 7.9, 1.6Hz, 1H), 7.30 (s, 1H), 7.16 (ddd, J=8.5, 7.2, 1.3Hz, 1H ), 6.56 (d, J=2.5 Hz, 1H), 6.50 (dd, 7=8.7, 2.5 Hz, 1H), 3.89 (s, 3H), 3.71-3.50 (m, 4H), 3.12-3.08 (m, 4H), 1.49 (s, 9H); LC-MS calculated C ₂₆ H ₃₀ ClN ₇ O ₅ 555.2, found 555.9 (M+H ⁺ ).

Step 2. Preparation of tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5-chloropyrimidin-2-yl)amino)-3methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in Step 2 of Example 6 above, tert-butyl 4(4-((4-((2-aminophenyl)amino)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperazine-1-carboxylate (900 mg, 70%).

LC-MS calculated C ₂₆ H ₃₂ BrN ₇ O ₃ 525.2, found 526.0 (M+H ⁺ ).

Step 3. Preparation of tert-butyl 4-(4-((4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino)-5-chloropyrimidin-2-yl)amino)-3 -methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in Step 3 of Example 6 above, tert-butyl 4(4-((5-chloro-4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino )pyrimidin-2-yl)amino)-3methoxyphenyl)piperazine-1-carboxylate (13.5 mg, 39%).

1H NMR (500 MHz, CDCl3) δ 8.03-7.90 (m, 3H), 7.87 (d, J=8.7 Hz, 1H), 7.46-7.28 (m, 3H), 7.20 (t, J=7.6 Hz, 1H) , 6.50 (s, 1H), 6.34 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.58 (t, J=5.0 Hz, 4H), 3.04 (t, J=5.0 Hz, 4H) , 1.48(s, 18H).

Step 4: Preparation of 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperazine.

In the same manner as described in Step 4 of Example 6 above, 4-(4-((5-chloro4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperazine (3.6 mg, quantitative yield).

1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), 7.93-7.81 (m, 1H), 7.50 (dd, J=7.7, 1.9 Hz, 1H), 7.43-7.24 (m, 3H), 6.73 ( s, 1H), 6.53 (d, J=8.7 Hz, 1H), 3.85 (s, 3H), 3.43-3.40 (m, 8H); LC-MS calculated C ₂₁ H ₂₅ ClN ₈ O ₃ S 504.2, found 504.8 (M+H ⁺ )

Example 30 was prepared according to Reaction Example 20 below.

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Reaction Example 20

Example 30 Preparation of 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperazine.

Step 1. Preparation of tert-butyl 4-(4-((5-bromo-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in Step 1 of Example 6 above, tert-butyl 4(4-((5-bromo-4-((2-nitrophenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl was prepared. )piperazine-1-carboxylate (70 mg, 12%).

1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 8.86 (d, J=8.8 Hz, 1H), 8.30-8.25 (m, 2H), 8.04 (s, 1H), 7.60 (t, J= 8.0 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.61 (s, 1H), 3.90 (s, 3H), 3.69 (br s, 4H), 3.16 (br s, 4H), 1.52- 1.44(s, 9H); LC-MS calculated C ₂₆ H ₃₀ BrN ₇ O ₅ 599.2, found 600.7 (M+H+).

Step 2. Preparation of tert-butyl 4-(4-((4-((2-aminophenyl)amino)-5-bromopyrimidin-2-yl)amino)-3methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in Step 2 of Example 6 above, tert-butyl 4(4-((4-((2-aminophenyl)amino)-5-bromopyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperazine-1-carboxylate (50 mg, 74%).

LC-MS calculated C ₂₆ H ₃₃ BrN ₇ O ₃ 569.2, found 569.8 (M+H+).

Step 3. Preparation of tert-butyl 4-(4-((5-bromo-4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino)pyrimidin-2-yl)amino)- 3-methoxyphenyl)piperazine-1-carboxylate.

In the same manner as described in step 3 of Example 6 above, tert-butyl 4(4-((5-bromo-4-((2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)phenyl)amino )pyrimidin-2-yl)amino)3-methoxyphenyl)piperazine-1-carboxylate (20 mg, 33%).

¹ H NMR (300 MHz, CD3OD) δ 8.07 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.38 ( dd, J=7.7, 1.5 Hz, 1H), 7.31 (td, J=7.8, 1.7 Hz, 1H), 7.27-7.19 (m, 1H), 6.62 (s, 1H), 6.39 (s, 1H), 3.84 (s,

3H), 3.62-3.52 (m, 4H), 3.09 (br s, 4H), 1.49 (s, 9H), 1.48 (s, 9H); LC-MS calculated C ₃₁ H ₄₁ BrN ₆ O ₇ S 748.2, found 748.6 (M+H+).

Step 4: Preparation of 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperazine.

In the same manner as described in Step 4 of Example 6 above, 4-(4-((5-bromo4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl) was prepared. piperazine (16.9 mg, quantitative yield).

1H NMR (500 MHz, CD ₃ OD) δ 8.13 (s, 1H), 7.90 (s, 1H), 7.50 (dd, J=7.7, 1.6 Hz, 1H), 7.41-7.25 (m, 3H), 6.74 ( d, J=2.5 Hz, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.45 (q, J=4.1, 3.6 Hz, 4H), 3.39 (dd, J=6.7, 3.3 Hz, 4H ); LCMS calculated C ₂₁ H ₂₅ BrN ₈ O ₃ S 548.1, found 548.7 (M+H+).

The compound of Example 31 was prepared according to Reaction Example 21 below.

Reaction Example 21

Example 31 Preparation of N-(2-((2-((2-methoxy-4-(piperazin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 1 of Example 1 above, N-(2-((2-χλορ5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (199 mg, 18%) was prepared.

1H NMR (300 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.23 (br s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.46-7.28 (m, 3H), 6.27 (br s , 1H), 3.05 (s, 3H); LC-MS calculated C12H10CW3N4O2S 366.0, found 366.8 (M+H+).

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Step 2: Preparation of N-(2-((2-((2-methoxy-4-(piperazin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Step 2 of Example 1 above, N-(2-((2-((2-methoxy4-(piperazin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl) amino) phenyl) methanesulfonamide (54.2 mg,

65%).

1H NMR (300 MHz, CD3OD) δ 8.32 (br s, 1H), 7.68 (br s, 1H), 7.49 (dd, J=7.4, 2.1 Hz, 1H), 7.43-7.29 (m, 3H), 6.69 ( br s, 1H), 6.39 (br s, 1H), 3.85 (s, 3H), 3.39 (br s, 8H), 2.93 (s, 3H); LC-MS calculated C ₂₃ H ₂₆ F ₃ N ₇ O ₃ S 537.2, found 537.8 (M+H+).

Example 32 was prepared according to Reaction Example 22 below.

Reaction Example 22

Example 32 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

Step 1. Obtaining 5-chloro-N ² -(2-methoxy-4-morpholinophenyl)-N ⁴ -(2-nitrophenyl)pyrimidine-2,4diamine.

In the same manner as described in step 1 of Example 6 above, 5-chloro-N ² -(2methoxy-4-morpholinophenyl)-N ⁴ -(2-nitrophenyl)pyrimidine-2,4-diamine (125.2 mg, 39 %).

1H NMR (300 MHz, CDCl ₃ ) δ 11.08 (s, 1H), 10.31 (s, 1H), 8.52 (d, J=7.9 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.10 ( s, 1H), 7.69 (d, J=5.8 Hz, 1H), 7.57-7.47 (m, 1H), 7.33-7.30 (m, 1H), 7.11 (s, 1H), 6.86 (d, J=7.1 Hz , 1H), 4.12 (br s, 4H), 3.87 (s, 3H), 3.44 (br s, 4H).

LC-MS calculated C ₂₁ H ₂₂ ClN ₆ O ₄ 457.1, found 456.9 (M+H+).

Step 2: Preparation of N ⁴ -(2-aminophenyl)-5-chloro-N ² -(2-methoxy-4-morpholinophenyl)pyrimidine-2,4diamine.

In the same manner as described in step 2 of Example 6 above, N ⁴ -(2-aminophenyl)-5-chloro-N ² -(2-methoxy-4-morpholinophenyl)pyrimidine-2,4-diamine (43.2 mg, 92 %).

LC-MS calculated C ₂₁ H ₂₄ ClN ₆ O ₂ 427.2, found 426.9 (M+H+).

Step 3: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide.

^{Triethylamine (} 50 µl, 0.40 mmol) and methanesulfonyl chloride (30 µl, 0.30 mmol) at 0°C. The above reaction mixture was stirred overnight at ambient temperature. The above mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (CH ₂ Cl ₂ /EtOAc, 5:1) to give N-(2-((5-chloro-2-((2-methoxy-4- morpholinophenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (16.1 mg, pale yellow solid) in 32% yield.

1H NMR (300 MHz, CDCI3) δ 8.07 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.70-7.67 (m, 1H), 7.53-7.50 (m, 1H), 7.45 (br s , 1H), 7.34-7.30 (m, 2H), 7.27 (br s, 1H), 6.47 (sd, J=2.5 Hz, 1H), 6.30 (dd, J=8.9, 2.5 Hz, 1H), 3.883.85 (m, 4H), 3.83 (s, 3H), 3.10-3.07 (m, 4H), 2.90 (s, 3H); LC-MS calculated C ₂₂ H ₂₆ ClN ₆ O ₄ S 505.1, found 504.9 (M+H+).

Example 33 Preparation of N-(2-((5-chloro-2-((4-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)piperidin-1-yl)2-methoxyphenyl) )amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, N-(2-((5-chloro-2-((4-(4-((3R,5S)3,5-dimethylpiperazin-1-yl)piperidine) -1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (10.7 mg, 18%).

1H NMR (300 MHz, CD3OD) δ 9.65 (s, 1H), 9.31 (dd, J=7.3, 2.1 Hz, 1H), 9.14-9.04 (m, 2H), 9.06-8.95 (m, 1H), 9.00- 8.86 (m, 2H), 8.44 (sd, J=2.5Hz, 1H), 8.20 (dd, J=8.9, 2.5Hz, 1H), 5.54 (s, 3H), 5.41 (d, J=14.7Hz, 2H ), 5.22-5.02 (m, 3H), 4.82-4.60 (m, 3H), 4.52 (s, 3H), 4.32 (t, J=12.3 Hz, 2H), 3.76 (d, J=12.6 Hz, 2H) , 3.623.40 (m, 2H), 2.95 (d, J=6.4 Hz, 6H); LC-MS (M+H+) calculated C29H40CIN8O3S 615.3, found 615.1.

Example 34 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, N-(2-((5-chloro-2-((2methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide (15.3 mg, 27%).

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1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 1H), 7.38 (qd, J=7.3, 1.8

Hz, 2H), 7.25 (d, J=8.7 Hz, 1H), 6.70 (sd, J=2.5 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.10 (dd, J=19.2, 8.3 Hz, 2H),

3.92 (d, J=13.2 Hz, 2H), 3.84 (s, 3H), 3.81-3.68 (m, 2H), 3.65-3.48 (m, 2H), 3.48-3.34 (m, 1H), 3.29-3.15 ( m,

2H), 2.97 (s, 3H), 2.93-2.79 (m, 2H), 2.28 (d, J=12.1 Hz, 2H), 1.87 (qd, J=12.3, 4.2 Hz, 2H); LC-MS (M+H ⁺ ) calculated C ₂₇ H ₃₅ ClN ₇ O ₄ S 588.2, found 588.0.

Example 35 Preparation of N(2-((5-chloro-2-((2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1yl)phenyl)amino)pyrimidin-4-yl)amino) phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, K-(2-((5-chloro-2-((2methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl) was prepared amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide (7.8 mg, 14%).

1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 1H), 7.38 (qd, J=7.3, 1.8 Hz, 2H) , 7.25 (d, J=8.7Hz, 1H), 6.70 (sd, J=2.5Hz, 1H), 6.50 (d, J=8.8Hz, 1H), 4.10 (dd, J=19.2, 8.3Hz, 2H) , 3.92 (d, J=13.2 Hz, 2H), 3.84 (s, 3H), 3.81-3.68 (m, 2H), 3.65-3.48 (m, 2H), 3.48-3.34 (m, 1H), 3.29-3.15 (m, 2H), 2.97 (s, 3H), 2.93-2.79 (m, 2H), 2.28 (d, J=12.1 Hz, 2H), 1.87 (qd, J=12.3, 4.2 Hz, 2H); LC-MS (M+H ⁺ ) calculated C ₂₇ H ₃₅ ClN ₇ O ₃ S 572.2, found 572.0.

below.

Example 36 was prepared according to Reaction Example 23

Reaction Example 23

Example 36 Preparation of (N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl )sulfamoyl)carbamate.

Step 1. Preparation of 5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(2nitrophenyl)pyrimidine-2,4-diamine.

In the same manner as described in Step 1 of Example 6 above, 5-χλορ-Ν2-(4(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(2-nitrophenyl)pyrimidine- 2,4-diamine (120 mg, 45%).

1H NMR (500 MHz, chloroform-d) 10.65 (s, 1H), 9.00 (dd, J=8.7, 1.3 Hz, 1H), 8.29 (dd, J=8.5, 1.6 Hz, 1H), 8.21 (s, 1H ), 8.00 (d, J=8.7 Hz, 1H), 7.68-7.58 (m, 1H), 7.23-7.26 (m, 2H), 7.23-7.14 (m, 1H), 6.60 (d, J=2.5 Hz, 1H), 6.54 (dd, J=8.8, 2.6 Hz, 1H), 3.91 (s, 3H), 3.70 (d, J=11.8 Hz, 2H), 2.75 (td, J=12.2, 2.4 Hz, 2H), 2.41 (bs, 7H), 2.02 (d, J=12.4 Hz, 2H), 1.80-1.68 (m, 2H).

Step 2: Preparation of N4-(2-aminophenyl)-5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2methoxyphenyl)pyrimidine-2,4-diamine.

In the same manner as described in Step 2 of Example 6 above, N4-(2aminophenyl)-5-chloro-N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)pyrimidine-2 ,4-diamine (90 mg, 85%).

1H NMR (500 MHz, chloroform-d) 8.04 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.38-7.36 (m, 2H), 7.19 (td, J=7.7, 1.5 Hz, 1H ), 6.92-6.86 (m, 2H), 6.77 (s, 1H), 6.52 (d, J=2.6 Hz, 1H), 6.33-6.29 (m, 1H), 3.85 (s, 3H), 3.84-3.77 ( m, 2H), 3.66-3.57 (m, 3H), 2.68 (td, J=12.2, 2.3 Hz, 3H), 2.47-2.38 (bs, 8H), 2.00 (dd, J=11.9, 3.2 Hz, 2H) , 1.72-1.68 (m, 2H).

Step 3. Preparation of tert-butyl (N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino) phenyl)sulfamoyl)carbamate.

In the same manner as described in Step 3 of Example 6 above, tert-butyl (N-(2-((5chloro-2-((4-(4-(dimethylamino))piperidin-1-yl))-2-methoxyphenyl )amino)pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate (62 mg, 48%).

1H NMR (500 MHz, DMSO-d ₆ ) 8.06 (s, 1H), 7.9-7.88 (m, 1H), 7.78 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.277.21 ( m, 1H), 7.12-7.04 (m, 2H), 6.61 (d, J=2.5 Hz, 1H), 6.38 (dd, J=8.9, 2.5 Hz, 1H), 3.78 (s, 3H), 3.72 (d , J=12.2 Hz, 2H), 2.66-2.54 (m, 9H), 1.92 (d, J=12.4 Hz, 2H), 1.65-1.54 (m, 2H), 1.36 (s, 9H).

Step 4: Preparation of (N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl )sulfamoyl)carbamate.

In the same manner as described in step 4 of Example 6 above, (N-(2-((5-χλορ-2-((4-(4(dimethylamino))piperidin-1-yl)-2-methoxyphenyl)amino )pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate (30 mg, 60%).

1H NMR (300 MHz, methanol-d4) 8.04 (dd, J=8.0, 1.7 Hz, 1H), 8.00 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.47 (dd, J=7.7 , 1.8 Hz, 1H), 7.33-7.21 (m, 2H), 6.66 (d, J=2.6 Hz, 1H), 6.44 (dd, J=8.8, 2.5 Hz, 1H), 3.86 (s, 3H),

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3.69 (d, J=12.1Hz, 2H), 2.75-2.65 (m, 2H), 2.36 (bs, 7H), 2.02 (d, J=12.3Hz, 2H), 1.66 (dd, J=12.1, 3.8Hz ,

2H).

Example 37 was prepared according to Reaction Example 24 below.

Reaction Example 24

Example 37 Preparation of (N(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)sulfamoyl)carbamate.

Step 1. Preparation of 5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)N4-(2-nitrophenyl)pyrimidin-2,4- diamine.

In the same manner as described in Step 1 of Example 6 above, 5-chloro-I2-(2methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-( 2-nitrophenyl)pyrimidine-2,4-diamine (130 mg, 44%).

1H NMR (500 MHz, chloroform-d) 10.65 (s, 1H), 9.00 (dd, J=8.6, 1.3 Hz, 1H), 8.29 (dd, J=8.5, 1.7 Hz, 1H), 8.21 (s, 1H ), 7.99 (d, J=8.7 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.29 (s, 1H), 7.21-7.13 (m, 1H), 6.59 (d, J=2.5 Hz , 1H), 6.53 (dd, J=8.8, 2.5 Hz, 1H), 3.90 (s, 3H), 3.71 (d, J=11.8 Hz, 2H), 2.80-2.69 (m, 6H), 2.64-2.42 ( m, 4H), 2.37 (s, 3H), 2.00 (d, J=12.4 Hz, 2H), 1.81-1.70 (m, 2H).

Step 2: Preparation of N4-(2-aminophenyl)-5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1yl)piperidin-1-yl)phenyl)pyrimidin-2,4-diamine .

In the same manner as described in Step 2 of Example 6 above, N4-(2-aminophenyl)-5-chloro-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1- yl)phenyl)pyrimidine-2,4diamine (110 mg, 89%).

1H NMR (500 MHz, chloroform-d) 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.40-7.34 (m, 2H), 7.18 (td, J=7.6, 1.5 Hz, 1H ), 6.92-6.86 (m, 2H), 6.76 (s, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.32 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.81 (bs, 2H), 3.62 (d, J=11.9 Hz, 3H), 2.72-2.36 (m, 12H), 2.34 (s, 3H), 1.96 (d, J=12.4 Hz, 2H), 1.77-1.67 ( m, 3H).

Step 3. Obtaining tert-butyl (N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl)amino)phenyl)sulfamoyl)carbamate.

In the same manner as described in Step 3 of Example 6 above, tert-butyl (N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazine-1- yl)piperidin-1-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)sulfamoyl)carbamate (65 mg, 44%).

1H NMR (500 MHz, DMSO-d ₆ ) 8.83 (s, 1H), 8.06 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.50 (d, J= 8.7 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.14-7.03 (m, 2H), 6.60 (d, J=2.5 Hz, 1H), 6.39 (dd, J=8.8, 2.4 Hz, 1H), 3.77 (s, 3H), 3.69 (d, J=12.1 Hz, 3H), 2.80-2.58 (m, 10H), 2.43 (bs, 4H), 1.85 (d, J=12.0 Hz, 3H), 1.56-1.47 (m, 2H), 1.38 (s, 9H).

Step 4: Preparation of (N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1yl)phenyl)amino)pyrimidin-4- yl)amino)phenyl)sulfamoyl)carbamate.

In the same manner as described in Step 4 of Example 6 above, (N(2-((5-chloro-2-((2methoxy-4-(4-(4-methylpiperazin-1-yl))piperidin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate (50 mg, 66%).

1H NMR (300 MHz, methanol-d4) δ 8.01 (dd, J=7.9, 1.6 Hz, 1H), 7.98 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.44 (dd, J= 7.7, 1.7 Hz, 1H), 7.23-7.17 (m, 2H), 6.63 (d, J=2.5 Hz, 1H), 6.41 (dd, J=8.8, 2.5 Hz, 1H), 3.83 (s, 3H), 3.66 (d, J=12.2 Hz, 2H), 2.79-2.38 (m, 11H), 2.30 (s, 3H), 2.00 (d, J=12.3 Hz, 2H), 1.736-1.58 (m, 1H).

Examples 38 and 39 were prepared according to Reaction Example 25 below.

Reaction Example 25

where the compound obtained after performing step 3 is the compound of example 38, and the compound obtained after performing step 4 is the compound of example 39.

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Example 38 Preparation of N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)αmino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

Step 1. Preparation of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate.

In the same manner as described in step 1 of Example 19 above, tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate (400 mg, 78%) was prepared.

1H NMR (500 MHz, DMSO-d6) 7.88 (d, J=9.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.58 (dd, J=9.5, 2.5 Hz, 1H), 6.50 ( d, J=2.5 Hz, 1H), 4.01-3.95 (m, 2H), 3.91 (s, 3H), 3.59-3.51 (m, 1H), 3.09-3.00 (m, 2H), 1.86-1.77 (m, 2H), 1.44-1.35 (m, 11h).

Step 2. Obtaining tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)carbamate.

In the same manner as described in step 2 of Example 19 above, tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)carbamate (320 mg, 87%) was prepared.

¹ H NMR (500 MHz, DMSO-d6) 6.85 (d, J=7.8 Hz, 1H), 6.57-6.51 (m, 2H), 6.33 (d, J=8.4 Hz, 1H), 4.87 (bs, 2H) , 3.75 (s, 3H), 3.41-3.34 (m, 2H), 2.59 (t, J=11.8 Hz, 2H), 1.79 (d, J=12.1 Hz, 2H), 1.56-1.45 (m, 2H), 1.40(s, 9H).

Step 3: Preparation of N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)αmino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide.

In the same manner as described in step 3 of Example 19 above, N-(2-((2-((4(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4- yl)amino)phenyl)methanesulfonamide (80 mg, 49%).

¹ H NMR (300 MHz, DMSO-d6) 9.31 (s, 1H), 8.97 (bs, 1H), 8.16 (s, 1H), 7.95-7.88 (bs, 2H), 7.83 (d, J=3.7 Hz, 1H), 7.47-7.40 (m, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.30-7.23 (m, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.40 (d, J =8.9Hz, 1H), 3.78(s, 3H), 3.73(d, J=12.7Hz, 2H), 3.22(bs, 1H), 2.97(s, 3H), 2.80(t, J=12.6Hz, 2H ), 1.97 (d, J=11.9 Hz, 2H), 1.69-1.54 (m, 1H).

Example 39 Preparation of N-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2yl)amino)-3-methoxyphenyl)piperidin-4-yl)acetamide.

In the same manner as described in Example 15 above, N-(1-(4-((5-χλορ-4-((2(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3- methoxyphenyl)piperidin-4-yl)acetamide (25 mg, 78%).

1H NMR (500 MHz, DMSO-d6) 9.28 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J=7.7Hz, 1H), 7.42 (d, J=8.7Hz, 1H), 7.37 (dd, J=7.8, 1.6Hz, 1H), 7.24 (d, J=7.9Hz, 1H), 7.19 (td, J=7.6, 1.6Hz, 1H), 6.61 (d, J=2.5Hz, 1H), 6.38 (dd, J=8.7, 2.5Hz, 1H), 3.76 (s, 3H), 3.70 (bs , 1H), 3.61 (d, J=12.4 Hz, 2H), 2.96 (s, 3H), 2.75 (t, J=10.7 Hz, 1H), 1.86-1.79 (m, 5H), 1.55-1.44 (m, 2H).

Example 40 was prepared according to Reaction Example 26 below.

Reaction Example 26

Example 40 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl )methanesulfonamide.

Step 1. Preparation of tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate.

In the same manner as described in step 1 of Example 19 above, tert-butyl (1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (450 mg, 84%) was prepared.

1H NMR (300 MHz, chloroform-d) 8.02 (d, J=9.3 Hz, 1H), 6.44 (dd, J=9.4, 2.6 Hz, 1H), 6.34 (d, J=2.5 Hz, 1H), 4.07- 3.98 (m, 2H), 3.97 (s, 3H), 3.10-2.96 (m, 2H), 2.75 (s, 3H), 1.85-1.76 (m, 2H), 1.50 (s, 9H).

Step 2. Preparation of tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate.

In the same manner as described in step 2 of Example 19 above, tert-butyl (1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(methyl)carbamate (400mg, 96%) was prepared.

1H NMR (300 MHz, chloroform-d) δ 6.66 (d, J=8.3 Hz, 1H), 6.56 (bs, 1H), 6.50-6.40 (m, 1H), 3.86 (s, 3H), 3.53 (d, J=12.2 Hz, 3H), 2.80 (s, 3H), 2.71 (d, J=12.2 Hz, 2H), 1.99-1.83 (m, 2H), 1.80-1.69 (m, 2H), 1.50 (s, 9H ).

Step 3: Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl )methanesulfonamide.

In the same manner as described in step 3 of Example 19 above, N(2-((5-chloro-2-((2methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidine was prepared -4-yl)amino)phenyl)methanesulfonamide (50 mg, 33%).

1H NMR (300 MHz, DMSO-d6) 8.96 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.48 (d,

- 32 041822

J=8.7 Hz, 1H), 7.29-7.19 (m, 1H), 6.94 (td, J=7.7, 1.6 Hz, 1H), 6.81 (t, J=7.7 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H),

6.46 (dd, J=8.7, 2.5 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=12.6 Hz, 2H), 2.90-2.81 (m, 1H), 2.78 (s, 3H), 2.71 (d,

J=12.2 Hz, 2H), 2.49 (s, 3H), 1.99 (d, J=12.3 Hz, 2H), 1.59-1.50 (m, 2H).

Compounds of examples 41-43 were prepared according to Reaction Example 27 below.

Reaction Example 27

in which R is a substance reactive with the starting material, the compound in which R ⁶ is -NH(CH ₂ ) ₂ OH is the compound of Example 41, the compound in which R ⁶ is -NH(CH ₂ ) ₂ OCH ₃ is the compound of Example 42, and the compound in which R ⁶ is -NH(CH ₂ ) ₂ N(CH ₃ ) ₂ is the compound of Example 43.

Example 41 Preparation of N-(2-((5-chloro-2-((4-(4-((2-hydroxyethyl)amino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidin-4-yl)amino )phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, K-(2-((5-chloro-2-((4-(4-((2hydroxyethyl)amino)piperidin-1-yl)-2-methoxyphenyl) was prepared amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide (25 mg, 46%).

¹ H NMR (300 MHz, methanol^) 8.06 (s, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.44-7.35 (m, 2H), 7.31 (d , J=8.7 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 3.93-3.81 (m, 7H), 3.23 (t, J=5.2 Hz , 2H), 2.99 (s, 3H), 2.87 (dd, J=13.4, 11.2 Hz, 2H), 2.25 (d, J=12.4 Hz, 2H), 1.90-1.73 (m, 2H).

Example 42 Preparation of N-(2-((5-chloro-2-((2-methoxy-4-(4-((2-methoxyethyl)amino)piperidin-1yl)phenyl)amino)pyrimidin-4-yl) amino)phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, N-(2-((5-chloro-2-((2-methoxy-4-(4((2-methoxyethyl)amino)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (22 mg, 40%).

1H NMR (300 MHz, methanol-d ₄ ) 8.06 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.56-7.50 (m, 1H), 7.42-7.35 (m, 2H), 7.33 ( d, J=8.6 Hz, 1H), 6.70 (d, J=2.5 Hz, 1H), 6.50 (d, J=8.9 Hz, 1H), 3.91-3.80 (m, 5H), 3.73-3.65 (m, 2H ), 3.45 (s, 3H), 3.32-3.27 (m, 2H), 2.98 (s, 3H), 2.85 (t, J=12.0 Hz, 2H), 2.28-2.19 (m, 2H), 1.87-1.72 ( m, 2H).

Example 43 Preparation of N-(2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)amino)piperidin-1-yl)-2methoxyphenyl)amino)pyrimidine-4- yl)amino)phenyl)methanesulfonamide.

In the same manner as described in Example 19 above, K-(2-((5-chloro-2-((4-(4-((2(dimethylamino)ethyl)amino)piperidin-1-yl))- 2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (10 mg, 18%).

1H NMR (300 MHz, methanol-d ₄ ) δ 8.07 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.54 (dd, J=7.6, 1.9 Hz, 1H), 7.457.41 (m , 1H), 7.38 (dd, J=7.5, 2.0 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.61-6.50 (m, 1H) , 3.90 (d, J=11.7 Hz, 2H), 3.86 (s, 3H), 3.64-3.54 (m, 4H), 3.50-3.40 (m, 1H), 3.02 (s, 6H), 3.00 (s, 4H ), 2.93 (d, J=11.6 Hz, 2H), 2.28 (d, J=12.4 Hz, 2H), 1.94-1.78 (m, 2H).

The chemical structure of the compounds obtained in examples 1-43, was presented and listed in table. 1-3 below.

- 33 041822

Table 1

Example Chemical structure Example Chemical structure 1 . n o o IJ _L HN f NH Ck υ^ν κγ / l XJ ^Ν d of 2 _h Η ^Ο Ο II J HN । [ NH Ck AX J UAXJ Ν Ν γ ^H 3 °4aJ χ^ΝΗ °' ^N rr° NN ^H X 4 X ^H ° ° Jr J HN G NH ⁿ % 5 AX / ° o IL 6 °Λ X) ^c| \H 11X1! Ν N ^H θ- 7 ⁿ ^h ,n_^ HN X NH ^Β Αγ° 8 οΧτχ ⁰ o JxJ HN X NH Xlxx^ Ν N ^H Οχ 9 . H °ΛI ij HN'^- ^/ X NH ^N 4 10 H S ^N X^N^ ° 0 aa.n^J HN Г 1 Cl J ...N. J X AND 7 ° / (xc/' z y—z zi r: ' / νχ Z...... _Ά / / Z—' / 12 2 ₀ /Xxo-X 4 ti °~\4 / X^Y Q \ 13 Z..... > ^z M ν θ 'νΖχ^ b X 14 . H _₽ N - . -- OH o ^S o J 1 HN N “ '- _s k N j 15 V Η V ^N v% o a d Yl £T^ ^H 4 16 . Hol. . . ^N HN N ' Cl - ^N 1 N' N V ^H 0.

- 34 041822

table 2

Example Chemical structure Example Chemical structure 17 . n S ^N - 'N^ 0 J ΗΝ Ν Cl J ' ^{1 N} Г and V ν' γ ⁿ 0. 18 . n ? Ai A ΗΝ A Ν Ck A l, AJ Ά ν g A ⁿ ° 19 Ο=φ o A—2 χζ _L ^Ζ Χ\ , ^ζ l A _o _ 20 8 m 0 b / gh AK ^A XZ _ Z A Z -A ...... - ° o 21 At ΖΧ FC /M χζ _ζ4 ζ A ° o 22 A , - ' N ' - ^he 0 _o ' 1 ^N ' ⁰ x N nm Gf ' Cl _x N, ¹ ' ^Ν 1 M NG 23 L N V^AA ° O IJ HN < NH X...... ⁿ <h 24 x H? Ach “HN r N SK X L. J ⁴ Ν N ⁿ to 25 ΗΝ-^Χ φ %Χ Φ ^C 'al 4XV ⁿ < 26 ν ^{Vos 0} 'b f y 1 J ΗΝ ' ^ν ' Δ Ν ⁿ F 27 Xf>ff a^nh ⁰ oLF /vAj HN AN CHA 28 X H \ Ν ·. h Ό,-. x HN A ^N A. A ^N 0 29 X A X° "^ί AaAa ζ ^h o A £ O thirty ^H 2A A _Z S _X Α Ί ° ⁰ A J HN^4 AN _H ⁱⁿ aA rr ^N A hhFf ⁿ F 31 X 0 5 ФΧΖ _η ζΑ\ 2 Y-« o o LL 32 °L T J HN ι ° “U·. A ⁿ 0^

- 35 041822

Table 3

Example Chemical structure Example Chemical structure 33 X / 2—-\ ....... and b Q ^o/ HZ V ^x \=/ / ^CH O 1 a 34 Η S ^Ν 1 Ο Ο ο 1 _Ν ΗΝ ⁰¹ μ ^Ν ι j Ο Ν Ν Τ' ^Η 4 35 7) about. o XZ _o 2 and/ ^: )=/ / ^h o o 36 I b /=< / \ ίο ⁴ z. Υζ ζι· Τ ο and < ο ζ— / 37 \ % '—And with. I Jr xz _z—(; z \ zOl \ / OT >= ° > ⁵ 38 J ² 4. / z^Vz 39 H HN ^ <γ γ ^α γΑ ° ζ a aJ Ν Ν ^Η 40 ''''θζΟ /7 ΗΝ < γ CK Τ\ ζ Νχ J Τα ΤΓ Ν Ν ^Η 41 X ΤΆι η ⁰ °ΑΖ ζ^ ΗΝ g OH ''/.jA' ^Η <κ 42 ζζ I ω/ }— ^/ δ 43 n ΗΝ ρ' γ Ν

Experimental Example 1 Measurement of wild-type EGFR and EGFR mutation inhibitory ability of the compound represented by the formula (1) of the present invention (H2,K4-diphsnylpyrimidine-2,4-diaminovos derivative).

In order to confirm the inhibitory ability of wild-type EGFR and EGFR mutation of the wild-type compound represented by the formula (1) of the present invention, an experiment was carried out as described below. The results are shown in table. 4 below.

Measurement of activity against wild-type EGFR and the compound mutated enzyme of the present invention was carried out experimentally using the HTRF system sold by Cisbio as follows. Wild type EGFR and dell9 mutated EGFR, dell9/T790M EGFR by purchasing recombinant proteins provided by Carna Biosciences, and dell9/T790M/C797S mutated EGFR enzyme were used as enzyme source by purchasing proteins provided by SignalChem.

The composition of the assay buffer used in the 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, 1 mM DTT. The enzymatic reaction was carried out using a peptide substrate labeled with ATP at a concentration of 50 mm and biotin at a concentration of 0.5 mm. An analysis of the effect of inhibition of EGFR activity of the compound was carried out according to the composition for reaction analysis below.

Component 1: 4 ml wild-type or mutated EGFR.

Component 2: 2 ml compound solution.

Component 3: 4 ml of peptide labeled with ATP and biotin.

The enzymatic reaction was initiated by mixing component 1 and component 2 and then adding component 3. After reacting for 2 hours at 37° C., 10 ml of a measuring solution consisting of streptavidin-XE665 provided by Cisbio and an anti-phosphotyrosine antibody was labeled

-36041822 europium was added to the enzymatic reaction solution, and the reaction was carried out for 1 hour at ambient temperature. Finally, the ratio of fluorescence values at 615 and 665 nm was obtained using Envision Perkin-Elmer equipment, and the enzymatic activity was quantified, and the inhibitory ability of the compound was confirmed. The measured values measured at seven compound concentrations were analyzed using the Prism program (version 5.01, Graphpad Software, Inc.) and the IC ₅₀ value of the compound, which is an indicator of inhibitory ability, was calculated.

Table 4

Example EGFR wild-type IC50 (μM) EGFR del 19 IC _{50 (} mkM) EGFR dell9/T790M IC ₅₀ (MkM) EGFR dell9/T790M/C797S IC50(MkM) 1 2.1 0.020 0.016 0.015 2 0.73 0.012 0.012 0.003 3 0.84 0.018 0.005 0.002 4 nd nd nd 0.72 5 4.3 0.033 0.013 0.014 6 0.39 0.026 0.010 0.011 7 >10 0.079 0.038 0.002 8 nd nd nd 0.36 9 nd nd nd 0.093 10 0.43 0.0007 0.004 0.0002 AND 0.28 0.0078 0.0031 0.006 12 1.2 0.022 0.13 0.002 13 1.9 0.013 0.25 0.033 14 1.4 0.006 0.095 0.034 15 nd nd nd 0.33 16 5.4 0.044 0.34 0.023 17 0.6 0.004 0.078 0.012 18 0.97 0.013 0.092 0.03 19 0.7 0.0007 0.069 0.042 20 nd nd nd 0.3 21 0.16 0.0001 0.014 0.005 22 0.26 0.0004 0.031 0.0008

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23 2.7 0.025 0.032 0.029 24 0.82 0.003 0.064 0.012 25 0.3 0.0002 0.018 0.009 26 nd nd nd 0.11 27 0.28 0.0003 0.021 0.001 28 0.64 0.0009 0.027 0.009 29 1.2 0.005 0.004 0.007 thirty 1.8 0.024 0.034 0.003 31 0.58 0.036 0.029 0.007 32 1.3 0.004 0.16 0.014 33 nd nd nd <0.001 34 nd nd nd <0.001 35 0.027 0.0011 0.0083 <0.001 36 nd nd nd 0.0003 37 0.0028 0.0071 0.0027 0.0002 38 nd nd nd 0.0005 39 nd nd nd 0.0003 40 nd nd nd 0.0004 41 nd nd nd 0.0002 42 nd nd nd 0.0003 43 nd nd nd 0.0006

In table. 4 above nd means no data.

As shown in Table. 4 above, it can be seen that all compounds of the examples according to the present invention show a relatively weak inhibitory effect on EGFR activity against wild-type EGFR, selectively higher inhibitory ability against EGFR mutation, in particular a higher inhibitory ability against EGFR del19/T790M/ C797S, which is a triple mutation.

Experimental Example 2 Measurement of inhibitory ability on wild-type Ba/F3 EGFR and Ba/F3 EGFR mutation in a Ba/F3 cell line of a compound represented by formula (1) according to the present invention (N2,N4-diphenylpyrimidine-2,4-diamine derivative).

In order to confirm the inhibitory ability of wild-type Ba/F3 EGFR and Ba/F3 EGFR mutation on the Ba/F3 cell line of the compound represented by formula (1) according to the present invention, an experiment was performed as described below. The results are shown in table. 5 below.

Measurement of activity against the EGFR cell line Ba/F3 wild-type and with a mutation of the connection according to the present level was carried out experimentally using the CellTiter-Glo system sold by Promega, as follows. The CellTiter-Glo assay is a method for measuring ATP present in cells under cell culture conditions to determine cell viability. Wild-type Ba/F3 EGFR and Ba/F3 EGFR del19, Ba/F3 EGFR del19/T790M, Ba/F3 del19/T790M/C797S mutated cell lines were used by purchasing cell lines supplied by Crown Bioscience, Inc. Ba/F3 EGFR wild-type and Ba/F3 EGFR del19, Ba/F3 EGFR del19/T790M, Ba/F3 del19/T790M/C797S mutated cell lines were cultured in a 37°C, 5% CO2 incubator with 1 µg of puromycin in RPMI containing 10% FBS, 1% penicillinstreptomycin.

Analysis of the effect of inhibitory ability on EGFR compounds was performed according to the analysis below.

2500 cells/90 μl were cultured by passage on a 96-well cell culture plate, and 24 hours later treated with the compound represented by formula (1) at concentrations of 0, 0.01, 0.03, 0.1, 0.3, 1 , 3, 10 (µM). After reacting for 72 hours, the compound-treated plate was allowed to stand for 30 minutes at ambient temperature and then treated with an additional 100 μl of reagent and shaken for 10 minutes at ambient temperature. Finally, the ratio of fluorescence values at 570 nm was obtained using the equipment and quantitatively measured, and the inhibitory ability of the compound was confirmed. The measured values measured at eight concentrations of the compound were analyzed using the Prism program (version 5.01, Graphpad Software, Inc.), and the IC ₅₀ value of the compound, which is an indicator of inhibitory ability, was calculated.

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Table 5

Example Ba/F3 EGFR wt IC ₅ o (µM) Ba/F3 EGFR del 19 IC ₅ o (µM) Ba/F3 EGFR dell9/T790M IC ₅ o (µM) Ba/F3 EGFR dell9/T790M/C797S IC 50 (µM) 1 >15 6.6 7.1 nd 2 2.8 3.8 1.8 2.4 3 4.1 1 1.2 1.6 5 2.4 0.26 0.57 0.79 6 >15 6.4 9 5.8 7 3.4 0.47 1.6 3.3 10 1 0.18 0.099 0.063 AND 0.34 0.0047 0.031 0.038 12 0.32 0.33 0.38 0.08 13 4.4 0.98 0.65 1.5 14 0.75 0.5 0.54 0.11 16 >10 >10 2.3 >10 17 2.1 2.2 1.7 0.68 18 4.4 2.7 1.4 2 19 3.1 1.1 0.66 0.97 21 2.2 3.6 0.55 1.7 22 nd 0.9 0.39 1.3 24 >10 0.45 0.32 0.41 25 0.34 0.21 0.78 0.027 27 nd 1.1 0.94 >10 28 1.4 1.4 0.69 1.7 29 2.8 1.9 2.1 2.9 thirty 5.4 0.68 0.85 2.7 32 8 1.9 1.3 3.3 33 nd nd nd 0.12 34 nd nd nd 0.16 35 nd nd nd 0.084 36 nd nd nd 0.93 37 nd nd nd 0.099 38 nd nd nd 0.84 39 nd nd nd 0.68 40 nd nd nd 0.5

In table. 5 above nd means no data.

It was confirmed that the compounds of the examples according to the present invention showed a high inhibitory ability against EGFR mutation, including EGFR del19/T790M/C797S, which is a triple mutation.

In addition, it can be seen that the compounds of the examples according to the present invention show a relatively weaker inhibitory activity against wild-type EGFR in the Ba/F3 cell line and a significantly higher inhibitory activity against EGFR mutation, including EGFR del19/T790M/C797S, which is a triple mutation.

Experimental Example 3 Measurement of the FLT kinase inhibitory ability of the compound represented by the formula (1) according to the present invention (N2,N4diphenylpyrimidine-2,4-diamine derivative).

In order to confirm the inhibitory ability of FLT kinase, which is also well known as a hematological cancer-related kinase, of the compound represented by formula (1) of the present invention, an experiment was performed as described below. The results are shown in table. 5 below.

FLT kinase inhibitory activity such as wild-type FLT1, FLT3, FLT4, and FLT3 mutants, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V),

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FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), was measured.

The specific experimental method is described below.

FLT3 kinase inhibition was performed using the KINOMEscan method (DiscoverX Inc.). The KINOMEscan method consists of the following processes. T7 bacteriophage labeled with FLT kinase was cultured by infecting E. coli derived from BL21. After being infected with E. coli at 0.4 MOI (multiplicity of infection), it was cultured for 90-150 min at 32° C. with E. coli lysis. Cellular debris was removed by centrifugation and filtration, and the kinase protein present in the supernatant was isolated. In addition, the kinase protein was labeled with DNA for qPCR measurement. Streptavidin-labeled magnetic beads were treated with a biotin-labeled standard compound and reacted for 30 minutes. The resulting beads were used as affinity beads to measure kinase activity. The binding reaction was initiated by mixing the kinase protein, the affinity beads associated with the ligand, and the compound. In this case, the buffer solution used was 20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT. All reactions were performed in a volume of 20 µl in a 384-well plate. After reacting for 1 h at ambient temperature, the beads were washed with a solution consisting of 1x PBS, 0.05% Tween 20. Finally, the bead-bound kinase was eluted using 1x PBS, 0.05% Tween 20, 0.5 μM of the standard compound without labeling with biotin. The affinity of the test compound was indirectly measured by qPCR quantification of the eluted kinase.

Table 6

Example Gene designation Modifier Kd (nM) 10 FLT1 > 10000 10 FLT3 3.7 10 FLT3(D835H) = 38 10 FLT3(D835V) = 0.29 10 FLT3(D835Y) = 4.2 10 FLT3(ITD) = 18 10 FLT3(ITD,D835V) = 0.32 10 FLT3(ITD,F691L) = 1.1 10 FLT3(K663Q) = 39 10 FLT3(N841I) = 6.5 10 FLT3(R834Q) 33 10 FLT4 = 200 And FLT1 = 910 And FLT3 = 1.2 eleven FLT3(D835H) " 1.8 And FLT3(D835V) = 0.082 And FLT3(D835Y) = 1.5 eleven FLT3(ITD) = 4.2 And FLT3(ITD,D835V) = 0.16 And FLT3(ITD,F691L) = 0.27 And FLT3(K663Q) 20 And FLT3(N841I) = 3.8 And FLT3(R834Q) = 19 eleven FLT4 81

As indicated in Table. 6 above, it was confirmed that the compounds of Examples 10 and 11 according to the present invention showed a selectively superior inhibitory ability against FLT3 kinase compared to FLT 1 and FLT 4, and also showed a high inhibitory ability against wild-type FLT3 as well as mutated forms of FLT3. , such as FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q) ).

Experimental Example 4 Evaluation of cell activity on the cell line Ba/F3 Del19/T790M/C797S according to combinatorial administration.

To confirm cell activity on the Ba/F3 Del19/T790M/C797S cell line when a compound of the present invention is administered in combination with standard drug

- 40 041822 means, cetuximab for use in single or combination therapy with anticancer chemotherapy in metastatic colorectal cancer, metastatic squamous cell epithelial head and neck cancer and the like, was used to evaluate cell activity in accordance with combinatorial administration.

In particular, brigatinib was used as a control drug, and each of 30 nM brigatinib, 30 nM of Example 10 of the present invention, and 15 nM of Example 11 was administered to the Ba/F3 Del19/T790M/C797S cell line in combination with 10 μg of cetuximab, which is a monoclonal antibody. Relative cell viability was measured and shown in FIG. 1-4.

In addition, when administered each of brigatinib, compounds of examples 10 and 11 according to the present invention at 30, 100, 300, 1000 nM alone or in combination with 10 μg of cetuximab, subsignaling activity on the a/F3 Del19/T790M/C797S cell line was assessed. , and the results are shown in Fig. 5-7.

Fig. 1 is a graph showing relative cell viability during administration of brigatinib in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by t-test (**P<0.001, *P>0.01)).

Fig. 2 is a graph showing relative cell viability during administration of the compound of Example 10 in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by t-test (**P<0.001, *P>0.01)).

Fig. 3 is a graph showing relative cell viability during administration of the compound of Example 11 in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by t-test (**P<0.001, *P>0.01)).

Fig. 4 is a graph showing relative cell viability during administration of cetuximab alone or in combination with cetuximab of the Ba/F3 Del19/T790M/C797S cell line (calculated by t-test (**P<0.001, *P>0.01) ).

Fig. 5 shows subsignaling activity during administration of brigatinib alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

Fig. 6 shows subsignaling activity during administration of Example 10 alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

Fig. 7 shows subsignal activity during administration of Example 11 alone or in combination with Ba/F3 Del19/T790M/C797S cell line cetuximab.

As shown in FIG. 1-4, it can be seen that the compounds of examples 10 and 11 according to the present invention show a lower cell viability of at least 30% on the cell line Ba/F3 Del19/T790M/C797S when administered alone than cetuximab, and show that the cell viability of cells is reduced by at least 50% when administered in combination with cetuximab than when administered alone, and thus exhibit superior cancer cell apoptosis capability in a triple EGFR mutant cell line even when administered alone, and also exhibit markedly increased anti-cancer effect when administered in combination with a standard drug.

In particular, it can be seen that the compounds of examples 10 and 11 according to the present invention show that cell viability is reduced by at least 20% than with the administration of brigatinib, which is a commonly used drug, in combination with cetuximab, and thus, show a better antitumor effect than brigatinib.

As shown in FIG. 5 and 6, it can be seen that the compounds of examples 10 and 11 according to the present invention show concentration-dependent activity on pERK, pAKT, pS6, which is a sub-signal of EGFR, even when administered alone, and also exhibit excellent activity when administered in combination with cetuximab.

In particular, it can be seen that the compounds of examples 10 and 11 according to the present invention show higher activity than brigatinib, which is a commonly used drug, in combination with cetuximab, and thus show a better anti-cancer effect than brigatinib. .

Therefore, the compound represented by formula (1) according to the present invention shows a high inhibitory ability against EGFR mutation, and thus can be effectively used for the treatment of cancer with EGFR mutation, such as EGFR del19, EGFR del19/T790M, EGFR del19 /T790M/C797S, EGFR L858R, EGFR L858R/T790MS, EGFR L858R/T790M/C797S and the like. In particular, the compound represented by formula (1) according to the present invention shows markedly higher inhibitory ability against EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S, which are a triple mutation, and thus can be effectively used for cancer treatment with EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S.

In addition, the compound represented by formula (1) according to the present invention shows high inhibitory ability against FLT3 and its mutation, such as FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3 (ITD,D835V), FLT3(ITD,F691L),

- 41 041822

FLT3(K663Q), FLT3(N841I), or FLT3(R834Q), and thus can be effectively used to treat cancer associated with FLT3 activity or a mutated form of FLT3, in particular hematological malignancy.

In addition, the compound represented by the formula (1) of the present invention shows a synergistic effect when administered in combination with a conventional drug, and thus can be effectively used when administered in combination with a conventional drug.

Formulation example 1. Preparation of powders.

Derivative represented by formula (1) 2 g.

Lactose 1 g

The powders were prepared by mixing the above ingredients and filling into a sealed bag.

Formulation Example 2 Preparation of tablets.

The derivative represented by the formula (1) 100 mg.

Corn starch 100 mg.

Lactose 100 mg.

Magnesium stearate 2 mg.

Tablets were prepared by mixing the above ingredients and then tableting according to conventional tablet manufacturing methods.

Formulation example 3. Preparation of capsules.

The derivative represented by the formula (1) 100 mg.

Corn starch 100 mg.

Lactose 100 mg.

Magnesium stearate 2 mg.

Capsules were prepared by mixing the above ingredients and then filling gelatin capsules according to conventional capsule manufacturing methods.

Formulation Example 4 Injection Receiving.

The derivative represented by the formula (1) 100 mg.

Mannitol 180 mg.

Na ₂ HPO ₄ -2H ₂ O 26 mg.

Distilled water 2974 mg.

Injections were prepared by containing the above ingredients in the content indicated above, in accordance with traditional methods for the manufacture of injections.

Formulation Example 5 Preparation of Medicinal Foods.

Derivative represented by formula (1), 500 ng.

A mixture of vitamins as needed.

Vitamin A acetate 70 mg.

Vitamin E 1.0 mg.

Vitamin 0.13 mg.

Vitamin B2 0.15 mg.

Vitamin B6 0.5 mg.

Vitamin B12 0.2 mg.

Vitamin C 10 mg.

Biotin 10 mg.

Nicotinamide 1.7 mg.

Folic acid 50 mg.

Calcium pantothenate 0.5 mg.

A mixture of minerals as needed.

Ferrous sulfate 1.75 mg.

Zinc oxide 0.82 mg.

Magnesium carbonate 25.3 mg.

Potassium dihydrogen phosphate 15 mg.

Calcium hydrogen phosphate 55 mg.

Potassium citrate 90 mg.

Calcium carbonate 100 mg.

Magnesium chloride 24.8 mg.

With regard to the mixing ratio of vitamins and minerals, ingredients relatively suitable for medicinal foods were mixed in accordance with the preferred examples, but the ratio may not necessarily be changed in practice. According to conventional methods for the manufacture of medicinal food products, the above ingredients were mixed and then obtained in the form of granules, and they can be used in the preparation of compositions of medicinal food products according to conventional methods.

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Claims (20)

Composition Example 6 Preparation of Health Drinks. Derivative represented by formula (1), 500 ng. Citric acid 1000 mg. Oligosaccharide 100 g Japanese apricot concentrate 2 g. Taurine 1 g Purified water added up to a total of 900 ml. According to conventional methods for making medicinal drinks, the above ingredients were mixed, then stirred and heated at 85 ° C for about 1 hour, and then the resulting solution was filtered, obtained in a sterilized container, sealed, sterilized, then stored in a refrigerator and used in the preparation of compositions medicinal drinks. With regard to the composition ratio, the ingredients relatively suitable for the preferred drinks were mixed according to the preferred examples, but the mixing ratio may optionally be changed in practice according to regional and ethnic preferences, such as class of demand, country of demand, destination of use, and volume. similar. INDUSTRIAL APPLICABILITY The N,N-diphenylpyrimidine-2,4-diamine derivative of the present invention can be effectively used for the treatment of cancer, in particular cancer with an EGFR mutation or cancer with FLT3 or a mutation thereof. CLAIM 1. Compound represented by formula (1) where R ¹ represents CH ₃ or NH ₂ ; R ² is hydrogen, halogen, methoxy or methyl, unsubstituted or substituted with one or more halogens; R ³ is hydrogen, halogen, or straight or branched C^alkyl; R ⁴ is a straight or branched C ^ alkyl and >.7 f Gu ₅ V - ⁷ is ^v ' or ^N where R is independently selected from the group consisting of hydrogen, straight or branched C1.3 alkyl, straight or branched hydroxyC1_3 alkyl, acetyl, -NR ^a R ^b , morpholinyl, pyrrolidinyl and unsubstituted or substituted piperidinyl or piperazinyl where R ^a and R ^b are independently hydrogen, straight or branched C1.3 alkyl, acetyl, straight or branched hydroxyC1. ₃ alkyl, straight or branched C1. ₃ alkoxyC1. ₂ alkyl, or straight or branched diCl. ₃ alkylaminoC1. ₂ alkyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of straight or branched _{C1_3} alkyl, straight or branched hydroxyC1. ₃ alkyl, acetyl and straight or branched C1. ₅ alkoxycarbonyl; its optical isomer or its pharmaceutically acceptable salt. 2. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ¹ is CH ₃ . 3. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ¹ is NH ₂ . 4. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ² is hydrogen, F, C1, W, methoxy or methyl, unsubstituted or substituted with one or more fluorine atoms; R ³ is hydrogen, F, C1 or straight or branched C1. ₃ alkyl and R ⁴ is straight or branched C1_ ₃ alkyl. 5. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ² is hydrogen, C1, W, methyl, CF ₃ or methoxy; R ³ is hydrogen or methyl and R ⁴ is methyl. -43041822 6. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ⁵ is independently selected from the group consisting of hydrogen, methyl, hydroxyethyl, acetyl, -NR ^a R ^b , morpholinyl, pyrrolidinyl and unsubstituted or substituted piperidinyl or piperazinyl, where R ^a and R ^b are independently hydrogen, straight or branched C1. ₃ alkyl, acetyl, straight or branched hydroxyC1. ₃ alkyl, straight or branched C1.zalkoxyC1.2 alkyl, or straight or branched diCialkylaminoC^alkyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl, hydroxymethyl, hydroxyethyl, acetyl, and t-butoxycarbonyl . 7. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ⁵ is independently selected from the group consisting of hydrogen, methyl, hydroxyethyl, acetyl, -NR ^a R ^b , morpholinyl, pyrrolidinyl and unsubstituted or substituted piperidinyl or piperazinyl, where R ^a and R ^b are independently hydrogen, methyl, acetyl, hydroxyethyl, -(CH ₂ )2 OCH ₃ or -(CH ₂ ) ₂ N(CH ₃ ) ₂ , and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl and t-butoxycarbonyl. 8. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ⁵ independently represents hydrogen, methyl, hydroxyethyl, acetyl, -NR ^a R ^b , morphoR ^a linyl, pyrrolidinyl, ' or where R ^a and R ^b are independently hydrogen, methyl, acetyl, hydroxyethyl, -(CH ₂ )2 OCH ₃ or -(CH ₂ )2N(CH ₃ ) ₂ , and R ^c and R ^d are independently hydrogen, methyl or ethyl, and R ⁶ is independently hydrogen, methyl, hydroxyethyl, acetyl, or t-butoxycarbonyl. 9. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ⁵ is independently hydrogen, methyl, hydroxyethyl, acetyl, -NH ₂ , -NH(CH ₃ ), -NH(C= O)CH ₃ , -NH(CH ₂ ) ₂ OH, -NH(CH ₂ ) ₂ OCH ₃ , -NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , -N(CH ₃ ) ₂ , morpholinyl, pyrrolidinyl, ' or <' ^d where R ^L and R independently represent hydrogen or methyl, and R independently represents hydrogen, methyl, hydroxyethyl, acetyl or tert-butoxycarbonyl. 10. A compound, its optical isomer _, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that V- ⁷ is . where R is independently -NH(CH ₃ ) or dd where R ^c and R ^d independently represent hydrogen and R ⁶ represents methyl. 11. The compound, its optical isomer or its pharmaceutically acceptable salt according to claim 1, characterized in that the compound represented by formula (1) is any one selected from the group consisting of the following compounds: <1> N-(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <2> R-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide ; <3> N-(2-((5-bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <4> N-(2-((5-methoxy-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <5> N-(2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <6> 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine; <7> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine; <8> M-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4-ylamino)phenyl)methanesulfonamide; <9> M-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <10> M-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4- yl)amino)phenyl)methanesulfonamide; <11> M-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide; <12> M-(2-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <13> M-(2-((5-chloro-2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin4-yl)amino)phenyl)methanesulfonamide ; -44041822 <14> N-(2-((5-chloro-2-((4-(1'-(2-hydroxyethyl)-[1,4'-binineridin]-4-yl)-2-methoxyphenyl) amino) nirimidin-4-yl) amino) phenyl) methanesulfonamide; <15> N-(2-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide; <16> N-(2-((2-((4-([1,4'-(binineridin]-4-yl)-2-methoxyphenyl)amino)-5-chloro-pyrimidin-4-yl)amino)phenyl )methanesulfonamide; <17> N-(2-((5-chloro-2-((2-methoxy-4-(1'-methyl-[1,4'-bipiperidin]-4-yl)phenyl)amino)pyrimidin-4yl )amino)phenyl)methanesulfonamide; <18> N-(2-((2-((4-(G-acetyl-[1,4'-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4yl)amino) phenyl)methanesulfonamide; <19> N-(2-((2-((4-(4-(4-acetylninerazin-1-yl)nineridin-1-yl)-2-methoxyphenyl)amino)-5-chloro-pyrimidin-4-yl) amino)phenyl)methanesulfonamide; <20> tert-Butyl 4-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperidin-4-yl )piperazine-1-carboxylate; <21> R-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin4-yl)amino) phenyl)methanesulfonamide; <22> N-(2-((5-chloro-2-((4-(4-(4-(2-hydroxyethyl)ninerazin-1-yl)nineridin-1-yl)-2-me'moxyphenyl) amino) nirimidin-4-yl) amino) phenyl) methanesulfonamide; <23> N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <24> R-(2-((2-((4-(4-(1-acetylpiperidin-4-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4yl)amino) phenyl)methanesulfonamide; <25> R-(2-((5-chloro-2-((2-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4- yl)amino)phenyl)methanesulfonamide; <26> tert-Butyl 4-(4-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)3-methoxyphenyl)piperazin-1-yl )piperidine-1-carboxylate; <27> R-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin4-yl)amino) phenyl)methanesulfonamide; <28> N-(2-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <29> 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine; <30> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine; <31> N-(2-((2-((2-methoxy-4-(piperazin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <33> N-(2-((5-chloro-2-((4-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)piperidin-1-yl)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <34> N-(2-((5-chloro-2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <35> R-(2-((5-chloro-2-((2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin4-yl)amino) phenyl)methanesulfonamide; <36> O(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4yl)amino)phenyl)sulfamoyl)carbamate; <37> O(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)sulfamoyl)carbamate; <38> N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide; <39> R-(1-(4-((5-Chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)acetamide ; <40> N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4yl)amino)phenyl)methanesulfonamide; <41> R-(2-((5-chloro-2-((4-(4-((2-hydroxyethyl)amino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl) amino)phenyl)methanesulfonamide; <42> R-(2-((5-chloro-2-((2-methoxy-4-(4-((2-methoxyethyl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl )amino)phenyl)methanesulfonamide and <43> N-(2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)amino)piperidin-1-yl)-2- methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide. 12. A method for producing a compound represented by formula (1) according to claim 1, comprising the step of reacting a compound represented by formula 2 and a compound represented by formula 3 to obtain a compound represented by formula 1 as indicated in Reaction Scheme 1 - 45 041822 where R ¹ , R ² , R ³ , R ⁴ and V Reaction Scheme 1 have the meanings as defined for formula (1) in claim 1; And X is a halogen. 13. A pharmaceutical composition for the prevention or treatment of cancer, containing the compound represented by formula (1), its optical isomer or its pharmaceutically acceptable salt according to claim 1 as an active ingredient. 14. Pharmaceutical composition according to claim 13, characterized in that the compound inhibits one or more selected from the group consisting of mutated EGFR (epidermal growth factor receptor), FLT3 and mutated FLT3. 15. Pharmaceutical composition according to claim 14, characterized in that the EGFR mutation is one or more selected from the group consisting of EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C797S, EGFR L858R, EGFR L858R/T790MS and EGFR L858R/T790M/C797S. 16. Pharmaceutical composition according to claim 14, characterized in that the FLT3 mutation is one or more selected from the group consisting of FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD ,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I) and FLT3(R834Q). 17. Pharmaceutical composition according to claim 13, characterized in that the cancer has a mutation expressed on one or more selected from the group consisting of EGFR, ALK, FAK, FLT3, JAK3, KIT and PLK4. 18. Pharmaceutical composition according to claim 13, characterized in that the cancer is one or more selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma , oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, embryonic ovarian carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, cholangiocarcinoma , colorectal cancer, chronic myeloid leukemia, chronic lymphatic leukemia, retinoblastoma, choroidal melanoma, cancer of the ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, cancer of the nasal cavity and near the nasal cavity, non-small cell lung cancer, cancer of the tongue, astrocytomas, me 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, soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, malignant tumor without identified primary focus, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, cancer penis, pharyngeal cancer, uterine choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, neurinoma auditory nerve, pancreatic cancer, cancer with lunar gland, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyoblastoma, laryngeal cancer, pleural cancer, hematologic malignancy, and thymus cancer. 19. The pharmaceutical composition according to claim 13, characterized in that the pharmaceutical composition enhances the anti-cancer effect through combined administration with an anti-cancer agent. 20. A therapeutic functional food product for the prevention or alleviation of cancer, containing the compound represented by formula (1), its optical isomer, or its pharmaceutically acceptable salt according to claim 1, as an active ingredient. -