WO2019112344A1 - Novel pyrimidine derivative having effect of inhibiting cancer cell growth and pharmaceutical composition containing same - Google Patents

Abstract

The present invention provides a novel pyrimidine derivative compound and a salt thereof. The pyrimidine derivative compound effectively inhibits the growth of cancer cells in which c797s-mutated EGFR expression and MET amplification, which are major resistance mechanisms of third generation EGFR anticancer drugs, have occurred, thereby being effectively usable in the treatment of lung cancer.

Description

Novel pyrimidine derivatives showing inhibitory effect on cancer cell growth and pharmaceutical compositions containing them

The present invention relates to a novel pyrimidine derivative which effectively inhibits cancer cell growth and a pharmaceutical composition containing the same.

Activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) have been found to be carcinogenic in some non-small cell lung cancer patients, and the low molecular weight epithelial growth factor receptor (EGFR Gefitnib, Erlotinib, etc. have been used as kinase inhibitors (Science 2004, 304: 1497-500; and New England Journal of Medicine 2004, 350: 2129-39).

In patients with non-small cell lung cancer whose mutation in EGFR activity has been confirmed, use of the above-mentioned gefitnib or erlotinib as a therapeutic agent results in resistance to drugs within 1 year in most patients (Clinical Cancer Research 2013 ; 19: 2240-7). The T790M mutation rate of epithelial growth factor receptor is observed up to 60% in this resistance mechanism. Thus, a 3 ^rd Generation EGFR inhibitor targeting the T790M Epidermal Growth Factor Receptor (EGFR) has been developed in lung cancer.

However, drug resistance of the third generation EGFR inhibitor has been reported, and C797S mutation and MET amplification have been reported as major resistance mechanisms (J Hematol Oncol. 2016, Jul. 22, 9 (1): 59 ; And Nature Medicine 2015, 21, 560-562; and Lung Cancer 2018, 118, 105-110; and ASCO2017 abstract 2572, 9020). The C797S mutation and MET amplification have been reported to be found separately but may be found at the same time (https://www.chi-med.com/wp-content/uploads/2017/06/ pre170603-met-amp-resistance. pdf).

The compounds that inhibit C797S reported in the literature are as follows:

Ken Uchibori et al. Reported that Brigatinib showed activity on C797S mutant cancers (nature communications 13 March 2017). However, this compound has reported no activity against MET (Lung Cancer: Targets and Therapy 2017: 8 169-177).

Yong Jia et al. Reported an allosteric inhibitor that exhibited activity in L858R-T790M-C797S-expressing cancer cell line. However, this compound does not report activity against Del19-T790M-C797S-expressing cancer cell line, nor does it report activity against MET (Nature 2016 Vol.534, 129-132).

Lee et al. Reported TRE-069, which shows activity in the T790M / C797S mutant kinase. However, this compound does not report the effective inhibition of the growth of T790M / C797S mutant cancers and does not report activity against MET (Bull. Korean Chem. Soc. 2017, Vol. 38, 1353-1357).

Therefore, development of drugs that effectively inhibit the growth of cancer cells resistant to C797S mutant Epidermal growth factor receptor (C797S EGFR) and MET amplification, which is the major resistance mechanism of the above-described third generation EGFR anticancer drug, is required .

[Prior Art Literature]

[Patent Literature]

PCT Patent Publication No. WO / 2009 / 143389A1

The present inventors have sought to develop new compounds that effectively inhibit the C797S mutant EGFR and MET amplification cancers, the major resistance mechanisms of the third generation EGFR anticancer agents. As a result, a novel pyrimidine derivative effective for cancer treatment was found. In particular, the novel pyrimidine derivatives have been found to exert excellent effects in the treatment of lung cancer.

Therefore, it is an object of the present invention to provide a novel pyrimidine derivative effective for treating cancer.

It is another object of the present invention to provide a pharmaceutical composition for treating lung cancer, which comprises the pyrimidine derivative.

It is another object of the present invention to provide a pharmaceutical composition for the treatment of C797S mutant EGFR expression and MET amplified lung cancer, which is a major resistance mechanism of the third generation EGFR anticancer drug among lung cancers.

In order to achieve the above object,

Claims 1. A compound represented by the following formula (1) or a salt thereof:

[Chemical Formula 1]

In this formula,

X and Y are each independently carbon or nitrogen,

Z is oxygen or a C1 to C4 alkyl group,

R_OneIs a C1 to C4 alkyl group, a C3 to C6 cycloalkyl group, a CF₃, Or a dimethylamine group,

R ₂ is an alkyl group having ₁ to 4 carbon atoms,

R ₃ is hydrogen or a halogen group,

R ₄ is hydrogen, a halogen group, CN, CF ₃ , an alkyl group having 1 to ₄ carbon atoms or an aminocarbonyl group,

R < ₅ > is hydrogen or a C1 to C4 alkyl group,

R ₆ is an alkyl group having from 1 to 4 carbon atoms,

R ₇ is hydrogen, an amine group substituted with at least one C1 to C4 alkyl group, or a piperazinyl group substituted or unsubstituted with at least one C1 to C4 alkyl group,

When Z is oxygen, it forms a double bond with S, S forms a single bond with N, and when Z is an alkyl group of C1 to C4, it forms a single bond with S, and S forms a double bond with N In addition,

In addition, R ₄ and R ₅ may be connected to form pyrrole, imidazole and thiophene.

In addition,

(1) or a salt thereof, which is used for the treatment of lung cancer.

In addition,

There is provided a pharmaceutical composition for treating lung cancer comprising, as an active ingredient, a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition,

There is provided a method for treating an animal having lung cancer, comprising administering to the animal an effective amount of the compound represented by Formula 1 above.

The novel pyrimidine derivative compounds of the present invention provide excellent effects in the treatment of cancer.

In addition, the pharmaceutical composition for treating lung cancer of the present invention comprising the pyrimidine derivative compound provides an excellent activity for the treatment of lung cancer, and more particularly, the C797S mutant EGFR and MET amplification due to the major resistance of the third generation EGFR anticancer drug ) Effectively inhibits the growth of cancer cells.

1 shows the phosphorylation inhibitory effect of the compounds of Examples 1 and 18 in Experimental Example 1 against C797S-expressing cancer cell lines.

Hereinafter, embodiments of the present invention will be described in detail. However, it should be understood that the present invention is not limited thereto, and the present invention is only defined by the scope of the following claims. In addition, a detailed description of a configuration that can be readily implemented by a person skilled in the art from known technologies will be omitted, even if it is indispensable to implement the present invention.

The term "compound of the present invention" or "compound of formula (1)" is used as a concept including both the compound itself and a salt thereof, unless otherwise stated below.

As used herein, the term "alkyl group" means straight and branched chain hydrocarbon groups having the specified number of carbon atoms. The alkyl group may be, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl,

The term of the terms "alkylsulfonyl" is alkyl -S (O ₂₎ - refers to. Where alkyl is defined above.

The present invention relates to a compound represented by the following general formula (1) or a salt thereof:

[Chemical Formula 1]

In this formula,

X and Y are each independently carbon or nitrogen,

Z is oxygen or a C1 to C4 alkyl group,

R ₁ is an alkyl group having ₁ to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, CF ₃ , Or a dimethylamine group,

R ₂ is an alkyl group having ₁ to 4 carbon atoms,

R ₃ is hydrogen or a halogen group,

R ₄ is hydrogen, a halogen group, CN, CF ₃ , an alkyl group having 1 to ₄ carbon atoms or an aminocarbonyl group,

R < ₅ > is hydrogen or a C1 to C4 alkyl group,

R ₆ is an alkyl group having from 1 to 4 carbon atoms,

R ₇ is hydrogen, an amine group substituted with at least one C1 to C4 alkyl group, or a piperazinyl group substituted or unsubstituted with at least one C1 to C4 alkyl group,

When Z is oxygen, it forms a double bond with S, S forms a single bond with N, and when Z is an alkyl group of C1 to C4, it forms a single bond with S, and S forms a double bond with N In addition,

In addition, R ₄ and R ₅ may be connected to form pyrrole, imidazole and thiophene.

The compound represented by Formula 1 may include the following compounds.

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylmethanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide;

Amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid ethyl ester was used in place of N- (2- Phenyl) -N-methylmethanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N, P, P-trimethylphosphinamide;

1-yl) phenyl) amino) -7H-purin-6-carboxylic acid ethyl ester was used in place of N- (2 - ((2- -Yl) amino) phenyl) -N-methylmethanesulfonamide;

Yl) phenyl) amino) -5-methylpyrimidine < RTI ID = 0.0 > (2-methoxy- 4-yl) amino) phenyl) -N-methylmethanesulfonamide;

Phenyl) amino) < RTI ID = 0.0 > pyrimidine < / RTI > (2-methoxy- 4-yl) amino) phenyl) -N-methylmethanesulfonamide;

Yl) phenyl) amino) -5- (trifluoromethoxy) phenyl] amino} -5- (4- (4- 4-yl) amino) phenyl) -N-methylmethanesulfonamide;

Phenyl) amino) -4 - ((2- (N-methylmethylsulfone (2-methoxyphenyl) Amido) phenyl) amino) pyrimidine-5-carboxylamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylethanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methylpropane-2-sulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methylcyclopropanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) - 1,1,1-trifluoro-N-methylmethanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methyl (N ', N'-dimethyl) sulfonamide;

((2 - ((5-chloro-2 - ((2-methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- 1- yl) phenyl) amino) 4-yl) amino) phenyl) imino) dimethyl- ⁶ -sulfanone;

Phenyl) amino) < RTI ID = 0.0 > pyrimidine < / RTI > (2-methoxy- 4-yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide;

Amino) pyrimidin-4-yl) amino) phenyl) -N-methyl (2-methoxy- Methanesulfonamide; And

Yl) phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin- 2,3-d] pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

More preferably, the compound represented by the formula (1)

In the above formula

X is nitrogen, Y is carbon, Z is oxygen,

R ₁ is an alkyl group having from ₁ to 4 carbon atoms,

R ₂ is an alkyl group having ₁ to 4 carbon atoms,

R ₃ is hydrogen or a halogen group,

R ₄ is a halogen group,

R < ₅ > is hydrogen,

R ₆ is an alkyl group having from 1 to 4 carbon atoms,

R ₇ may be a piperazinyl group or an amine group substituted with at least one C1 to C4 alkyl group or a piperazinyl group substituted or unsubstituted with at least one C1 to C4 alkyl group or a salt thereof.

Even more preferably, the compound of formula 1 and salts thereof may be:

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylmethanesulfonamide;

(2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide;

Amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid ethyl ester was used in place of N- (2- Phenyl) -N-methylmethanesulfonamide

The compound represented by the formula (1) of the present invention and a salt thereof can be used for the treatment of cancer. In particular, it can be used for the treatment of lung cancer. Among the lung cancer, treatment of lung cancer with C797S mutant Epidermal growth factor receptor (C797S mutant Epidermal growth factor receptor, C797S EGFR) and MET amplified cancer cell which is the main resistance mechanism of third generation EGFR anticancer drug Can be effectively used.

In the present invention, the compound represented by the formula (1) may be used in the form of a salt derived from an inorganic acid or an organic acid, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, , Benzoic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, maleic acid, And salts derived from at least one acid selected from the group consisting of phosphoric acid, toluene sulfonic acid and the like.

In addition,

The present invention relates to a compound represented by the above formula (1) or a salt thereof, which is used for treating lung cancer.

The present invention also relates to a pharmaceutical composition for the treatment of lung cancer, which comprises a compound represented by the above-mentioned general formula (1) as an active ingredient or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Further, the present invention relates to a method for treating an animal having lung cancer, which comprises administering an effective amount of the compound represented by Formula 1 to an animal.

The animal may be a human, and the lung cancer may be lung cancer with C797S mutant EGFR (C797S mutant Epidermal growth factor receptor, C797S EGFR) and MET-amplified resistant cancer cells.

The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or by intravenous injection, subcutaneous injection, Intraperitoneal injection, percutaneous injection, direct injection into tissues, and the like.

When the pharmaceutical composition of the present invention is prepared in the form of an oral formulation, pharmaceutically acceptable carrier may be any known component in the art without limitation as long as it does not interfere with the active expression of the active ingredient have.

Examples of the carrier include, but are not limited to, excipients, diluents, disintegrants, binders, lubricants, surfactants, emulsifiers, suspending agents, and diluents.

When the pharmaceutical composition of the present invention is prepared in the form of an injection, pharmaceutically acceptable carriers may be used without limitation as long as they do not interfere with the active expression of the active ingredient .

Specific examples thereof include water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, But is not limited thereto.

The dosage of the pharmaceutical composition of the present invention is preferably determined in consideration of the age, sex, condition of the patient, the degree of absorption of the active ingredient, the inactivation rate of the active ingredient, and the drug to be used. mg / kg (body weight) to 100 mg / kg (body weight).

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are for further illustrating the present invention and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention.

(1) Synthesis of compounds represented by formula (1)

The compounds represented by the following formula (1) according to the present invention can be easily prepared by, for example, referring to the method shown in the following Reaction Scheme 1:

 [Reaction Scheme 1]

Synthesis Example: Synthesis of N- (2 - ((5-chloro-2 - ((2-methoxy- ) Pyrimidin-4-yl) amino) phenyl) - N -Methylmethanesulfonamide < / RTI >

1-1. N -methyl- N - (2-nitrophenyl) methanesulfonamide

In Scheme 1, the structure 5 was obtained by dissolving 1-fluoro-2-nitrobenzene (3 g, 21.262 mmol) in acetonitrile (150 mL), adding cesium carbonate (10.4 g, 31.892 mmol) and N -methylmethanesulfonamide did. Then, the mixture was stirred at 80 DEG C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated under reduced pressure to obtain N -methyl- N- (2-nitrophenyl) methanesulfonamide (Compound 4) . The reaction was carried out without further separation.

1-2. N - (2-aminophenyl) - N - < / RTI > methylmethanesulfonamide

The N - methyl - N - (2- nitrophenyl) methane-sulfonamide (4.5g, 19.545mmol) in methanol (100mL), dichloromethane, and 10% palladium / charcoal (0.416g, 3.909mmol) was dissolved in (50mL) to Was added. And stirred under atmospheric pressure hydrogen for 2 hours. After completion of the reaction, filtration was performed using celite. The filtrate was evaporated under reduced pressure, then solidified using ethyl ether and n-pentane and filtered to obtain N - (2-aminophenyl) -N -methylmethanesulfonamide (Compound 3 ). The reaction was carried out without further separation.

1-3. N- (2 - ((2,5-dichloropyrimidin-4-yl) amino) phenyl) N - < / RTI > methylmethanesulfonamide

The resulting N - (2-aminophenyl) -N -methylmethanesulfonamide (8.3 g, 41.446 mmol) was dissolved in isopropyl alcohol (200 mL) and 2,4,5- trichloropyrimidine (12.163 g, 66.314 mmol) and N, N-diisopropylethylamine (21.428 g, 166 mmol) at room temperature. After stirring at 90 ° C for 12 hours, the reaction was terminated, and the reaction mixture was evaporated under reduced pressure and extracted with water and dichloromethane. The organic layer was washed with 2N hydrochloric acid, and the organic layer under reduced pressure N- (2 - ((2,5- dichloro-pyrimidin-4-yl) amino) phenyl) - N - methyl methane sulfonamide (Compound 2) . The reaction was carried out without further separation.

1-4. Preparation of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine

Dissolving the 2-methoxy-1-nitrobenzene (5g, 29.218mmol) to the structure 4-8 of Scheme 1, in acetonitrile (100mL) and potassium carbonate (8.076g, 58.435mmol) and the piperazine intermediate (5.4 g, 29.218 mmol) at room temperature. After stirring at 90 DEG C for 12 hours to terminate the reaction, the temperature was lowered to room temperature and the reaction solution was filtered. The filtrate was evaporated under reduced pressure to give 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (Compound 7 ). The reaction was carried out without further separation.

1-5. Preparation of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline

4-Nitrophenyl) piperidin-4-yl) -4-methylpiperazine (8.4 g, 25.118 mmol) was dissolved in methanol (250 mL), dichloromethane ) And 10% palladium / charcoal (0.802 g, 7.353 mmol) was added. After stirring for 2 hours under atmospheric pressure hydrogen atmosphere, the reaction was terminated and filtered using Celite. The filtrate was evaporated under reduced pressure, and 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (Compound 6 ) was obtained by solidifying n-hexane Respectively. The reaction was carried out without further separation.

1-6. (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) - N - < / RTI > methylmethanesulfonamide

The resulting N- (2 - ((2,5-dichloropyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide (11 g, 31.681 mmol) was dissolved in isopropyl alcohol (150 mL) (7.0 g, 23.127 mmol) and p-toluenesulfonic acid (6.0 g, 31.681 mmol) were added to a solution of 2-methoxy-4- (4- Was added at room temperature. After the reaction was completed by stirring at 90 DEG C for 12 hours, the reaction mixture was evaporated under reduced pressure to remove the solvent and extracted with a mixture of water and 10% methanol / dichloromethane. The separated organic layer was evaporated under reduced pressure and the residue was subjected to column chromatography to obtain N- (2 - ((5-chloro-2 - ((2-methoxy- 1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) - N - methyl-methane-sulfonamide (compound 1) was obtained (5 to 10% ammonia / methyl alcohol / dichloromethane).

(2) Synthesis of N-methylalkylsulfonamide

Sulfonyl chloride (1.0 eq.) Is slowly added to 2M methylamine (2.6 eq) dissolved in tetrahydrofuran at 0 < 0 > C. The temperature is raised to room temperature and stirred at the same temperature for 4 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and extracted with 2N hydrochloric acid and MC. The separated organic layer is evaporated under reduced pressure to obtain the target compound.

(3) Method for producing final compound

<Method 1>

The pyrimidine derivative (1.37 eq.) Is dissolved in isopropyl alcohol and aniline derivative (1.0 eq.) And para-toluenesulfonic acid (1.37 eq.) Are added at room temperature. Followed by stirring at 90 占 폚 for 12 hours. After completion of the reaction, the solvent is evaporated under reduced pressure, and the mixture is extracted with a mixture of water and 10% methanol / dichloromethane. The separated organic layer is evaporated under reduced pressure and subjected to column chromatography to obtain the target compound (5-10% ammonia / methyl alcohol / dichloromethane).

<Method 2>

(1.0 eq.) Was dissolved in 1,4-dioxane and treated with aniline derivative (1.0 eq.), Palladium acetate (0.14 eq.), 2,2'-bis (diphenylphosphino) Naphthyl (BINAP, 0.28 eq.) And potassium carbonate (2.3 eq.) Are added at room temperature. After refluxing and stirring for 12 hours, the temperature was lowered to room temperature. Filtration is carried out using celite, extraction is carried out using water and ethyl acetate, and the separated organic layer is evaporated under reduced pressure and subjected to column chromatography to obtain the target compound (5-10% methyl alcohol / dichloromethane).

(4) Deprotection method of a compound having a protecting group

<Method 1>

The compound having a protecting group was dissolved in 4M hydrochloric acid (1,4-dioxane). After stirring at room temperature for 3 hours, the reaction was terminated, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The separated organic layer was evaporated under reduced pressure and subjected to column chromatography to obtain the target compound.

Method 2. A compound having a protecting group was dissolved in a mixed solvent of methanol, 1,4-dioxane and water (3: 3: 1). Cesium carbonate (10.0 eq.) Was added at room temperature and stirred at 80 占 폚 for 3 hours. After completion of the reaction, the temperature was lowered to room temperature, and then water was added. The resulting solid was filtered and dried. The target compound was isolated using column chromatography.

Example 1: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

The final compound was prepared by the above method 1.

Yield: 48.2%; White Solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.41 (dd, J = 8.3, 1.5 Hz, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H J = 7.6, 1.5 Hz, 1H), 7.37 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.31 (dd, J = 8.0, 1.5 Hz, 2H), 3.27 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 2.5 Hz, (s, 3H), 2.98 (s, 3H), 2.73-2.63 (m, 2H), 2.64 (d, J = 12.4 Hz, 2H), 1.70 (qd, J = 12.0, 3.8 Hz, 4H).

Example 2: Preparation of N- (2 - ((5-chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide

The final compound was prepared by Method 2 above.

Yield: 15.9%; White solid;

^{1 H NMR (400 MHz, DMSO-} d6): δ 8.34 (s, 1H), 8.26 (s, 1H), 8.16 (bs, 1H), 8.09 (s, 1H), 7.59 (dd, J = 8.9, 5.9 J = 8.6 Hz, 1H), 6.42 (dd, J = 8.6 Hz, 1H) , 2.5 Hz, IH), 3.71-3.65 (m, 5H), 3.14 (s, 3H), 3.08 (s, 3H), 2.68-2.56 (m, 2H), 2.51-2.42 2.18 (m, 5H), 2.11 (s, 3H), 1.81 (d, J = 12.2 Hz, 2H), 1.47 (m, 2H). MS: ESI m / z 633.2 [M + H] &lt; + &gt;

Example 3: Preparation of N- (2 - ((5-chloro-2 - ((4- (4- (dimethylamino) piperidin- 1 -yl) -2- methoxyphenyl) amino) Yl) amino) phenyl) -N-methylmethanesulfonamide

The final compound was prepared by Method 2 above.

Yield: 17.7%; Off-white solid;

^{1 H NMR (400 MHz, DMSO-} d6): δ 8.24 (s, 2H), 8.06 (d, J = 1.9 Hz, 2H), 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.12 (td, J = 7.6, 1.5 Hz, 1H), 6.58 (S, 3H), 3.69 (s, 3H), 3.66 (d, J = ), 2.17 (m, 7H), 1.81 (d, J = 12.3 Hz, 2H), 1.46 (qd, J = 11.9, 3.8 Hz, 2H).

Example 4: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N, P, P-trimethylphosphinic amide

The final compound was prepared by Method 2 above.

Yield: 18.5%; Yellow solid;

^{1 H NMR (400 MHz, DMSO} -d6) δ 8.41 (s, 1H), 8.03 - 7.96 (m, 2H), 7.74 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 7.9, 1.6 Hz J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.33 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.24 1H), 6.57 (d, J = 2.5 Hz, 1H), 6.38 (dd, J = 8.9, 2.5 Hz, 1H) (s, 3H), 3.01 (s, 3H), 2.59 (t, J = 11.9 Hz, 2H), 2.51-2.42 , J = 12.6 Hz, 2H), 1.48 (q, J = 13.0, 11.8 Hz, 2H). MS: ESI m / z 637.2 [M + H] &lt; + &gt;

Example 5: Preparation of N- (2 - ((2- ((2-methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- - purin-6-yl) amino) phenyl) -N-methylmethanesulfonamide

The final compound was prepared by the above method 1.

Yield: 51.3%; Pale yellow solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.66 (dd, J = 8.4, 1.5 Hz, 1H), 8.44 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.44 - 7.29 (m (Dd, J = 8.0, 7.3, 1.5 Hz, 1H), 7.04 (s, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.48 2H), 3.28 (s, 3H), 3.01 (s, 3H), 2.73-2.57 (m, 6H), 2.55-2.27 (m, , 2H), 2.15 (s, 3H), 2.11-1.89 (m, 6H), 1.69 (qd, J = 12.2, 3.9 Hz, 2H).

Example 6: Preparation of N- (2 - ((2 - ((2-methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- -Methylpyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

The final compound was prepared by Method 2 above.

Yield: 29.3%; Beige color solid;

^{1 H NMR (400 MHz, DMSO} -d6): δ 8.98 (bs, 1H), 8.36 (s, 1H), 7.91 (bs, 1H), 7.78 (s, 1H), 7.51-7.42 (m, 1H), (D, J = 8.7, 2.5 Hz, 1H), 3.75-3.70 (m, 5H), 3.15 (s, 3H) 3H), 2.38-2. 20 (m, 5H), 2.13 (s, 3H), 3.01 (s, 3H) ), 1.81 (d, J = 12.5 Hz, 2H), 1.48 (m, 2H). MS: ESI m / z 595.1 [M + H] &lt; + &gt;

Example 7: Phenyl) amino) &lt; RTI ID = 0.0 &gt; pyrimidine &lt; / RTI &gt; (2-methoxy- 4-yl) amino) phenyl) -N-methylmethanesulfonamide

The final compound was prepared by Method 2 above.

Yield: 33.3%; Beige color solid;

^{1 H NMR (400 MHz, DMSO-} d6): δ 8.96 (bs, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.91 (bs, 1H), 7.51-7.42 (m, 1H), J = 8.7, 2.5 Hz, 1H), 3.75 (d, J = 12.2 Hz, 2H), 3.70 (d, J = , 3.10 (s, 3H), 3.02 (s, 3H), 2.68 (t, J = 11.9 Hz, 3H), 2.51-2.42 (m, 4H), 2.38-2.20 s, 3H), 1.82 (d, J = 12.5 Hz, 2H), 1.48 (m, 2H). MS: ESI m / z 606.2 [M + H] &lt; + &gt;

Example 8: N- (2 - ((2 - ((2-Methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- - (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

Yield: 20.6%; Beige color solid;

^{1 H NMR (400 MHz, DMSO} -d6): δ 9.02 (bs, 1H), 8.37 (s, 1H), 8.26 (bs, 1H), 7.90 (s, 1H), 7.51-7.42 (m, 1H), 3H), 6.60 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.7, 2.5 Hz, 1H), 3.77-3.70 (m, , 3.02 (s, 3H), 2.68 (t, J = 11.9 Hz, 3H), 2.51-2.42 (m, 4H), 2.39-2.21 = 12.5 Hz, 2H), 1.49 (m, 2H). MS: ESI m / z 649.2 [M + H] &lt; + &

Example 9: 2 - ((2-Methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin- - methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxamide

Yield: 17.5%; Beige color solid;

^{1 H NMR (400 MHz, DMSO-} d6): δ 8.94 (bs, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.96 (s, 2H), 7.87 (bs, 1H), 7.51- J = 8.7 Hz, 1H), 3.75 (d, J = 12.2 Hz, 1H), 7.42 (m, 1H), 7.16-7.00 2H), 3.68 (s, 3H), 3.07 (s, 3H), 3.00 (s, 3H), 2.68 (t, J = 11.9 Hz, 3H), 2.51-2.42 m, 5H), 2.07 (s, 3H), 1.81 (m, 2H), 1.48 (m, 2H). MS: ESI m / z 624.1 [M + H] &lt; + &gt;

Example 10: Preparation of N- (2 - ((5-chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N-methylethanesulfonamide

The final compound was prepared by the above method 1.

Yield: 55.6%; Pale yellow solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.42 - 8.29 (m, 2H), 8.10 - 7.98 (m, 2H), 7.42 - 7.30 (m, 2H), 7.23 - 7.13 (m, 1H), 6.51 ( 3H), 3.63 (d, J = 12.1 Hz, 2H), 3.28 (s, 3H) (M, 5H), 2.45 (d, J = 12.4 Hz, 1H), 2.40 (s, 3H), 1.99 , J = 19.2, 10.0 Hz, 4H), 1.74 (td, J = 12.0, 3.8 Hz, 3H), 1.45 (t, J = 7.4 Hz, 3H).

Example 11: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N-methylpropane-2-sulfonamide

The final compound was prepared by the above method 1.

Yield: 54.4%; Off white solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.34 (s, 1H), 8.32 - 8.19 (m, 1H), 8.10 - 7.99 (m, 2H), 7.43 - 7.32 (m, 2H), 7.28 (d, (D, J = 7.8 Hz, 7H), 7.24-7.03 (m, 2H), 6.54-6.48 3H), 2.86 (s, 3H), 2.86-2.76 (m, 4H), 2.68 (t, J = 11.8 Hz, 3H), 2.49 (s, 3H), 1.74 (d, J = 11.6 Hz, 3H), 1.70 (bs, 2H), 1.46 (d, J = 6.8 Hz, 6H).

Example 12: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N-methylcyclopropanesulfonamide

The final compound was prepared by the above method 1.

Yield: 50.7%; Pale yellow solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.40 (dd, J = 8.3, 1.5 Hz, 1H), 8.32 (s, 1H), 8.12 - 8.00 (m, 2H), 7.51 - 7.36 (m, 2H) , 7.34 (d, J = 1.6 Hz, 1H), 7.22-7.04 (m, 2H), 6.55-6.41 (m, 2H), 3.85 2H), 3.28 (d, J = 6.3 Hz, 1H), 2.81 (d, J = 25.8 Hz, 4H) (Dd, J = 11.3, 4.7 Hz, 2H), 1.75 (t, J = 12.1 Hz, 2H), 1.26-1.55 (dd, J = 8.0, 3.9 Hz, 2H) (m, 2 H), 1.01 (s, 2 H).

Example 13: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -1,1,1-trifluoro-N-methylmethanesulfonamide

Yield: 21.3%; Light Yellow Solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.41 (dd, J = 8.3, 1.5 Hz, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H J = 7.6, 1.5 Hz, 1H), 7.37 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.31 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.44 (dd, J = 8.8,2.5 Hz, 1H) 2H), 2.64 (s, 4H), 2.37 (tt, J = 11.9, 3.8 Hz, 1H), 2.24 , 2H), 1.70 (qd, J = 12.0, 3.8 Hz, 4H)

Example 14: N- (2 - ((5-Chloro-2 - ((2-methoxy- Amino) pyrimidin-4-yl) amino) phenyl) -N-methyl (N ', N'-dimethyl) sulfonamide

Yield: 17.4%; Beige color Solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.42 (dd, J = 8.3, 1.5 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H J = 7.6, 1.5 Hz, 1H), 7.35 (ddd, J = 8.5, 7.3, 1.5Hz, 1H), 7.30 2H), 2.97 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H) (s, 3H), 2.74 (s, 6H), 2.73-2.63 (m, 2H), 2.64 (d, J = 12.4 Hz, 2H), 1.70 (qd, J = 12.0, 3.8 Hz, 4H).

Example 15: ((2 - ((5-Chloro-2 - ((2-methoxy- ) Pyrimidin-4-yl) amino) phenyl) imino) dimethyl- λ ⁶ -sulfanone

Yield: 12.9%; Beige color Solid;

^{1 H NMR (400 MHz, Chloroform} -d) δ 8.46 (dd, J = 8.3, 1.5 Hz, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H J = 7.6, 1.5 Hz, 1 H), 6.53 (d, J = 8 Hz), 7.37 (m, 3H), 3.63 (d, J = 12.0 Hz, 2H), 3.29 (s, 6H), 2.73-2.63 (d, J = (m, 2H), 2.64 (s, 4H), 2.37 (tt, J = 11.9, 3.8 Hz, 1H) ).

Example 16: Preparation of N- (2 - ((5-cyano-2 - ((2-methoxy- ) Amino) pyrimidin-4-yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide

The final compound was prepared by Method 2 above.

Yield: 23.1%; Off-white solid;

¹ H NMR (400 MHz, DMSOd6 ):? 9.14 (bs, IH), 8.41 (s, IH), 8.24 (d, J = 1.3 Hz, J = 8.8, 5.9 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.83 (td, J = 8.3, 3.0 Hz, 1H), 6.59 (s, 3H), 2.65 (t, J = 11.5Hz, 2H), 2.51-2.42 (m, 2H) (m, 4H), 2.27 (m, 5H), 2.11 (s, 3H), 1.81 (d, J = 12.4 Hz, 2H), 1.55-1.40 (m, 2H).

Example 17: Preparation of N- (2 - ((5-chloro-2 - ((2-methoxy-4- (piperidin- -N-methylmethanesulfonamide &lt; / RTI &gt;

Proceeding to Final Compound Preparation Method 2, the deprotection method 2 was followed.

Yield: 60.8%; Tan color solid;

^{1 H NMR (400 MHz, Methanol} -d4) δ 8.15 (dt, J = 8.6, 2.2 Hz, 1H), 8.02 (d, J = 0.5 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), (Dd, J = 8.0, 1.5 Hz, 1H), 7.37 (ddd, J = 9.5, 6.2, 1.6 Hz, 1H), 7.26 (S, 3H), 3.10 (d, J = 12.3 Hz, 2H), 3.01 (s, 3H) J = 12.0, 3.6 Hz, 1H), 1.78 (d, J = 12.8 Hz, 2H), 1.63 (qd, J = 12.5 , 4.1 Hz, 2H). MS: ESI m / z 517.1 [M + H] &lt; + &gt;

Example 18: Preparation of N- (2 - ((2 - ((2-methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- Pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide

Proceeding to Final Compound Preparation Method 2 and deprotection by the deprotection method 2.

Yield: 47.1%; Tan color solid;

^{1 H NMR (400 MHz, DMSO} -d6) δ 11.22 (s, 1H), 8.21 (dd, J = 8.2, 1.5 Hz, 1H), 8.17 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H (Dd, J = 7.9,1.6 Hz, 1H), 7.36-7.28 (m, 1H), 7.19 J = 3.5, 2.2 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 6.40 (dd, J = 3H), 2.63-2.53 (m, 2H), 2.51-2.40 (m, 4H), 3.77 (s, 3H) , 2.25 (m, 5H), 2.10 (s, 3H), 1.81 (d, J = 10.2 Hz, 2H), 1.55-1.42 (m, 2H). MS: ESI m / z 620.2 [M + H] &lt; + &

Experimental Example 1: Measurement of kinase inhibitory activity

The compound 1 obtained in the above Example was measured for the inhibitory effect of C797S-containing epithelial growth factor (EGFR) kinase and MET kinase inhibitor, and the results are shown in Table 1 below. Kinase inhibitory activity was measured by the following method.

1. Each kinase was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM KKKGQEEEYVFIE, 1 mM sodium orthovanadate, 5 mM sodium-6-glycerophosphate, 10 mM magnesium acetate, [η- ³³ P] -ATP.

2. Evaluation compound (DMSO solution) and Mg / ATP were added to proceed the reaction.

3. After about 40 minutes at room temperature, the reaction was terminated by the addition of 10 uL of 0.5% phosphoric acid.

4. The reaction solution was divided into 0.5% 10uL and spotted on a P30 filtermat.

5. Washed 4 times with 0.425% phosphoric acid for about 4 minutes. Washed once with methanol, dried, and analyzed by scintillation counting to determine IC ₅₀ values.

Example EGFR (del19 / C797S) EGFR (del19 / T790M / C797S) MET (IC ₅₀ ) One 0.4 nM 0.08 nM 1 nM Brigatini - 2nM 70 nM TRE-069 - 6nM 120 nM

As shown in the experimental results of Table 1 above, the compounds prepared by the examples of the present invention show that the inhibitory effect of C797S-containing epithelial growth factor (EGFR) kinase, MET kinase inhibitor, on the activity of brittanyib and TRE-069 It was confirmed to be very good.

Experimental Example 2: Measurement of cancer cell growth inhibitory effect

The inhibitory effect of C797S-expressing triple mutant Ba / F3 cancer cell growth on the compounds obtained in the above Examples was measured. Kinase assays and anticancer efficacy assays using Ba / F3 stable cell lines were performed by the following method.

1. Gene construction: wild type and mutant EGFR were purchased from Addgene (wild type, # 11011; L858R, # 11012; L858R + T790M, # 32073; del19, # 32062; del19 + T790M, # 32072). All construction was a retroviral vector and finally completed the viral particle for infection.

2. Construction of Ba / F3 stable cell line: Murine lymphoid cells undergo IL-3 dependent growth. When each mutant EGFR construct is infected with these cell lines, the cells will survive without IL-3 because they become oncogenic addiction due to the expression of mutant EGFR. Using this principle, a stable cell line was constructed without puromycin selection. Briefly, each construction was infected with Ba / F3, and after 48 hours, IL-3 was removed while media exchange and cells were cultured. However, puromycin selection was performed for wild-type EGFR.

3. Identification of Ba / F3 stable cell line: All stable cell lines were subjected to western blotting to confirm the expression of each construct and EGFR activity (EGFR wild type and L858R are absent).

4. Cellular kinase activity changes (Western blotting) Cells were obtained after 5 hours treatment of drugs in each stable cell line in a dose-dependent manner. EBC lysis buffer (50 mM Tris-HCl pH 8.0, 120 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 0.3 mM phenylmethylsulfonylfluoride, 0.2 mM sodium orthovanadate, 0.5% NP- U / mL aprotinin) to make cell lysates. Antibodies to EGFR-related signaling molecules [p-EGFR (Tyr1173), EGFR, Akt, p-Erk, Erk, actin, from SantaCruz; p-Akt, from Cell signaling].

5. Antitumor effect assay by MTT assay: 2 X 10 ⁵ cells were seeded in a 96-well plate. After 24 hours, each of the drugs was treated in a dose-dependent manner, incubated for 72 hours, reacted with 15 μL MTT reagent for 4 hours, and then incubated with 100 μL 10% SDS for 24 hours. Changes in final OD were read at 595 nm. MTT results were analyzed by IC ₅₀ values through prism software.

GI ₅₀ values were calculated for each compound by 50% inhibition of cell growth. The results are shown in Table 2 below. Brigatinib, TRE-069, was used as the reference drug.

Example DEL19 / T790M / C797S (IC ₅₀ ) _{L858R / T790M / C797S (IC 50} ) One 210 nM 160 nM 2 222 nM 533nM 3 323nM 531nM * Brigatynum 560nM 860nM ** TRE-069 5,005nM 3,995nM

* Brigatini Nat: Nat. Commun. 2017 Mar 13; 8: 14768. ** TRE-069: Bull. Korean Chem. Soc. 2017, Vol. 38, 1353-1357.

As shown in the results of the experiment in Table 2, the compounds prepared by the examples of the present invention exhibit a remarkably inhibitory activity against the C797S mutant epithelial cell growth factor receptor-expressing cancer cell line as compared to the brittitanib and TRE-069 Respectively. On the other hand, briatitinib and TRE069 were found to be very inactive compared with the compounds of the present invention.

Claims (7)

A compound represented by the following formula (1) or a salt thereof: [Chemical Formula 1]

In this formula, X and Y are each independently carbon or nitrogen, Z is oxygen or a C1 to C4 alkyl group, R ₁ is an alkyl group having ₁ to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, CF ₃ , Or a dimethylamine group, R ₂ is an alkyl group having ₁ to 4 carbon atoms, R ₃ is hydrogen or a halogen group, R ₄ is hydrogen, a halogen group, CN, CF ₃ , an alkyl group having 1 to ₄ carbon atoms or an aminocarbonyl group, R &lt; ₅ &gt; is hydrogen or a C1 to C4 alkyl group, R ₆ is an alkyl group having from 1 to 4 carbon atoms, R ₇ is hydrogen, an amine group substituted with at least one C1 to C4 alkyl group, or a piperazinyl group substituted or unsubstituted with at least one C1 to C4 alkyl group, When Z is oxygen, it forms a double bond with S, S forms a single bond with N, and when Z is an alkyl group of C1 to C4, it forms a single bond with S, and S forms a double bond with N In addition, In addition, R ₄ and R ₅ may be connected to form pyrrole, imidazole and thiophene. The method according to claim 1, The compound represented by the formula (1) is the following compounds or a salt thereof: (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylmethanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide; Amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid ethyl ester was used in place of N- (2- Phenyl) -N-methylmethanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N, P, P-trimethylphosphinamide; 1-yl) phenyl) amino) -7H-purin-6-carboxylic acid ethyl ester was used in place of N- (2 - ((2- -Yl) amino) phenyl) -N-methylmethanesulfonamide; Yl) phenyl) amino) -5-methylpyrimidine &lt; RTI ID = 0.0 &gt; (2-methoxy- 4-yl) amino) phenyl) -N-methylmethanesulfonamide; Phenyl) amino) &lt; RTI ID = 0.0 &gt; pyrimidine &lt; / RTI &gt; (2-methoxy- 4-yl) amino) phenyl) -N-methylmethanesulfonamide; Yl) phenyl) amino) -5- (trifluoromethoxy) phenyl] amino} -5- (4- (4- 4-yl) amino) phenyl) -N-methylmethanesulfonamide; Phenyl) amino) -4 - ((2- (N-methylmethylsulfone (2-methoxyphenyl) Amido) phenyl) amino) pyrimidine-5-carboxylamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylethanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methylpropane-2-sulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methylcyclopropanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) - 1,1,1-trifluoro-N-methylmethanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) phenyl) -N-methyl (N ', N'-dimethyl) sulfonamide; ((2 - ((5-chloro-2 - ((2-methoxy-4- (4- (4- methylpiperazin- 1 -yl) piperidin- 1- yl) phenyl) amino) 4-yl) amino) phenyl) imino) dimethyl- ⁶ -sulfanone; Phenyl) amino) &lt; RTI ID = 0.0 &gt; pyrimidine &lt; / RTI &gt; (2-methoxy- 4-yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide; Amino) pyrimidin-4-yl) amino) phenyl) -N-methyl (2-methoxy- Methanesulfonamide; And Yl) phenyl) amino) -7H-pyrrolo [2,3-d] pyrimidin- 2,3-d] pyrimidin-4-yl) amino) phenyl) -N-methylmethanesulfonamide The method according to claim 1, X is nitrogen, Y is carbon, Z is oxygen, R ₁ is an alkyl group having from ₁ to 4 carbon atoms, R ₂ is an alkyl group having ₁ to 4 carbon atoms, R ₃ is hydrogen or a halogen group, R ₄ is a halogen group, R &lt; ₅ &gt; is hydrogen, R ₆ is an alkyl group having from 1 to 4 carbon atoms, R ₇ is a piperazinyl group substituted or unsubstituted with one or more C 1 to C 4 alkyl group-substituted amine groups or one or more C 1 to C 4 alkyl groups. The method of claim 3, The compound represented by Formula 1 is the following compound or a salt thereof: (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine 4-yl) amino) phenyl) -N-methylmethanesulfonamide; (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidine Yl) amino) -4-fluorophenyl) -N-methylmethanesulfonamide; And Amino) pyrimidin-4-yl) amino) piperidine-1-carboxylic acid ethyl ester was used in place of N- (2- Phenyl) -N-methylmethanesulfonamide The method according to claim 1, The salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, mandelic, tartaric, Is a salt derived from at least one acid selected from the group consisting of maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid Or a salt thereof. A pharmaceutical composition for the treatment of lung cancer, comprising a compound according to any one of claims 1 to 5 as an active ingredient or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The method according to claim 6, Wherein said lung cancer is C797S mutant Epidermal Growth Factor Receptor (EGFR) expressing lung cancer and MET amplified lung cancer.

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