KR102327053B1 - Quinazoline, Quinoline Derivatives and Their Use as EGFR Kinase Inhibitors - Google Patents

Abstract

The present invention relates to a quinazoline, a quinoline derivative, and use as an EGFR kinase inhibitor, wherein a pharmaceutical composition comprising the quinazoline, a quinoline derivative of Formula 1, or a pharmaceutically acceptable salt thereof is EGFR (del E746-A750/T790M). By inhibiting /C797S) kinase, it is effective in treating diseases related to EGFR (del E746-A750/T790M/C797S) such as non-small cell lung cancer.

Description

Quinazoline, Quinoline Derivatives and Their Use as EGFR Kinase Inhibitors

The present invention relates to quinazoline, quinoline derivatives and uses as EGFR kinase inhibitors, and more particularly, by inhibiting EGFR (del E746-A750/T790M/C797S) kinase, such as in non-small cell lung cancer, EGFR (del E746-A750/ T790M/C797S)) and relates to a pharmaceutical composition comprising quinazoline, a quinoline derivative, or a pharmaceutically acceptable salt thereof, which can treat a disease.

Epidermal growth factor receptor (EGFR) is a type of protein tyrosine kinases and is an enzyme that plays an important role in cell growth, differentiation, and survival. It is a membrane protein receptor located on the cell membrane. It is composed of a receptor outside the cell and a tyrosine kinase inside the cell. It exists as a monomer, but when the epidermal growth factor binds to the receptor, it is converted into a dimer and the terminal phosphate group of ATP is a tyrosine residue of the substrate protein. It is known that activation occurs by accelerating the process of introduction into However, it has been reported that when an EGFR-activating mutation occurs, such signal transduction is excessively progressed, resulting in proliferative diseases such as Non-Small-Cell Lung Cancer.

The best known EGFR-activating mutations are the in-frame deletion of exon 19 (E746-A750) and the L858R point mutation of exon 21. Tyrosine kinase inhibitors have been developed to overcome the proliferative disease caused by these mutations, and Gefitinib and Erlotinib, which have been approved by the FDA, are representative first-generation inhibitors. All of them are reversible inhibitors that act as a mechanism to block ATP binding by competitively binding with ATP at the ATP binding site.

If these reversible inhibitors are used continuously for 12-16 months, secondary mutations that cause drug resistance occur, and the T790M point mutation accounts for the highest rate among them. It is known that the T790M point mutation exhibits drug resistance due to a decrease in the binding force to the inhibitor as the binding force to ATP increases. In order to overcome drug resistance, an irreversible second-generation inhibitor capable of forming a covalent bond with the cysteine at position 797, which is known to have high nucleophilicity among amino acids, has been developed. Neratinib, Afatinib, and Dacomitinib are known inhibitors, with improved efficacy against mutations compared to the first-generation inhibitors.

However, when the second-generation inhibitor is injected at a dose to suppress the T790M mutation, it inhibits not only the mutation but also the activity of unmutated wild-type EGFR in normal cells, resulting in serious side effects such as skin rash, diarrhea, and weight loss. It has been reported that it shows a limit to the therapeutic effect as it worsens. To overcome this, a mutant-selective and irreversible inhibitor that does not inhibit the activity of wild-type EGFR has been developed. WZ 4002, Rociletinib, Osimertinib, and Nazartinib are the most well-known, and they are classified as third-generation inhibitors.

Drug resistance to osimertinib, a third-generation inhibitor, was first reported in 2015. This is because 797 cysteine, which forms a covalent bond with an irreversible inhibitor, is a low nucleophilic amino acid, and the binding force to the inhibitor is weakened due to point mutation, and C797S point mutation is the most known form. A small molecule inhibitor approved by the FDA that can overcome such drug resistance has not yet been reported, and in particular, it is necessary to develop a small molecule inhibitor for a triple mutation having all of the above mutations.

Among the reported triple mutations, in the case of the L858R/T790M/C797S mutation, since the activity-inhibited monomer and the activated dimer exist at the same time, treatment with the antibody, cetuximab, inhibits the conversion of the activity to the inhibited monomer. Although the effect could be confirmed, it is known that it is difficult to expect an inhibitory effect by cetuximab because most of the del E746-A750/T790M/C797S mutations exist as activated monomers. A small molecule inhibitor that inhibits the activity of the triple mutant has been recently reported through several studies, but it is limited to inhibiting the activity of the L858R/T790M/C797S mutant and has no selectivity with wild-type EGFR, so the therapeutic agent is unknown del E746-A750 The development of a small molecule inhibitor that selectively inhibits the activity of the /T790M/C797S mutant is desired.

Accordingly, the present inventors have found that the quinazoline or quinoline derivative represented by Formula 1 selectively inhibits the activity of the EGFR delE746-A750/T790M/C797S mutation, thereby causing EGFR (del E746-A750/T790M/C797S) mutation-related diseases, such as abnormal The present invention has been completed after confirming that it can be used to treat or prevent proliferative diseases resulting from cell growth, function or behavior.

An object of the present invention is to provide a quinazoline, a quinoline derivative, or a pharmaceutically acceptable salt thereof capable of treating diseases related to EGFR (del E746-A750/T790M/C797S), such as non-small cell lung cancer, and a method for preparing the same. have.

Another object of the present invention is to provide a pharmaceutical composition for treating or preventing EGFR activity-related diseases, including quinazoline, a quinoline derivative, or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt.

[Formula 1]

in formula 1

V and W are each independently hydrogen (H) or methoxy (OCH ₃ )

X and Y are each independently carbon (C) or nitrogen (N),

Z is nitrogen (N) or oxygen (O),

R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy(-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -Dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _2-3 -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl, -(CH ₂ ) _1-2 - C5-C6 heterocyclyl wherein said aryl, heteroaryl or heterocyclyl is unsubstituted or methyl, ethyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, -(CH ₂ ) ₂ -alcohol ( OH) may be substituted with one substituent selected from the group consisting of,

R ₂ is hydrogen, methyl(CH ₃ ) or —(CH ₂ ) _1-2 -C5-C6 heterocyclyl _{cyclized with R 1 ,}

R ₃ is aryl, wherein said aryl is unsubstituted or methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ , It may be substituted with 1 to 3 substituents from the group consisting of _{-CONHCH 3 .}

The present invention also provides a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt comprising the steps of:

(a) reacting a compound of Formula 2 with R ₁ ZH to produce a compound of Formula 3;

(b) Suzuki coupling the compound of Formula 3 obtained in step (a) with R ₂ B(OH) ₂ to produce a compound of Formula 4;

(c) generating a compound of Formula 5 by performing Suzuki coupling of the compound of Formula 4 obtained in step (b) with R ₂ B(OH) _{2 ;} and

(d) reacting the compound of Formula 5 obtained in step (c) with R ₁ ZH to produce a compound of Formula 1.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

in the chemical formula

V and W are each independently hydrogen (H) or methoxy (OCH ₃ )

X and Y are each independently carbon (C) or nitrogen (N),

Z is nitrogen (N) or oxygen (O),

R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy(-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -Dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _2-3 -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl, -(CH ₂ ) _1-2 - C5-C6 heterocyclyl wherein said aryl, heteroaryl or heterocyclyl is unsubstituted or methyl, ethyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, -(CH ₂ ) ₂ -alcohol ( OH) may be substituted with one substituent selected from the group consisting of,

R ₂ is hydrogen, methyl(CH ₃ ) or —(CH ₂ ) _1-2 -C5-C6 heterocyclyl _{cyclized with R 1 ,}

R ₃ is aryl, wherein said aryl is unsubstituted or methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ , It may be substituted with 1 to 3 substituents from the group consisting of _{-CONHCH 3 .}

The present invention also provides a pharmaceutical composition for treating or preventing EGFR activity-related diseases, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

Since the compound of Formula 1 according to the present invention and a pharmaceutically acceptable salt thereof exhibit inhibitory activity against EGFR (del E746-A750/T790M/C797S) kinase, EGFR (del E746-A750/T790M/C797S) mutation and It can be used to treat or prevent a related disease, such as a proliferative disease resulting from abnormal cell growth, function or behavior.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is those well known and commonly used in the art.

In the present invention, the quinazoline or quinoline derivative represented by Formula 1 selectively inhibits the activity of the EGFR delE746-A750/T790M/C797S mutation, thereby causing EGFR (del E746-A750/T790M/C797S) mutation-related diseases, such as abnormal cell growth. , it could be confirmed that it can be used to treat or prevent proliferative diseases resulting from function or behavior.

Accordingly, in one aspect, the present invention relates to a compound represented by Formula 1 or a pharmaceutically acceptable salt.

[Formula 1]

in formula 1

V and W are each independently hydrogen (H) or methoxy (OCH ₃ )

X and Y are each independently carbon (C) or nitrogen (N),

Z is nitrogen (N) or oxygen (O),

R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy(-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -Dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _2-3 -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl, -(CH ₂ ) _1-2 - C5-C6 heterocyclyl wherein said aryl, heteroaryl or heterocyclyl is unsubstituted or methyl, ethyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, -(CH ₂ ) ₂ -alcohol ( OH) may be substituted with one substituent selected from the group consisting of,

R ₂ is hydrogen, methyl(CH ₃ ) or —(CH ₂ ) _1-2 -C5-C6 heterocyclyl _{cyclized with R 1 ,}

R ₃ is aryl, wherein said aryl is unsubstituted or methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ , It may be substituted with 1 to 3 substituents from the group consisting of _{-CONHCH 3 .}

Hereinafter, the present invention will be described in more detail.

The terms used to define the compounds according to the present invention have the following meanings.

Specific examples of the term “halogen” include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), and in particular, fluorine (F) and chlorine (Cl).

The term "cyano" may be represented by -CN, and has a triple bond as an atomic group in which carbon and nitrogen are bonded one atom at a time, and another atom or functional group is bonded to a carbon atom to be hydrogen cyanide, metal cyanide or nitrile have.

(The term "nitro" refers to a functional group represented _{by -NO 2 .)}

The term "C1-4 alkyl" means a monovalent linear or branched saturated hydrocarbon moiety having from 1 to 4 carbon atoms and consisting solely of carbon and hydrogen atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like. Examples of "branched alkyl" include isopropyl, isobutyl, tert-butyl, and the like.

The term "C1-3 alkoxy" refers to a formula -O-C1-3 alkyl, including, but not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

The term "aryl" includes at least one ring having a shared pi electron system, including, for example, monocyclic or fused-ring polycyclic (i.e., rings that divide adjacent pairs of carbon atoms) groups. . That is, unless otherwise defined in the present specification, aryl may include phenyl, naphthyl, etc., biaryl. In an embodiment of the present invention, aryl refers to an aromatic ring having 6 to 10 carbon atoms.

The term "Cyclic alkyl" refers to a cyclic, saturated hydrocarbon moiety containing only carbon and hydrogen atoms, having 5 to 6 carbon atoms. Examples of such cyclic alkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, and the like.

The term "heteroaryl", unless otherwise defined, is an aromatic ring having 5 or 6 ring atoms including 1 to 4 hetero atoms selected from the group consisting of N, O and S, or the heteroaryl ring is a benzene ring or refers to a bicyclic ring fused to another heteroaryl ring. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl , oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Examples of bicyclic heteroaryl include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzooxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztria zolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl and the like.

The term “heterocyclyl” denotes a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms comprising, in addition to carbon atoms, 1 to 3 heteroatoms selected from N, O and S. For example, heterocyclyl is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pipe Lidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, ho furoperazinyl, oxazepanil, dihydroindolyl, dihydrofuryl, dihydroimidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or It is benzodioxanyl.

The term "treatment" when used in a subject exhibiting symptoms of disease means stopping or delaying the progression of a disease.

The term "pharmaceutical composition" may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, as needed together with the compound of the present invention.

The term "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of a compound.

The term “carrier” refers to a substance that facilitates the addition of a compound into a cell or tissue.

The term "diluent" is defined as a substance that is diluted in water which not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound.

Other terms and abbreviations used in this specification may be interpreted as meanings commonly understood by those of ordinary skill in the art to which the present invention pertains unless otherwise defined.

According to a more specific embodiment of the present invention, the compound of Formula 1 is a quinazoline derivative represented by Formula 1-1, a quinoline derivative represented by Formula 1-2, or an isoquinoline derivative represented by Formula 1-3 can be

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

According to an embodiment of the present invention, R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy (-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _{2 -3} -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl , -(CH ₂ ) _1-2 -C5-6 heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may be unsubstituted or substituted. Specifically, the aryl, heteroaryl or heterocyclyl is methyl, halogen, methoxy, trifluoromethoxy, hydroxy, cyano, nitro, amino, C1-6 alkyl, C1-6 alkoxy, -CO-C1- It may be substituted with 1 to 3 substituents selected from the group consisting of 6 alkyl, -CO-NH2, -SO ₂ -C1-6 alkyl, -SO ₂ -NH _{2 and aryl.} More specifically, the aryl or heteroaryl may be substituted with one substituent selected from the group consisting of methyl, halogen, methoxy, and trifluoromethoxy.

According to another embodiment of the present invention, when R ₁ is -(CH ₂ ) _n -aryl (n=1 to 2), the aryl group may be phenyl.

According to another embodiment of the present invention, when R ₁ is -(CH ₂ ) _n -cyclic alkyl (n=0 to 1), the cyclic alkyl group is 1 selected from cyclopentynyl and cyclohexynyl. It may be more than one kind of substituent.

According to another embodiment of the present invention, when R ₁ is -(CH ₂ ) _n -heteroaryl (n=1 to 2), the heteroaryl group is pyridine (eg, 2-, 3-, or 4-pyridine). ), furanyl, pyrazinyl, and may be one or more substituents selected from pyridazinyl.

According to another embodiment of the present invention, when R ₁ is -(CH ₂ ) _n -heterocyclyl (n=1 to 2), the heterocyclyl group is one selected from morpholinyl and tetrahydrofuranyl. It may be more than one kind of substituent.

In addition, according to another embodiment of the present invention, R ₁ may be any one selected from the group represented by the following structural formula (1).

[Structural Formula 1]

According to an embodiment of the present invention, R ₂ may be hydrogen, methyl (CH ₃ ), or -(CH ₂ ) _n -heterocyclyl (n=1 to 2) _{cyclized with R 1 .} Preferably R ₂ is piperazine represented by _{-CH 2} CH ₂ NR ₄ CH ₂ CH ₂ -R _{1 , R 4} is C _1-2 alkyl or -(CH ₂ ) ₂ -alcohol (-(CH ₂ ) ₂ -OH).

According to an embodiment of the present invention, R ₃ is aryl, wherein the aryl may be unsubstituted or substituted. Specifically, the aryl or heteroaryl is methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ And -CONHCH ₃ It may be substituted with 1 to 3 substituents from the group consisting of.

According to another embodiment of the present invention, when R ₃ is an aryl group, it may be phenyl.

According to another embodiment of the present invention, R ₃ may be any one selected from the group represented by the following structural formula (2).

[Structural Formula 2]

In the present invention, Formula 1 is

(A1) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A2) 2-(2-methoxyphenyl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine;

(A3) 3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A4) 4-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A5) 2-(2-aminophenyl)-N-(pyridin-3-ylmethyl)amino)quinazolin-4-amine;

(A6) 4-methyl-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A7) 4-fluoro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A8) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzene-1,4-diol;

(A9) 4-methoxy-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A10) 4-chloro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A11) 5-fluoro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A12) 2-methyl-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A13) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-6-(trifluoromethyl)phenol;

(A14) 2-chloro-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A15) 2-methoxy-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A16) 2,4-difluoro-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A17) 2-(4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)phenol;

(A18) 4-methoxy-2-(4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)phenol;

(A19) 2-(4-((pyridin-4-ylmethyl)amino)quinazolin-2-yl)phenol;

(A20) 4-methoxy-2-(4-((pyridin-4-ylmethyl)amino)quinazolin-2-yl)phenol;

(A21) 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile;

(A22) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-4-(trifluoromethyl)phenol;

(A23) 5-methyl-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A24) 2-(4-(benzylamino)quinazolin-2-yl)phenol;

(A25) 2-(4-((4-methylbenzyl)amino)quinazolin-2-yl)phenol;

(A26) 2-(4-((4-methoxybenzyl)amino)quinazolin-2-yl)phenol;

(A27) 2-(4-((4-fluorobenzyl)amino)quinazolin-2-yl)phenol;

(A28) 2-(4-((4-(trifluoromethyl)benzyl)amino)quinazolin-2-yl)phenol;

(A29) 2-(4-((3-methylbenzyl)amino)quinazolin-2-yl)phenol;

(A30) 2-(4-((3-methoxybenzyl)amino)quinazolin-2-yl)phenol;

(A31) 2-(4-((3-fluorobenzyl)amino)quinazolin-2-yl)phenol;

(A32) 2-(4-((3-(trifluoromethyl)benzyl)amino)quinazolin-2-yl)phenol;

(A33) 2-(4-((2-methylbenzyl)amino)quinazolin-2-yl)phenol;

(A34) 2-(4-(pyridin-3-ylmethoxy)quinazolin-2-yl)phenol;

(A35) 2-(6,7-dimethoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A36) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-4-(trifluoromethoxy)phenol;

(A37) 2-(4-(((5-methoxypyridin-3-yl)methyl)amino)quinazolin-2-yl)phenol;

(A38) 2-(4-(((5-methoxypyridin-3-yl)methyl)amino)quinazolin-2-yl)phenol;

(A39) 2-(4-(methyl(pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A40) 2-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)phenol;

(A41) 4-methoxy-2-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)phenol;

(A42) 4-hydroxy-3-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)benzonitrile;

(A43) methyl 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzoate;

(A44) 1-(4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenyl)ethan-1-one;

(A45) 2-(4-((1-(pyridin-3-yl)ethyl)amino)quinazolin-2-yl)phenol;

(A46) 2-(6-methoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A47) 2-(7-methoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A48) 2-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A49) 4-methoxy-2-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)phenol;

(A50) 4-hydroxy-3-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile;

(A51) 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzoic acid;

(A52) 4-hydroxy-N-methyl-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzamide;

(A53) 2-phenyl-N-(pyridin-3-ylmethyl)quinazolin-4-amine;

(A54) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzene-1,3-diol; and

(A55) 4-ethoxy-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol.

Although the scope of the present invention is not limited thereto, the quinazoline derivative of Chemical Formula 1-1 and the quinoline compound of Chemical Formula 1-2 according to the present invention are more specifically selected from the group consisting of Chemical Formulas 6 to 60 below. can be one

According to an embodiment of the present invention, the quinazoline or quinoline compound may form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts in the present invention include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, and methane; It may be an acid addition salt formed with a sulfonic acid such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., according to the present invention containing a free carboxy substituent [Formula 1-1] The quinazoline derivative compound represented by Formula 1-2 and the quinoline derivative compound represented by Formula 1-2 may be the above acid addition salts and salts of sodium, calcium and ammonium, and a pharmaceutically acceptable salt is an addition salt, for example, lithium; An alkali metal or alkaline earth metal salt formed by sodium, potassium, calcium, magnesium, etc., an amino acid salt such as lysine, arginine, or guanidine, dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methyl It may be an organic salt such as amine, diethanolamine, choline, triethyl amine, or the like.

The quinazoline derivative of Formula 1-1 and the quinoline compound of Formula 1-2 according to the present invention may be converted into a salt thereof by a conventional method, and the preparation of the salt may be prepared using the structure of Formula 1 without a separate explanation. Based on this, it can be easily performed by those skilled in the art.

Hereinafter, unless otherwise specified, the quinazoline derivative of Formula 1-1 and the quinoline compound of Formula 1-2 include pharmaceutically acceptable salts thereof, and they are all interpreted to be included in the scope of the present invention. should be For convenience of description, in the present specification, they are simply expressed as a compound of Formula 1.

In another aspect, the present invention relates to a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt comprising the following steps.

(a) reacting a compound of Formula 2 with R ₁ ZH to produce a compound of Formula 3;

(b) Suzuki coupling the compound of Formula 3 obtained in step (a) with R ₂ B(OH) ₂ to produce a compound of Formula 4;

(c) generating a compound of Formula 5 by performing Suzuki coupling of the compound of Formula 4 obtained in step (b) with R ₂ B(OH) _{2 ;} and

(d) reacting the compound of Formula 5 obtained in step (c) with R ₁ ZH to produce a compound of Formula 1.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

in the chemical formula

V and W are each independently hydrogen (H) or methoxy (OCH ₃ )

X and Y are each independently carbon (C) or nitrogen (N),

Z is nitrogen (N) or oxygen (O),

R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy(-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -Dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _2-3 -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl, -(CH ₂ ) _1-2 - C5-C6 heterocyclyl wherein said aryl, heteroaryl or heterocyclyl is unsubstituted or methyl, ethyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, -(CH ₂ ) ₂ -alcohol ( OH) may be substituted with one substituent selected from the group consisting of,

R ₂ is hydrogen, methyl(CH ₃ ) or —(CH ₂ ) _1-2 -C5-C6 heterocyclyl _{cyclized with R 1 ,}

R ₃ is aryl, wherein said aryl is unsubstituted or methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ , It may be substituted with 1 to 3 substituents from the group consisting of _{-CONHCH 3 .}

The preparation method is summarized in a reaction scheme as follows.

[Scheme A]

[Formula 2] [Formula 3] [Formula 1-1]

The compound of Formula 2 as the starting material of Scheme A may be, for example, 2,4-dichloroquinazoline.

The compound of Formula 3 is obtained by introducing an amine or alcohol through a nucleophilic substitution reaction using a weak base at the 4th position of the formula (2). A Suzuki-type reaction using Chemical Formula 3, a boron compound (eg, boronic acid), a palladium catalyst (II), and an aqueous sodium carbonate solution as a base is used, and heating at 150° C. using microwaves using DME as a solvent. and stirring to substitute _{R 2} in the 2nd position of the Capricorn.

[Scheme B]

[Formula 4] [Formula 5] [Formula 1-2]

The compound of Formula 2 as the starting material of Scheme B may be, for example, 2,4-dichloroquinoline.

A Suzuki-type reaction using Chemical Formula 5, a boron compound (e.g., boronic acid), a palladium catalyst (II), and an aqueous sodium carbonate solution as a base is used. Substitute R _{2 for Capricorn.} The compound of Formula 1-2 is obtained by introducing an amine or alcohol through a nucleophilic substitution reaction using a weak base at the 4th position of the formula (6).

However, those of ordinary skill in the art to which the present invention pertains can prepare the compounds of Chemical Formulas 1-1 and 1-2 by various methods based on the structures of Chemical Formulas 1-1 and 1-2, and , all of these methods should be construed as being included in the scope of the present invention.

That is, compounds of Formula 1-1 and Formula 1-2 can be prepared by arbitrarily combining various synthetic methods described herein or disclosed in the prior art, which are understood to be within the scope of the present invention, and Formula 1-1, The method for preparing the compound of Formula 1-2 is not limited to that described above.

Also, in another aspect, the present invention relates to EGFR (del E746-A750/T790M/C797S) kinase inhibitory use of the quinazoline derivative of Formula 1-1 and the quinoline compound of Formula 1-2 or a pharmaceutically acceptable salt thereof. it's about That is, the present invention relates to a pharmaceutical composition for treating or preventing EGFR activity-related diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

Specifically, the present invention relates to proliferation resulting from abnormal cell growth, function or behavior, comprising the compound of Formula 1-1, Formula 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It relates to a pharmaceutical composition capable of treating or preventing a disease. Specifically, the compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may be used as a therapeutic agent for a proliferative disease resulting from EGFR (del E746-A750/T790M/C797S) mutation.

The proliferative disease is, for example, cancer, wherein the cancer is leukemia, brain tumor, kidney cancer, stomach cancer, oral cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colorectal cancer, rectal cancer, peritoneal cancer , peritoneal metastasis, pancreatic cancer, esophageal cancer, and the like, but are not limited thereto.

In one embodiment of the present invention, the disease related to the EGFR activity may be non-small cell lung cancer among abnormal cell growth diseases.

In the present invention, the quinazoline derivative of Formula 1-1 and the quinoline derivative of Formula 1-2 or a pharmaceutically acceptable salt thereof have an activity of inhibiting EGFR (del E746-A750/T790M/C797S) kinase.

Accordingly, in another aspect, the present invention relates to an EGFR kinase inhibitor comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a use as an EGFR kinase inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In addition, in another aspect, the present invention provides a method for treating EGFR activity-related diseases by administering a pharmaceutical composition for the treatment or prevention of EGFR activity-related diseases comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. it's about how

The inhibitory activity of the EGFR (del E746-A750/T790M/C797S) kinase of the quinazoline derivative of Formula 1-1 and the quinoline compound of Formula 1-2 or a pharmaceutically acceptable salt thereof according to the present invention is strosporin ( Staurosporine), a known kinase inhibitor, was also measured and used as a reference. In addition, in order to confirm the competitive inhibitory effect on ATP, 1 μM of ATP was treated, and the reaction buffer and the compound according to the present invention were incubated together in a medium to obtain an IC ₅₀ value, which is the degree of enzymatic activity of the substance. The IC ₅₀ value is a concentration of a compound capable of inhibiting the activity of an enzyme by 50%, and the smaller the value, the greater the effect. This will be described later in the following experimental examples.

According to an embodiment of the present invention, a salt dissolved in a buffer solution is used as a diluent, and a commonly used buffer solution may be a phosphate buffered saline that mimics the salt form of a human solution. Because buffer salts can control the pH of a solution at low concentrations, the buffer diluent does not modify the biological activity of the compound.

The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions which also contain a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention may be generally prepared according to a conventional method, and may be administered in a pharmaceutically or veterinarily appropriate form.

The pharmaceutical composition of the present invention is administered orally in the form of tablets, capsules, sugar-coated, film-coated tablets, liquid solutions or suspensions, or parenterally through subcutaneous, intramuscular or intravenous injection or infusion. can be administered.

The dosage may be determined according to various factors including the age, weight and condition of the patient and the route of administration. The daily dosage may vary within wide limits and may be adapted to the individual requirements in each individual case. However, in general, when the present compound is administered alone to adults, the dosage adopted for each route of administration is 0.0001 to 50 mg/kg of body weight, and in the range of 0.001 to 10 mg/kg of body weight, for example, 0.01 to 1 mg/kg of body weight. can

Such dosages may be given, for example, from 1 to 5 times per day. For intravenous injection, a suitable daily dose is 0.0001 to 1 mg/kg body weight, preferably 0.0001 to 0.1 mg/kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

Hereinafter, the present invention will be described in detail with reference to a preferred embodiment of the present invention and the effect of EGFR (del E746-A750/T790M/C797S) kinase inhibitory activity. However, these Examples are for explaining the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited thereby.

[Example]

<Production Example>

According to the present invention, the quinazoline derivative represented by Formula 1-1 was prepared according to the following general preparation procedure.

<General manufacturing procedure 1>

According to the following Reaction Scheme A-1, a starting material (1 equivalent) and triethylamine (1.2 equivalent) were dissolved in tetrahydrofuran, and an amine or alcohol (1.1 equivalent) was added, followed by stirring at room temperature overnight under nitrogen-substituted conditions. . After removing the solvent under reduced pressure, the mixture was diluted with dichloromethane, and then water was added to separate the layers. The aqueous layer was extracted twice with dichloromethane. The combined organic solvent layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The resulting mixture was crystallized by adding hexane, washed with hexane, filtered, and the remaining solvent was removed in a vacuum to obtain an intermediate.

<General manufacturing procedure 2>

According to the following Scheme A-1, the material obtained from General Procedure 1 (1 equivalent), arylboronic acid (1.2 equivalent), tetrakis(triphenyl phosphine)palladium(0)(0.1 equivalent), 2M aqueous sodium carbonate solution ( 2 equivalents) and dimethoxyethane were placed in a microwave vial and the mixture was heated at 150°C for 2 hours. After completion of the reaction, after cooling to room temperature, water was added, and the mixture was extracted three times with dichloromethane, and the combined organic solvent layer was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure. And a quinazoline compound was obtained through column chromatography.

[Scheme A-1]

<General manufacturing procedure 3>

According to the following Scheme A-2, starting material (1 equivalent), bis(pinacolato)diboron (1.2 equivalents), bis(diphenylphosphine)ferrocene-palladium () (0.05 equivalent), bis(diphenylphosph Fin) ferrocene (0.05 equivalents) and potassium acetate (3 equivalents) were placed in a reaction vessel under reduced pressure to remove moisture, and then argon gas was substituted. This was dissolved in anhydrous 1,4-dioxane and stirred at 90 °C overnight. After adding water, the organic layer was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated, and the resulting mixture was used as it is in the next reaction.

[Scheme A-2]

<General manufacturing procedure 4>

According to Scheme B-1, starting material (1 equivalent), arylboronic acid (1.2 equivalents), tetrakis(triphenyl phosphine)palladium (0) (0.1 equivalent), 2M aqueous sodium carbonate solution (2 equivalents) and toluene mixture was heated at 120 overnight. After completion of the reaction, after cooling to room temperature, water was added, and the mixture was extracted three times with dichloromethane, and the combined organic solvent layer was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure. And an intermediate was obtained through column chromatography.

<General manufacturing procedure 5>

According to the following Reaction Scheme B-1, the material (1 equivalent) and triethylamine (1.2 equivalent) obtained from the general preparation procedure 1 are dissolved in isopropyl alcohol, and an amine or alcohol (1.1 equivalent) is added to the nitrogen-substituted condition. Stir overnight at 70°C. After removing the solvent under reduced pressure, the mixture was diluted with dichloromethane, water was added, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic solvent layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. And a quinoline derivative was obtained through column chromatography.

[Scheme B-1]

<General manufacturing procedure 6>

According to Scheme C-1, a starting material (1 equivalent) was dissolved in 1,4-dioxane, and an amine (1.1 equivalent) was added thereto, followed by stirring at 100° C. overnight under nitrogen-substituted conditions. After removing the solvent under reduced pressure, the mixture was diluted with dichloromethane, water was added, and the layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic solvent layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. An intermediate was obtained through column chromatography.

<General manufacturing procedure 7>

According to the following Scheme C-1, the material obtained from General Procedure 1 (1 equivalent), arylboronic acid (1.2 equivalents), tetrakis(triphenyl phosphine)palladium (0) (0.1 equivalent), 2M aqueous sodium carbonate solution ( 2 equivalents) and dimethoxyethane were placed in a microwave vial and the mixture was heated at 150°C for 2 hours. After completion of the reaction, after cooling to room temperature, water was added, and the mixture was extracted three times with dichloromethane, and the combined organic solvent layer was washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure. And the isoquinazoline compound was obtained through column chromatography.

[Scheme C-1]

<General manufacturing procedure 8>

According to the following Scheme D-1, the starting material (1 equivalent), amine (1 equivalent), triethylamine (2.5 equivalent) and tetrahydrofuran were placed in a microwave vial and the mixture was stirred at 110° C. for 75 minutes. The precipitate was dissolved with methanol, diluted with dichloromethane, and water was added to separate the layers. The aqueous layer was extracted twice with dichloromethane. The combined organic solvent layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. An intermediate was obtained through column chromatography.

<Example 1> 2-chloro-N- (pyridinyl-3-methyl) quinazolin-4-amine

According to Scheme 1 below, 2,4-dichloroquinazoline (1 g, 5.03 mmol), 3-(aminomethyl)pyridine (0.563 ml, 5.53 mmol) and triethylamine (0.841 ml, 6.03 mmol) were prepared above general The reaction was carried out according to procedure 1. The obtained solid was filtered, washed with hexane, and the solvent was removed in vacuo to obtain 2-chloro-N-(pyridinyl-3-methyl)quinazolin-4-amine. (1.32 g, yield 97%)

[Scheme 1]

The obtained compound corresponds to an intermediate of the specific quinazoline compound according to the present invention.

¹ H NMR (400 MHz, Chloroform-d) ? 8.67 - 8.63 (m, 1H), 8.58 (dd, J = 4.8, 1.7 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.77 - 7.74 (m, 1H), 7.71 (ddd, J = 8.5, 1.3 , 0.6 Hz, 1H), 7.47 (ddd, J = 8.3, 6.7, 1.5 Hz, 1H), 7.31 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 6.30 (s, 1H), 4.90 (d, J = 5.6 Hz, 2H).

<Example 2> 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

According to Scheme 2 below, 3-bromo-4-hydroxybenzonitrile (200 mg, 1.01 mmol), bis (pinacolato) diboron (307.8 mg, 1.21 mmol), bis (diphenylphosphine) ferrocene- Palladium () (41.2 mg, 0.0505 mmol), bis (diphenylphosphine) ferrocene (28 mg, 0.0505 mmol), and potassium acetate (297.4 mg, 3.03 mmol) were reacted according to General Procedure 3 above. After adding water, the organic layer was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated, and the resulting mixture was used as it is in the next reaction.

[Scheme 2]

The obtained compound corresponds to the starting material of the specific quinazoline compound according to the present invention.

1H NMR (400 MHz, Chloroform-d) δ 7.51 (s, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.96 (dd, J = 8.9, 3.2 Hz, 1H), 6.81 (d, J = 8.9, 1H) 3.77 (s, 3H), 1.36 (s, 12H)

<Example 3> 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile

According to Scheme 3 below, 2-chloro-N- (pyridinyl-3-methyl) quinazolin-4-amine (50 mg, 0.185 mmol), 4-hydroxy-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborola-2-yl)benzonitrile (54.3mg 0.222mmol), tetrakis(triphenyl phosphine)palladium(0)(21.3mg, 0.0185mmol), 2M aqueous sodium carbonate solution (0.185 ml, 0.369 mmol), dimethoxyethane was placed in a reaction vessel for microwaves, and the reaction was carried out according to the general procedure 1 above. And a quinazoline compound was obtained through column chromatography. (17 mg, yield: 26%)

[Scheme 3]

The obtained compound corresponds to the specific quinazoline compound (A9) according to the present invention, [Formula 14].

¹ H NMR (400 MHz, DMSO-d6) δ 14.12 (s, 1H), 9.38 (s, 1H), 8.74 (s, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.35 (d, J) = 8.2 Hz, 1H), 7.87 - 7.81 (m, 3H), 7.77 (dd, J = 8.3, 1.3 Hz, 1H), 7.58 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.35 (dd, J = 7.9, 4.7 Hz, 1H), 6.96 (dd, J = 8.9, 3.2 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.90 (s, 2H), 3.75 (s, 3H).

<Example 4> 2- (4-chloroquinolin-2-yl) phenol

According to Scheme 4 below, 2,4-dichloroquinoline (200 mg, 1.01 mmol), (2-hydroxyphenyl)boronic acid (0.1393 g 1.01 mmol), tetrakis(triphenyl phosphine)palladium(0)(58.4) mg, 0.0505 mmol), a 2M aqueous sodium carbonate solution (1 ml, 2.02 mmol), and a mixture of toluene were reacted according to General Procedure 1 above. And an intermediate was obtained through column chromatography. (30 mg, yield: 12%)

[Scheme 4]

The obtained compound corresponds to an intermediate of the specific quinoline compound according to the present invention.

¹ H NMR (400 MHz, Chloroform-d) δ 14.79 (s, 1H), 8.26 - 8.20 (m, 1H), 8.14 (s, 1H), 8.06 (dd, J = 8.4, 1.2 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.81 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.65 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.39 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 7.09 (dd, J = 8.3, 1.2 Hz, 1H), 6.98 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H).

<Example 5> 2-(4-((pyridin-3-ylmethyl)amino)quinolin-yl)phenol

According to Scheme 5 below, 2-(4-chloroquinolin-2-yl)phenol (30 mg, 0.117 mmol), 3-(aminomethyl)pyridine (0.013 ml, 0.129 mmol) and triethylamine (0.02 ml, 0.141 mmol) ) was carried out according to the general procedure 5 above. Through column chromatography, 2-(4-((pyridin-3-ylmethyl)amino)quinolin-yl)phenol was obtained. (5 mg, yield 13%)

[Scheme 5]

The obtained compound corresponds to the specific quinoline compound (B1) according to the present invention, [Formula 14].

¹ H NMR (400 MHz, Chloroform-d) δ 15.91 (s, 1H), 8.77 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.80 - 7.72 (m, 3H), 7.69 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.06 - 7.01 (m, 2H) , 6.88 (t, J = 7.6 Hz, 1H), 5.42 (s, 1H), 4.71 (d, J = 5.3 Hz, 2H).

<Example 6> 3-chloro-N- (pyridin-3-ylmethyl) isoquinolin-1-amine

1,3-dichloroisoquinoline (100 mg, 0.505 mmol) was dissolved in 1,4-dioxane (1.5 ml) according to Scheme 6, and 3-(aminomethyl)pyridine (0.0566 ml, 0.555 mmol) was added to the The reaction was carried out according to General Procedure 6. And an intermediate was obtained through column chromatography. (24 mg, yield: 18%)

[Scheme 6]

The obtained compound corresponds to an intermediate of the specific isoquinoline compound according to the present invention.

¹ H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 2.3 Hz, 1H), 8.56 (dd, J = 4.9, 1.6 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.73 - 7.66 (m, 1H), 7.63 - 7.58 (m, 2H), 7.44 (ddd, J = 8.3, 6.1, 2.1 Hz, 1H), 7.29 (dd, J = 7.6, 4.6 Hz, 1H), 7.02 (d, J) = 0.9 Hz, 1H), 5.61 (s, 1H), 4.86 (d, J = 5.5 Hz, 2H).

Although there are differences in the structure and physical properties of the substituents depending on the type of the substituents, the reaction principles and conditions of the examples according to the present invention are the same for compounds containing substituents not described in the above examples. Therefore, it will be apparent to those of ordinary skill in the art that compounds including these substituents can be easily implemented based on the disclosure of Examples and common knowledge in the art.

In addition, for the synthesis of the specific quinazoline and quinoline derivative compounds according to the present invention, each final compound or each intermediate is described in detail by the above examples, so those skilled in the art to which the present invention belongs It will be apparent that the quinazoline and quinoline compounds can be easily carried out as a whole.

In the present invention, the quinazoline derivatives or quinoline derivative compounds specifically disclosed by the formulas 1-1 to 1-2 are shown in [Table 1] below.

[Table 1]

<Experimental Example 1> Measurement of EGFR (del E746-A750/T790M/C797S) inhibitory activity

Measurement of EGFR (del E746-A750/T790M/C797S) kinase inhibitory activity for a specific compound represented by Formula 1 according to the present invention was carried out as follows.

In order to measure the biological and biochemical inhibitory effect of the EGFR (del E746-A750/T790M/C797S) kinase inhibitor according to the present invention, Reaction Biology Corp. (Malvern, PA, USA) was commissioned to measure the activity according to the concentration. However, the measured results are shown as IC ₅₀ values in Table 2 below.

The IC ₅₀ value is the molar concentration of the compound used when the enzyme or cell activity is inhibited to 50%.

[Table 2]

As shown in <Experimental Example 1> and Table 2, the quinazoline and quinoline compounds represented by Formula 1 according to the present invention can effectively inhibit the activity of EGFR (del E746-A750/T790M/C797S) kinase. can confirm.

<Experimental Example 2> Measurement of EGFR (del E746-A750/T790M/C797S) inhibitory activity

InterBioScreen Ltd. The following compounds purchased from (Chernogolovka, Russia) were also requested by Reaction Biology Corp. (Malvern, PA, USA) to measure the activity according to the concentration. The measured results are shown as IC ₅₀ values in Table 3 below. The IC ₅₀ value is the molar concentration of the compound used when the enzyme or cell activity is inhibited to 50%.

[Table 3]

As shown in <Experimental Example 2> and Table 3, the quinazoline and quinoline compounds represented by Formula 1 according to the present invention can effectively inhibit the activity of EGFR (del E746-A750/T790M/C797S) kinase. can be checked

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the invention be defined by the claims and their equivalents.

Claims (8)

A pharmaceutical composition for preventing or treating cancer expressing a mutant EGFR having E746-A750 deletion, T790M substitution, and C797S substitution, including the compound represented by Formula 1 or a pharmaceutically acceptable salt.
[Formula 1]

in formula 1
V and W are each independently hydrogen (H) or methoxy (OCH ₃ )
X and Y are each independently carbon (C) or nitrogen (N),
Z is nitrogen (N) or oxygen (O),
R ₁ is -(CH ₂ ) _2-3 -alcohol (OH), -(CH ₂ ) _2-3 -methoxy(-(CH ₂ ) _2-3 -OCH ₃ ), -(CH ₂ ) _2-3 -Dimethylamine(-(CH ₂ ) _2-3 -N(CH ₃ ) ₂ ), -(CH ₂ ) _2-3 -diethylamine(-(CH ₂ ) _2-3 -N(CH ₂ CH ₃ ) ₂ ), -(CH ₂ ) _1-2 -aryl, -(CH ₂ ) _0-1 -C6 cyclicalkyl, -(CH ₂ ) _1-2 -C6 heteroaryl, -(CH ₂ ) _1-2 - C5-C6 heterocyclyl wherein said aryl, heteroaryl or heterocyclyl is unsubstituted or methyl, ethyl, halogen, methoxy, trifluoromethyl, trifluoromethoxy, -(CH ₂ ) ₂ -alcohol ( OH) may be substituted with one substituent selected from the group consisting of,
R ₂ is hydrogen, methyl(CH ₃ ) or —(CH ₂ ) _1-2 -C5-C6 heterocyclyl _{cyclized with R 1 ,}
R ₃ is aryl, wherein said aryl is unsubstituted or methyl, halogen, hydroxy, amino, methoxy, ethoxy, cyano, trifluoromethyl, -OCF ₃ , -COOH, -COOCH ₃ , -COCH ₃ , It may be substituted with 1 to 3 substituents from the group consisting of _{-CONHCH 3 .}
According to claim 1, wherein R ₂ is -CH ₂ CH ₂ NR ₄ CH ₂ CH ₂ -R ₁ Represented by piperazine, R ₄ is C _1-2 alkyl or -(CH ₂ ) ₂ -alcohol (- (CH ₂ ) ₂ -OH) A pharmaceutical composition, characterized in that.
The pharmaceutical composition according to claim 1, wherein R ₁ is one selected from the following formulas.

The pharmaceutical composition according to claim 1, wherein R ₃ is one selected from Formulas.

According to claim 1, wherein Formula 1 is
(A1) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A2) 2-(2-methoxyphenyl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine;
(A3) 3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A4) 4-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A5) 2-(2-aminophenyl)-N-(pyridin-3-ylmethyl)amino)quinazolin-4-amine;
(A6) 4-methyl-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A7) 4-fluoro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A8) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzene-1,4-diol;
(A9) 4-methoxy-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A10) 4-chloro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A11) 5-fluoro-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A12) 2-methyl-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A13) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-6-(trifluoromethyl)phenol;
(A14) 2-chloro-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A15) 2-methoxy-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A16) 2,4-difluoro-6-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A17) 2-(4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)phenol;
(A18) 4-methoxy-2-(4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)phenol;
(A19) 2-(4-((pyridin-4-ylmethyl)amino)quinazolin-2-yl)phenol;
(A20) 4-methoxy-2-(4-((pyridin-4-ylmethyl)amino)quinazolin-2-yl)phenol;
(A21) 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile;
(A22) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-4-(trifluoromethyl)phenol;
(A23) 5-methyl-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A24) 2-(4-(benzylamino)quinazolin-2-yl)phenol;
(A25) 2-(4-((4-methylbenzyl)amino)quinazolin-2-yl)phenol;
(A26) 2-(4-((4-methoxybenzyl)amino)quinazolin-2-yl)phenol;
(A27) 2-(4-((4-fluorobenzyl)amino)quinazolin-2-yl)phenol;
(A28) 2-(4-((4-(trifluoromethyl)benzyl)amino)quinazolin-2-yl)phenol;
(A29) 2-(4-((3-methylbenzyl)amino)quinazolin-2-yl)phenol;
(A30) 2-(4-((3-methoxybenzyl)amino)quinazolin-2-yl)phenol;
(A31) 2-(4-((3-fluorobenzyl)amino)quinazolin-2-yl)phenol;
(A32) 2-(4-((3-(trifluoromethyl)benzyl)amino)quinazolin-2-yl)phenol;
(A33) 2-(4-((2-methylbenzyl)amino)quinazolin-2-yl)phenol;
(A34) 2-(4-(pyridin-3-ylmethoxy)quinazolin-2-yl)phenol;
(A35) 2-(6,7-dimethoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A36) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)-4-(trifluoromethoxy)phenol;
(A37) 2-(4-(((5-methoxypyridin-3-yl)methyl)amino)quinazolin-2-yl)phenol;
(A38) 2-(4-(((5-methoxypyridin-3-yl)methyl)amino)quinazolin-2-yl)phenol;
(A39) 2-(4-(methyl(pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A40) 2-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)phenol;
(A41) 4-methoxy-2-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)phenol;
(A42) 4-hydroxy-3-(4-((pyrazin-2-ylmethyl)amino)quinazolin-2-yl)benzonitrile;
(A43) methyl 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzoate;
(A44) 1-(4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenyl)ethan-1-one;
(A45) 2-(4-((1-(pyridin-3-yl)ethyl)amino)quinazolin-2-yl)phenol;
(A46) 2-(6-methoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A47) 2-(7-methoxy-4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A48) 2-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A49) 4-methoxy-2-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)phenol;
(A50) 4-hydroxy-3-(4-((pyridazin-3-ylmethyl)amino)quinazolin-2-yl)benzonitrile;
(A51) 4-hydroxy-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzoic acid;
(A52) 4-hydroxy-N-methyl-3-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzamide;
(A53) 2-phenyl-N-(pyridin-3-ylmethyl)quinazolin-4-amine;
(A54) 2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)benzene-1,3-diol; and
(A55) A pharmaceutical composition selected from the group consisting of 4-ethoxy-2-(4-((pyridin-3-ylmethyl)amino)quinazolin-2-yl)phenol.
delete delete The pharmaceutical composition according to claim 1, wherein the cancer expressing the EGFR variant having the E746-A750 deletion, the T790M substitution, and the C797S substitution is non-small cell lung cancer.