WO2015188747A1 - Phenyl-substituted triazine compound serving as egfr inhibitor and applications thereof - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry and specifically relates to a phenyl-substituted triazine compound providing epidermal growth factor receptor (EGFR) inhibition effects, a pharmaceutical composition comprising the compound, and uses of the compound or pharmaceutical composition serving as a medicament for cancer treatment. The compound provided in the present invention provides great inhibitory activities against mutant EGFR kinases, expresses excellent selectivity, and is expected to become a medicament having specific therapeutic effects against drug-resistant tumors and specifically EGFR mutation-induced drug-resistant tumors.

Description

Phenyl substituted triazine compounds as EGFR inhibitors and applications thereof Technical field

The present invention belongs to the field of medical chemistry, and particularly relates to a phenyl substituted triazine compound having an epidermal growth factor receptor inhibitory action, a pharmaceutical composition containing the same, and the compound or pharmaceutical composition as a cancer therapeutic drug. use.

Background technique

The Epidermal Growth Factor Receptor (EGFR) is an expression product of the proto-oncogene C-erbB-1 and is a member of the EGFR family. The EGFR family includes four members, EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3), and ERBB4 (HER-4). EGFR is divided into three parts: extracellular region, transmembrane region and intracellular region. The extracellular region is a ligand binding region composed of 621 amino acids at the amino terminus. When bound to a ligand, dimerization occurs and dimerization occurs. The receptor further undergoes cross-linking phosphorylation, activates the TK subregion of the intracellular region, triggers a series of intracellular changes that ultimately cause differentiation, proliferation and transformation of the cells.

When EGFR is highly expressed or abnormally expressed, it may cause the enhancement of downstream signaling or cause continuous activation of EGFR after mutation, and finally promote cell proliferation, invasion, metastasis, angiogenesis, etc., causing the development of cancer. The use of EGFR-tyrosine kinase inhibitor (TKI) for EGFR has become the gold standard in the field of non-small cell lung cancer treatment. However, clinical use found that gefitinib, erlotinib and other EGFR inhibitors after 10 months of treatment, patients will develop drug resistance, studies showed that resistance is related to EGFR gene T790M, L858R mutation and MET oncogene. At the same time, first-generation EGFR inhibitors lack the selectivity of wild-type EGFR and mutant EGFR.

Therefore, the development of drugs that are effective against tumor patients that are resistant to EGFR mutations, especially the development of drugs that can further improve the selectivity, enhance efficacy, and reduce side effects of wild-type EGFR and mutant EGFR, will have a good application prospect.

Summary of the invention

It is an object of the present invention to provide a compound having the epidermal growth factor receptor inhibitory activity of the formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

Another object of the invention is to provide a process for the preparation of a compound of formula I according to the invention, or an isomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula I according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystalline and pharmaceutically acceptable carrier, and a package A pharmaceutical composition comprising a compound of formula I of the invention, or an isomer thereof, a pharmaceutically acceptable salt, hydrate, solvate or crystallization and another antiviral agent.

A further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the treatment and/or prevention of cancer, and a formula of the invention Use of a compound of I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of cancer.

In view of the above object, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

among them:

X is selected from the group consisting of hydrogen, halogen, alkyl, amino and alkylamino;

Each R _{1 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halo, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkane Alkyl acyl group, amino acyl group, alkyl acyl group, alkyl acylamino group, nitro group, cyano group, aryl group and heteroaryl group, wherein m is selected from 1, 2, 3 and 4, and when m is 2, each R ₁ The atom to which they are attached may together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which is optionally selected from alkyl, haloalkanes. Substituting one or more groups of a group, an alkoxy group, an amino group, a hydroxyl group, a halogen, and an oxo group;

Each R _{2 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halo, amino, aminoalkyl, alkylamino, nitro and cyano, wherein n is selected from 1, 2 and 3;

R _{3 is} selected from the group consisting of an amino group, an alkylamino group, and a nitrogen-containing heterocycloalkyl group, which is optionally substituted with one or more groups selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an amino group, and a hydroxyl group;

Q is selected from the group consisting of O and N(R ₄ ), wherein R _{4 is} selected from the group consisting of hydrogen and alkyl.

In some preferred embodiments, X is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, amino, C _1-6 alkylamino, and (C _1-6 alkyl)(C _1-6 alkyl)amino, Further preferably, X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino, methylamino and dimethylamino.

In some preferred embodiments, each R _{1 is} independently selected from the group consisting of hydrogen, phenyl, hydroxy, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _{1 -6} alkoxy, halo C _1-6 alkoxy, halogen, amino, amino-C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkyl , C _1-6 alkylamino acyl, amino acyl, C _1-6 alkyl acyl, C _1-6 alkyl acylamino, nitro and cyano, wherein m is selected from 1, 2, 3 and 4, when m is 2, each R ₁ is attached thereto atoms may together form a C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, phenyl, or C _5-6 membered heteroaryl, said C _3-6 The cycloalkyl, C _3-6 heterocycloalkyl, phenyl or C _5-6 membered heteroaryl is optionally selected from C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkane Substituting one or more groups of an oxy group, an amino group, a hydroxyl group, a halogen, and an oxo group;

Further preferably, each R _{1 is} independently selected from the group consisting of hydrogen, phenyl, hydroxy, carboxy, C _1-6 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy , halo C _1-3 alkoxy, halogen, amino, amino-C _1-3 alkyl, C _1-3 alkylamino, C _1-3 alkylamino C _1-3 alkyl, C _{1- 3} alkylamino group, amino group, C _1-3 alkyl group, C _1-3 alkyl acylamino, nitro and cyano, wherein m is selected from 2, 3 and 4, when m is 2, Each R ₁ and the atom to which it is attached may together form a C _3-6 cycloalkyl group, a C _3-6 oxacycloalkyl group, a phenyl group or a C _5-6 membered heteroaryl group, said C _3-6 cycloalkyl group , C _3-6 oxacycloalkyl, phenyl or C _5-6 membered heteroaryl optionally selected from C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy Substituting one or more groups of an amino group, a hydroxyl group, a halogen, and an oxo group.

In some specific embodiments, each R _{1 is} independently selected from the group consisting of hydrogen, phenyl, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy , trifluoromethyloxy, fluoro, chloro, bromo, iodo, amino, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methyl Amino, methylamino, dimethylamino, ethylamino, diethylamino, amino, methyl, ethyl, methylacylamino, ethylacylamino, nitro and cyano, wherein m Selected from 1, 2, 3 and 4, when m is 2, each R ₁ and its attached atom may together form a cyclopentyl group, a cyclohexyl group, a tetrahydropyrrolyl group, an oxolyl group, a dioxolyl group. (e.g., 1,3-dioxocyclopentyl), oxetanyl or dioxanyl (e.g., 1,4-dioxanyl), phenyl, furyl, pyrazolyl, pyridyl or pyridyl Rumo group, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, oxolyl, dioxolyl, oxacyclohexyl, dioxanyl, phenyl, furyl, pyrazole The base, pyridyl or pyrrolyl group is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo and oxo.

In some preferred embodiments, each R _{2 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkane Oxy, halo C _1-6 alkoxy, halogen, amino, amino C _1-6 alkyl, C _1-6 alkylamino, nitro and cyano, wherein n is selected from 1, 2 and 3;

Further preferably, each R _{2 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, halogen, amino, amino C _1-3 alkyl, C _1-3 alkylamino, nitro and cyano, wherein n is selected from 1, 2 and 3.

In some specific embodiments, each R _{2 is} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, fluoro, wherein n is selected from 1 , 2 and 3.

In some preferred embodiments, R _{3 is} selected from the group consisting of amino, C _1-6 alkylamino, (C _1-6 alkyl)(C _1-6 alkyl)amino, nitrogen-containing five-membered heterocycloalkyl, and a nitrogen six-membered heterocycloalkyl group, which is optionally substituted with one or more groups selected from the group consisting of C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, amino, hydroxy;

Further preferably, R _{3 is} selected from the group consisting of amino, methylamino, dimethylamino, tetrahydropyrrolyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, optionally selected from C _1-3 alkyl Substituting one or more groups of a halogenated C _1-3 alkyl group, a C _1-3 alkoxy group, an amino group, and a hydroxyl group.

In some specific embodiments, R ₃ is dimethylamino.

In some preferred embodiments, Q is selected from the group consisting of O and N(R ₄ ), wherein R _{4 is} selected from hydrogen and C _1-6 alkyl; further preferably, R _{4 is} selected from hydrogen and C _1-3 alkyl; Still more preferably, R _{4 is} selected from the group consisting of hydrogen, methyl and ethyl.

In some embodiments, Q is N (R _4), wherein R ₄ is selected from hydrogen and methyl.

In some specific embodiments, the compound of the invention is a compound of Formula I, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein:

X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino, methylamino and dimethylamino;

Each R _{1 is} independently selected from the group consisting of hydrogen, phenyl, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl Base, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyloxy, fluoro, chloro, bromo, iodo, amino, amino Methyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino, methylamino, dimethylamino, ethylamino, diethylamino An acyl group, an aminoacyl group, a methyl acyl group, an ethyl acyl group, a methyl acylamino group, an ethyl acylamino group, a nitro group and a cyano group, wherein m is selected from 1, 2, 3 and 4;

Each R _{2 is} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, fluoro, wherein n is selected from 1, 2 and 3;

R ₃ is dimethylamino; and

Q is N(R ₄ ) wherein R _{4 is} selected from the group consisting of hydrogen and methyl.

In some specific embodiments, the compound of the invention is a compound of Formula I, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or crystal thereof, wherein:

X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino, methylamino and dimethylamino;

m is 2, two R ₁ and the atom to which they are attached may together form a cyclopentyl group, a cyclohexyl group, a tetrahydropyrrolyl group, a 1,3-dioxocyclopentyl group, a 1,4-dioxocyclohexyl group, a phenyl group, a furan group. Or pyrazolyl, pyridyl or pyrrolyl, said cyclopentyl, cyclohexyl, tetrahydropyrrolyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclohexyl, phenyl, furan a group, pyrazolyl, pyridyl or pyrrolyl is optionally substituted with one or more groups selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo and oxo;

Each R ₂ is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, fluoro, wherein n is selected from 1, 2 and 3;

R _{3 is} selected from the group consisting of amino, methylamino, dimethylamino, tetrahydropyrrolyl, piperidinyl, piperazinyl, 4-methylpiperazinyl;

Q is N(R ₄ ) wherein R _{4 is} selected from the group consisting of hydrogen and methyl.

In a specific embodiment, the invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:

In another aspect, the invention provides a process for the preparation of a compound of formula I according to the invention, comprising the steps of:

among them:

The raw material of Formula 1 and the raw material of Formula 2 are subjected to a nucleophilic reaction to prepare an intermediate of Formula 3;

The intermediate of formula 3 is reacted with the starting material of formula 4 to produce an intermediate of formula 5;

The intermediate of formula 5 is reacted with a starting material of formula 6 to produce an intermediate of formula 7;

The intermediate of formula 7 is subjected to a nitro reduction reaction to produce an intermediate of formula 8;

The intermediate of formula 8 is reacted with acryloyl chloride to produce a compound of formula I;

The above X, R ₁ , R ₂ , m, n, Q, R ₃ have the definitions in the formula I.

In a third aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

In some embodiments, the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more compounds selected from the group consisting of Nie, erlotinib, lapatinib, afatinib, vandetanib, carnitinib, apatinib, dacomitinib, pelitinib, WZ4002 AG-490, AZD8931, etc.

The compound, isomer, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. . Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Oral administration Examples of the preparation include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.

In a fourth aspect, the present invention provides a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention, and a method for treating and/or preventing a tumor, and in the preparation of a medicament for treating and/or preventing cancer Use of a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention, to a tumor-prone population or tumor patient The pharmaceutical composition is effective to reduce the incidence of tumors and prolong the life of tumor patients.

In some embodiments, the invention provides a method of treating a tumor having resistance to a compound, a isomer, a solvate, a crystal or a prodrug of the invention, or a pharmaceutical composition of the invention, comprising The medicinal tumor patient is administered a therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the invention or a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention. In other embodiments, the invention provides a compound, isomer, solvate, crystal or prodrug of the invention, or a pharmaceutical composition of the invention, in the manufacture of a medicament for treating a tumor having drug resistance application. The drug-resistant tumor may be a tumor resistant to a plurality of drugs, preferably a tumor resistant to an EGFR inhibitor, for example, to a first, second, or third generation EGFR inhibitor, for example, to a gefitidine Nie, erlotinib and lapatinib have drug-resistant tumors. Such tumors include, but are not limited to, solid tumors, preferably lung cancer, head and neck tumors, colorectal cancer, bladder cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cancer, liver cancer, ovarian cancer. More preferably, the tumor is non-small cell lung cancer. In some embodiments, the invention provides a method of treating a tumor having resistance to a compound, isomer, solvate, crystal or prodrug of Formula I of the invention, wherein the tumor carries an EGFR mutated gene. In one embodiment, the EGFR mutated gene carried by the tumor is a T790M mutation in exon 20. In another embodiment, the EGFR mutated gene carried by the tumor is a L858R mutation and/or a deletion/insertion mutation in exon 21. In another embodiment, the EGFR mutated gene carried by the tumor is a T790M and L858R double mutation. In other embodiments, the invention provides a compound, isomer, solvate, crystal or prodrug of the invention of the invention for use in treating a tumor, or a pharmaceutical composition of the invention, wherein the therapeutic effect of the tumor is manifested in Outstanding efficacy, high selectivity and / or fewer side effects. In still other embodiments, the present invention provides a method, a method for treating a tumor, of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, the method comprising A therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the formula I of the present invention or a pharmaceutical composition of the present invention is administered to a patient in need thereof, and the resulting therapeutic effect on the tumor is highlighted. Efficacy, high selectivity and / or fewer side effects.

Definition of Terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning

"Isomers" of the invention include the compounds cis conformation, conformational isomer and enantiomer. A conformational isomer refers to a cis-trans isomer of the cis or trans configuration. A conformational isomer refers to a stereoisomer resulting from the rotation of a single bond.

The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, and the acid may be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid and the like.

The "solvate" of the present invention means a complex formed by a combination of a solute (such as the active compound of the present invention, a salt of the active compound) and a solvent (such as water). Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.

"Crystalline" as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.

The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.

A "pharmaceutical composition" according to the invention is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.

The "application in the preparation of a medicament for treating and/or preventing a tumor" of the present invention means that the growth, development and/or metastasis of the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof. The compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.

The "alkyl group" of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably an alkyl group having 12 or less carbon atoms, more preferably an alkyl group having 6 or less carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl Base, cyclohexyl, n-hexyl, isohexyl, 2,2,-methylbutyl and 2,3-dimethylbutyl. The "C _1-6 alkyl group" of the present invention means a linear, branched or cyclic saturated hydrocarbon group having 1 to 6 carbon atoms. The present invention is "C _1-3 alkyl" means a saturated hydrocarbon radical containing 1-3 carbon atoms, a straight-chain, branched chain or cyclic. The term includes substituted or unsubstituted alkyl groups, which may be optionally substituted with one or more groups selected from the group consisting of alkyl, alkoxy, aryloxy, alkylamino, arylamino, halogen. , hydroxy, amino, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.

The "alkoxy group" of the present invention means an -O-alkyl group.

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine.

The "haloalkyl group" of the present invention means an alkyl group substituted with at least one halogen atom.

The "haloalkoxy group" of the present invention means an alkoxy group substituted with at least one halogen, preferably a C _1-6 alkoxy group substituted with at least one halogen, and further preferably a halogenated C _1-3 alkoxy group, suitably Halogenated C _1-3 alkoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy , difluoroethoxy, trichloroethoxy, trifluoroethoxy.

The "alkylamino group" of the present invention means an amino group substituted with an alkyl group, and includes a monoalkylamino group and a dialkylamino group.

The "aminoalkyl group" of the present invention means an alkyl group substituted with an amino group.

The "alkylaminoalkyl group" of the present invention means an alkyl group substituted with an alkylamino group.

The "alkylamino acyl group" of the present invention means an alkylamino-C(O)- group.

The "alkyl acylamino group" of the present invention means an alkyl-C(O)-amino- group.

The "cycloalkyl" of the present invention means a cyclic alkyl group including, but not limited to, a cyclopropyl group, a cyclobutane group, a cyclopentyl group, and a cyclohexane group.

The "heterocycloalkyl group" of the present invention means a cyclic alkyl group containing at least one hetero atom selected from the group consisting of N, O and S. The "nitrogen-containing heterocycloalkyl group" of the present invention means a cyclic alkyl group having at least one N atom. The "oxyheterocycloalkyl group" of the present invention means a cyclic alkyl group having at least one O atom.

The "aryl group" of the present invention means a phenyl group, a biphenyl group or a naphthyl group, preferably a phenyl group. The term includes both substituted and unsubstituted groups. The aryl group may be optionally substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, hydroxy, nitro Amino, single Alkylamino, bisalkylamino, arylamino, alkyl acyl, aminoacyl, alkylaminoacyl, acylamino, -CN, aryl or heteroaryl.

"Heteroaryl group" in the present invention refers to a 3-10 membered heteroaromatic ring system containing 1-4 heteroatoms selected from N, O and S heteroatom, preferably C _3-7 membered heteroaromatic ring system, such as thiophene , pyridine, imidazole, furan, pyrrole, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4- Suitable oxadiazoles, 1,3,4-oxadiazoles and the like, and suitable heteroaryl rings include, but are not limited to, thiophene, pyridine, imidazole. The term includes both substituted and unsubstituted groups. The heteroaryl ring may be optionally substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, hydroxy, nitro Base, amino, monoalkylamino, bisalkylamino, arylamino, alkyl acyl, aminoacyl, alkylaminoacyl, acylamino, -CN, aryl or heteroaryl.

detailed description

The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention.

Example 1 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-(1-methylcarbamoyl)) Phenyl))-1,3,5-triazin-2-amino)phenyl)acrylamide

Step 1: Synthesis of 4-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine

In a 100 ml reaction flask, 4-fluoro-2-methoxy-5-nitroaniline (4.0 g, 21.5 mmol) and DIPEA (8.32 g, 64.5 mmol) were added sequentially, dissolved in 60 ml of tetrahydrofuran, cooled to 0-2 °C, 2,4-dichloro-1,3,5-triazine (3.14g, 21.08mmol) was added in portions, added, reacted for 5h, the reaction was stopped, 60ml of water was added, stirred, filtered, and the filter cake was washed with water. The title compound was dried and used directly in the next step.

Step 2: N-(4-Fluoro-2-methoxy-5-nitrophenyl)-3-(1-N-methyl-benzoyl)-1,3,5-triazine-2- Amine synthesis

In a 30 ml microwave reaction flask, 3-(N-methylformylamino)phenylboronic acid (900 mg, 5.03 mmol) was added in sequence, and the product obtained in Step 1 was 4-chloro-N-(4-fluoro-2-methoxy). 5-5-nitrophenyl)-1,3,5-triazin-2-amine (1.50 g, 5.03 mmol), tetratriphenylphosphine palladium (231 mg, 0.04 eq) and cesium carbonate (4.9 g, 15 mmol) Dissolved with 1,4-dioxane/H ₂ O (8 ml / 1 ml), argon-replaced, microwaved at 110 ° C for 45 min, concentrated and purified by column chromatography.

Step 3: 3-(4-((4-(2-(Dimethylamino)ethyl(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-1,3 Synthesis of 5-triazin-2-yl)-N-methylbenzamide

The step N product N-(4-fluoro-2-methoxy-5-nitrophenyl)-3-(1-N-methyl-benzoyl)-1,3 was added in sequence to a 50 ml single-mouth bottle. , 5-triazin-2-amine (230 mg, 0.58 mmol), N,N,N'-trimethylethylenediamine (117.0 mg, 1.16 mmol) and DIPEA (224 mg, 1.74 mmol), with 10 ml of dioxane The mixture was dissolved in a mp.

Step 4: 3-(4-((4-(2-(Dimethylamino)ethyl(methyl)amino)-2-methoxy-5-aminophenyl)amino)-1,3, Synthesis of 5-triazin-2-yl)-N-methylbenzamide

Step 3: 3-(4-((4-(2-(dimethylamino)ethyl)ethyl)methyl)-2-methoxy-5-nitrobenzene was added to a 50 ml single-mouth bottle Amino)-1,3,5-triazin-2-yl)-N-methylbenzamide (146 mg, 0.30 mmol), 10% Pd-C (15 mg, 0.1 eq) and 10 mL methanol, 1 H _{2 was} reduced for 1 h under standard atmospheric pressure and filtered to give the title compound.

Step 5: N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-(1-methyl) Synthesis of carbamoylphenyl))-1,3,5-triazin-2-amino)phenyl)acrylamide:

In a 50 ml single-mouth bottle, the product obtained in Step 4 was added 3-(4-((4-(2-(dimethylamino)ethyl)methyl)amino)-2-methoxy-5-aminophenyl Amino)-1,3,5-triazin-2-yl)-N-methylbenzamide (98 mg, 0.22 mmol) and diisopropylethylamine (71.0 mg, 0.55 mmol), 15 ml anhydrous The methylene chloride was dissolved, and a solution of EtOAc (EtOAc, m.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 2.25 (6H, d), 2.37-2.41 (m, 2H), 2.72 (3H, s), 2.80 (3H, s), 2.92 (2H, m) , 3.81 (3H, s), 5.75-5.77 (1H, d), 6.24-6. (1H, d), 6.42-6.48 (1H, m), 7.02 (1H, s), 7.62 (1H, s), 8.02-8.03(1H,d), 8.27(1H,s),8.59(2H,s),8.77(1H,s),8.83,(1H,s),9.27(1H,s),10.11(1H,s ).

ESI-Ms m/z: 505.3 [M+H].

Example 2 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3,4-(methylenedioxy) Phenyl))-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4-(methylenedioxy)benzene boronate, The title compound was obtained according to the method of Example 1 using N,N,N'-trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 2.25 (6H, d), 2.40 (2H, s), 2.70 (4H, s), 2.91 (2H, m), 3.81 (3H, s), 5.74 -5.76(1H,d), 6.12(2H,s), 6.27-6.30(1H,m), 6.40-6.45(1H,m),7.02(2H,s),7.90(1H,s),8.09-8.14 (1H, d), 8.66 (1H, s), 8.90-8.95 (1H, s), 10.02 (1H, s).

ESI-Ms m/z: 492.3 [M+H].

Example 3 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxyphenyl)-) 1,3,5-triazin-2-amino)phenyl)acrylamide

4-Fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxybenzene boronate, N,N,N'- The title compound was obtained according to the method of Example 1 using trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 2.21 (s, 6H), 2.36-2.39 (t, 2H), 2.68 (s, 3H), 2.88-2.89 (t, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 5.73-5.77 (d, 1H), 6.23-6.29 (d, 1H), 6.39-6.48 (dd, 1H), 6.99-7.04 (m, 3H), 8.28 (s, 1H), 8.39-8.42 (m, 2H), 8.64 (s, 1H), 8.96 (brs, 1H), 10.10 (s, 1H).

ESI-Ms m/z: 478.3 [M+H].

Example 4 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-carbamoylphenyl)-) 1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-carbamoylbenzene borate, N,N,N'- The title compound was obtained according to the method of Example 1 using trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 2.28 (s, 6H), 2.35-2.39 (t, 2H), 2.73 (s, 3H), 2.89-2.91 (t, 2H), 3.81 (s, 3H), 5.75-5.79 (d, 1H), 6.24-6.27 (d, 1H), 6.39-6.44 (dd, 1H), 7.03 (s, 1H), 7.42 (s, 1H), 7.60 (s, 1H) , 8.06-8.17 (m, 3H), 8.59 (s, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 9.25 (s, 1H), 10.10 (s, 1H).

ESI-Ms m/z: 491.4 [M+H].

Example 5 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-) Dihydrobenzo[1,4]dioxin-6-yl)-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, benzo-1,4-dioxane-6-boronic acid, N The title compound was obtained according to the method of Example 1 using N, N'-trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.10 (s, 1H), 8.65 (s, 2H), 8.35 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.43-6.38 (m, 2H), 5.77-5.75 (d, 1H), 4.32-4.28 (d, 4H), 3.80 (s, 3H), 2.88 (s) , 2H), 2.73 (s, 4H), 2.34 - 2.32 (s, 2H), 2.09 (s, 5H).

ESI-Ms m/z: 506.3 [M+H].

Example 6 N-(2-((2-(4-methylpiperazin-1-yl)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-) Oxyphenyl)-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxybenzeneboronic acid, N-methyl-2-(4) The title compound was obtained according to the procedure of Example 1 using m.p.p.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.34 (s, 1H), 8.66 (s, 1H), 8.39 (s, 4H), 7.04 (s, 2H), 6.96 (s, 1H), 6.15 -6.59(s,1H), 6.28(s,1H), 5.76-5.61(d,1H),3.84-3.82(s,6H),3.57-3.48(m,3H),2.70(s,4H), 2.50 (s, 4H), 2.39-2.29 (m, 3H), 2.13 - 2.08 (s, 4H).

ESI-Ms m/z: 533.4 [M+H].

Example 7 N-(2-((2-(piperidin-1-yl)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dihydro)) Benzo[1,4]dioxin-6-yl)-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, benzo-1,4-dioxane-6-boronic acid, N The title compound was obtained according to the procedure of Example 1 using methylene-2-(piperidin-1-yl)ethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.37 (s, 1H), 9.01 (bs, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 7.95-7.94 (m, 1H) , 7.84(s,1H), 6.95(s,2H),6.62-6.56(m,1H),6.26-6.23(m,1H),5.75-5.73(d,1H),4.31-4.27(m,4H) , 3.80 (s, 3H), 2.98 (m, 2H), 2.69 (s, 3H), 2.35-2.32 (m, 6H), 1.47 (m, 4H), 1.36 (m, 2H).

ESI-Ms m/z: 546.5 [M+H].

Example 8 N-(2-((2-(piperidin-1-yl)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxyphenyl) )-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxybenzeneboronic acid, N-methyl-2-(piperidin The title compound was obtained according to the method of Example 1 using pyridine-1-yl)ethylamine and </RTI>

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.40 (s, 1H), 9.01 (bs, 1H), 8.66 (s, 1H), 8.40 (m, 2H), 8.17 (s, 1H), 7.04 (m, 2H), 6.96 (s, 1H), 6.64-6.58 (m, 1H), 6.28-6.25 (m, 1H), 5.77-5.75 (d, 1H), 3.84-3.82 (s, 6H), 3.00 - 2.99 (m, 2H), 2.70 (s, 3H), 2.5 (m, 2H), 2.40 - 2.36 (m, 4H), 1.49 (m, 4H), 1.37 (m, 2H).

ESI-Ms m/z: 518.4 [M+H].

Example 9 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-(4-fluoro-3-methylphenyl) )-1,3,5-triazin-2-ylamino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-methyl-4-fluorobenzeneboronic acid, N,N,N' The title compound was obtained according to the method of Example 1 using trimethylethylenediamine and allyl chloride as starting materials.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 2.33 (9H, m), 2.54-2.56 (2H, t), 2.67-2.70 (3H, s), 2.98 (2H, t), 3.84 (3H, s), 5.76-5.78 (1H, d), 6.26-6.30 (1H, d), 6.52-6.57 (1H, m), 7.03 (1H, s), 7.27-7.28 (1H, m), 8.16 (1H, d), 8.31 - 8.32 (1H, s), 8.43 - 8.47 (1H, s), 8.73 (1H, s), 8.86-9.39 (1H, s), 10.00 (1H, s).

ESI-Ms m/z: 480.4 [M+H].

Example 10 N-(2-((2-(piperidin-1-yl)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,3-dihydro-) 1-nonanone-5-yl)-1,3,5-triazin-2-amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 5-bromo-1-indanone, N-methyl-2-( The title compound was obtained according to the procedure of Example 1 using hexanes.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.39 (s, 1H), 8.79 (s, 1H), 8.46-7.43 (d, 1H), 8.30 (m, 3H), 7.75 (m, 1H) , 6.98 (m, 1H), 6.67-6.57 (m, 1H), 6.3.-6.25 (m, 1H), 5.79-5.75 (m, 1H), 3.83 (s, 3H), 2.99 (m, 4H), 2.71 (s, 3H), 2.35-2.27 (m, 8H), 1.47 (m, 4H), 1.37 (m, 2H).

ESI-Ms m/z: 541.64 [M+H].

Example 11 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-5-tert-butyl) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-tert-butyl-5-methyl-benzeneboronic acid, N,N The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.90 (s, 1H), 9.13 (s, 1H), 8.72 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.44 (s, 1H), 7.02 (s, 1H), 6.66 (s, 1H), 6.22-6.66 (d, 1H), 5.73-5.76 (d, 1H), 3.83 (s, 3H) ), 3.30 (s, 3H), 2.50 (s, 3H), 2.67 (t, 2H), 2.48 (t, 2H), 2.22 (s, 6H), 1.29 (s, 9H).

ESI-Ms m/z: 518.3 [M+H].

Example 12 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,2-difluoro-1, 3-benzodioxan-5-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 5-bromo-2,2-difluoro-1,3-benzo The title compound was obtained according to the method of Example 1 using dioxin, N,N,N,3-triethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, CDCl} 3 -d 6) δ: 10.20 (s, 1H), 9.69 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.52 (s, 1H), 8.37-8.39(d,1H),7.54-7.57(d,1H),6.99-7.08 (d,2H),6.35-6.38(d,1H),5.74-5.77(d,1H),3.86(s,3H ), 3.31 (t, 2H), 2.75 (t, 2H), 2.62 (s, 3H), 2.41 (s, 6H).

ESI-Ms m/z: 528.0 [M+H].

Example 13 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-fluoro-4,5-di) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-fluoro-4,5-dimethoxyphenylboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, CDCl} 3 -d 6) δ: 10.07 (s, 1H), 9.12 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 7.84-7.88 (d, 2H ), 7.03 (s, 1H), 6.39-6.44 (m, 1H), 6.23-6.27 (m, 1H), 5.74-5.76 (m, 1H), 3.89 (s, 6H), 3.82 (s, 3H), 2.90 (t, 2H), 2.71 (s, 3H), 2.36 (t, 2H), 2.22 (s, 6H).

ESI-Ms m/z: 526.1 [M+H].

Example 14 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,5-difluoro-4-) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-bromo-2,6-difluoroanisole, N,N The title compound was obtained according to the method of Example 1 using N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, CDCl} 3 -d 6) δ: 9.89 (s, 1H), 9.00 (s, 1H), 8.76 (s, 1H), 8.13 (s, 3H), 7.02 (s, 1H), 6.58 (s, 1H), 6.29-6.32 (d, 1H), 5.75-5.77 (d, 1H), 4.04 (s, 3H), 3.84 (s, 3H), 3.27 (s, 3H), 3.04 (s, 2H), 2.68 (s, 2H), 2.42 (s, 6H).

ESI-Ms m/z: 514.3 [M+H].

Example 15 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-methylbenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-methylbenzeneboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 10.10 (s, 1H), 9.20 (s, 1H), 8.73 (s, 1H), 8.36 (s, 1H), 8.30 (s, 2H), 7.52 - 7.50 (d,1H), 7.03(s,1H), 6.45–6.24(m,2H), 5.78–5.74(d,1H),3.81(s,3H),2.90–2.87(t,2H),2.73(s , 3H), 2.42 (s, 3H), 2.35 - 2.31 (m, 2H), 2.21 (s, 6H).

ESI-Ms m/z: 496.4 [M+H].

Example 16 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-fluorophenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-fluorobenzeneboronic acid, N,N,N'- The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 10.10 (s, 1H), 9.14 - 8.99 (m, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.21. (s, 1H), 7.56 (s, 1H), 7.04 (s, 1H), 6.45–6.39 (m, 1H), 6.30–6.27 (m, 1H), 5.77–5.75 (d, 1H), 3.82 (s, 3H), 2.90 (s, 2H), 2.73 (s, 3H), 2.36 ( s, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 500.2 [M+H].

Example 17 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4-dimethoxybenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4-dimethoxybenzeneboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 10.11 (s, 1H), 9.04 (s, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 8.10-8.07 (d, 1H), 7.89 (s, 1H), 7.09-7.00 (m, 2H), 6.46-6.37 (m, 1H), 6.27-6.21 (d, 1H), 5.77-5.74 (d, 1H), 3.84 (s, 6H), 3.12 (s, 2H), 2.90 (s, 3H), 2.72 (s, 3H), 2.37 - 2.24 (m, 2H), 2.22 (s, 6H).

ESI-Ms m/z: 508.2 [M+H].

Example 18 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-)phenyl)-1, 3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-biphenylboronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using diamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 10.10 (s, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.53(s,2H),7.83-7.76(m,5H), 7.53-7.50(m,2H),7.44-7.41(m,1H),7.03(s,1H),6.48-6.43(m,1H), 6.30-6.27 (m, 1H), 5.78-5.76 (m, 1H), 3.82 (s, 3H), 2.92 (s, 2H), 2.73 (s, 3H), 2.40 (s, 2H), 2.25 (s, 6H).

ESI-Ms m/z: 524.2 [M+H].

Example 19 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4-dimethylphenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4-dimethylphenylboronic acid, N,N,N'- The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 10.13 (s, 1H), 9.14 (s, 1H), 8.90 (s, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 8.19-8.16 (d, 1H), 7.29-7.27 (d, 1H), 7.04 (s, 1H), 6.47-6.40 (m, 1H), 6.29-6.25 (d, 1H), 5.79-5.76 (d, 1H), 3.83 (s, 3H), 2.91 (s, 2H), 2.73 (s, 3H), 2.36-2.34 (s, 2H), 2.30 (s, 6H), 2.23 (s, 6H).

ESI-Ms m/z: 476.2 [M+H].

Example 20 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4,5-trimethoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4,5-trimethoxybenzeneboronic acid, N,N,N '-Trimethylethylenediamine, allyl chloride and diisopropylethylamine as raw materials, according to the examples The title compound was prepared by the method of 1.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.99 (s, 1H), 9.73 (s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 7.68 (s, 2H), 6.98 (s, 2H), 6.28-6.23 (s, 1H), 5.76-5.73 (d, 1H), 3.84 (s, 9H), 3.74 (s, 3H), 2.90-2.86 (m, 2H), 2.75 (s , 6H), 2.34 - 2.31 (m, 2H), 2.21 (s, 3H).

ESI-Ms m/z: 538.0 [M+H].

Example 21 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-fluoro-4-methylbenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-fluoro-4-methylbenzeneboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.08 (s, 1H), 9.00 (s, 1H), 8.73 (s, 1H), 8.27-8.11 (m, 3H), 7.44 (s, 1H) , 7.03(s,1H), 6.45–6.26(m,2H), 5.78–5.75(d,1H),3.81(s,3H),2.90–2.88(t,2H),2.73(s,3H),2.35 – 2.32 (m, 5H), 2.21 (s, 6H).

ESI-Ms m/z: 480.0 [M+H].

Example 22 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-chloro-3,4,5) –trimethoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2-chloro-3,4,5-trimethoxybenzeneboronic acid, N The title compound was obtained according to the procedure of Example 1 using N, N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.94 (s, 1H), 9.39 (s, 1H), 8.71 (s, 1H), 8.14 (s, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 6.54-6.49 (m, 1H), 6.22-6.19 (s, 1H), 5.74-5.72 (d, 1H), 3.83 (s, 9H), 2.68 (s, 3H), 2.55 (s , 2H), 2.50 (s, 5H), 2.33 (s, 6H).

ESI-Ms m/z: 571.9 [M+H].

Example 23 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methoxyphenyl)-)- 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-methoxybenzeneboronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using methylenediamine, allyl chloride and diisopropylethylamine.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.08 (s, 1H), 9.21 (s, 1H), 8.75 (s, 1H), 8.48 (m, 1H), 8.38 (s, 1H), 8.20 (m, 1H), 7.61 - 7.58 (m, 2H), 7.03 (s, 1H), 6.47 - 6.38 (m, 1H), 6.28 - 6.22 (d, 1H), 5.77 - 5.74 (m, 1H), 3.81 (s, 3H), 2.99-2.90 (m, 5H), 2.72 (s, 3H), 2.37 (t, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 478.3 [M+H].

Example 24 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(4-methoxyphenyl)-1,3) ,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxybenzeneboronic acid, N,N,-dimethylethanolamine The title compound was obtained according to the procedure of Example 1 using lylyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.71 (s, 1H), 9.03 (brs, 1H), 8.64 (s, 1H), 8.37-8.32 (m, 3H), 7.05-7.03 (m, 2H), 6.93 (s, 1H), 6.52–6.47 (m, 1H), 6.26-6.23 (d, 1H), 5.74-5.72 (d, 1H), 4.12 (m, 2H), 3.82 (m, 6H) , 2.64 - 2.62 (m, 2H), 2.28 (s, 6H).

ESI-Ms m/z: 465.2 [M+H].

Example 25 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-5-chloro-) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-5-methylphenylboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.11 (s, 1H), 9.06 (s, 1H), 8.76 (s, 1H), 8.22-8.17 (m, 3H), 7.50 (s, 1H) , 7.04(s,1H), 6.45–6.40(m,1H), 6.27–6.24(d,1H), 5.77-5.75(d,1H),3.82(s,3H),2.89(t,2H),2.72 (s, 3H), 2.40 (s, 3H), 2.36 (t, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 496.2 [M+H].

Example 26 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-fluoro-5-chloro-benzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-5-fluorobenzeneboronic acid, N,N,N'- The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.13 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 8.22-8.17 (m, 2H) , 7.70 (s, 1H), 7.04 (s, 1H), 6.43 - 6.38 (m, 1H), 6.30 - 6.26 (m, 1H), 5.77 - 5.75 (d, 1H), 3.82 (s, 3H), 2.88 (t, 2H), 2.73 (s, 3H), 2.33 (t, 2H), 2.21 (s, 6H).

ESI-Ms m/z: 500.2 [M+H].

Example 27 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(3-fluoro-5-chloro-phenyl)-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-5-fluorobenzeneboronic acid, N,N,-dimethyl The title compound was obtained according to the procedure of Example 1 using hexanesamine, </RTI> </RTI> <RTIgt;

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.68 (s, 1H), 9.27 (s, 1H), 8.80 (s, 1H), 8.78-8.70 (m, 1H), 8.25-8.11 (m, 2H), 7.68 (s, 1H), 6.95 (s, 1H), 6.49 - 6.48 (m, 1H), 6.27 - 6.263 (m, 1H), 5.74 - 5.72 (d, 1H), 4.21 (t, 2H) , 3.81 (s, 3H), 2.63 (t, 2H), 2.28 (s, 6H).

ESI-Ms m/z: 487.2 [M+H].

Example 28 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-trifluoromethyl-5-) Chloro-phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-5-trifluoromethylbenzeneboronic acid, N,N, The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.10 (s, 1H), 9.41 (s, 1H), 8.78-8.70 (m, 4H), 7.90 (s, 1H), 7.04 (s, 1H) , 6.45–6.36 (m, 1H), 6.26–6.20 (m, 1H), 5.77-5.73 (d, 1H), 3.80 (s, 3H), 2.88 (t, 2H), 2.73 (s, 3H), 2.34 (t, 2H), 2.22 (s, 6H).

ESI-Ms m/z: 550.2 [M+H].

Example 29 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methylphenyl)-1) ,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-methylbenzeneboronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.10 (s, 1H), 9.18 (s, 1H), 8.75 (s, 1H), 8.48 (m, 1H), 8.36 (s, 1H), 8.10 (m,1H), 7.65-7.63 (m, 2H), 7.03 (s, 1H), 6.60–6.58 (m, 1H), 6.33–6.30 (d, 1H), 5.81-5.79 (m, 1H), 3.81 (s, 3H), 3.10 (m, 2H), 2.73 (s, 3H), 2.38 (t, 2H), 2.30 (s, 3H), 2.26 (s, 6H).

ESI-Ms m/z: 462.3 [M+H].

Example 30 N-(2-((2-(1-pyrrolidinyl)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(N,N-N) Methylcarbamoyl)phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-(N,N-dimethylcarbamoyl)benzeneboronic acid, N The title compound was obtained according to the procedure of Example 1 using m-(2-pyrrolidin-1-yl-ethyl)-amine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.76 (s, 1H), 9.22 (brs, 1H), 8.75 (s, 1H), 8.48 (m, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 7.61 - 7.58 (m, 2H), 7.02 (s, 1H), 6.53 - 6.44 (m, 1H), 6.27 - 6.21 (d, 1H), 5.77 - 5.73 (m, 1H), 3.85 (s, 3H), 2.98 (s, 6H), 2.94-2.91 (m, 4H), 2.71 (s, 3H), 2.55-2.53 (m, 4H), 1.73 (m, 4H).

ESI-Ms m/z: 545.4 [M+H].

Example 31 N-(2-((2-(1-pyrrolidinyl)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxyphenyl)) -1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxybenzeneboronic acid, N-methyl-(2-pyrrole The title compound was obtained according to the procedure of Example 1 from methylene-l-ethyl-ethyl)-amine, allylic acid chloride and diisopropylethylamine.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.75 (s, 1H), 9.64 (brs, 1H), 8.67 (s, 1H), 8.43-8.40 (m, 2H), 8.19 (s, 1H) , 7.06-7.00 (m, 3H), 6.58–6.49 (m, 1H), 6.30–6.25 (d, 1H), 5.78-5.75 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H) , 3.06–3.02 (m, 2H), 2.70–2.67 (m, 9H), 1.77 (m, 4H).

ESI-Ms m/z: 504.3 [M+H].

Example 32 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(N, N-dimethyl) Carbamoyl)phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-(N,N-dimethylcarbamoyl)benzeneboronic acid, N The title compound was obtained according to the procedure of Example 1 using N, N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.07 (s, 1H), 9.22 (brs, 1H), 8.75 (s, 1H), 8.50-8.49 (m, 1H), 8.37 (s, 1H) , 8.20-8.16 (m, 1H), 7.61 - 7.58 (m, 2H), 7.03 (s, 1H), 6.46 - 6.37 (m, 1H), 6.28 - 6.22 (d, 1H), 5.77 - 5.74 (d, 1H), 3.80 (s, 3H), 2.98-2.90 (m, 8H), 2.72 (s, 3H), 2.36 (t, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 519.4 [M+H].

Example 33 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(N, N-dimethyl) Base amino)phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-(N,N-dimethylamino)benzeneboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.07 (s, 1H), 9.20 (brs, 1H), 8.76 (s, 1H), 8.50-8.48 (m, 1H), 8.37 (s, 1H) , 8.22-8.18 (m, 1H), 7.63 - 7.59 (m, 2H), 7.03 (s, 1H), 6.46 - 6.40 (m, 1H), 6.28 - 6.23 (d, 1H), 5.78-5.75 (d, 1H), 3.83 (s, 3H), 3.00-2.95 (m, 8H), 2.73 (s, 3H), 2.35 (t, 2H), 2.22 (s, 6H).

ESI-Ms m/z: 491.2 [M+H].

Example 34 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methyl-5-((4-(3,4-dimethoxyphenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methyl-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4-dimethoxybenzeneboronic acid, N,N,N'- The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.58 (s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.19 (s, 1H), 7.08–7.06 (s, 1H), 6.45–6.37 (m, 1H), 6.25–6.19 (d, 1H), 5.78-5.74 (d, 1H), 3.83 (s, 4H), 3.75 (s, 3H), 2.84 (s, 2H), 2.68 (s, 3H), 2.38 (m, 2H), 2.24 (s, 6H), 2.18 (s, 3H).

ESI-Ms m/z: 492.3 [M+H].

Example 35 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methyl)

-5-((4-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methyl-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4,5-trimethoxyphenylboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.68 (s, 1H), 8.69 (s, 1H), 8.18 (s, 1H), 7.64 (s, 2H), 7.19 (s, 1H), 6.47 – 6.37 (m, 1H), 6.24–6.18 (d, 1H), 5.77-5.74 (d, 1H), 3.78 (s, 5H), 3.73 (s, 5H), 2.85 (s, 2H), 2.67 (s) , 3H), 2.39 (m, 2H), 2.24 (s, 6H), 2.19 (s, 3H).

ESI-Ms m/z: 522.0 [M+H].

Example 36 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-(4-phenyl)

-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, phenylboronic acid, N,N,N'-trimethylethylenediamine, The title compound was obtained according to the procedure of Example 1 using lylyl chloride and diisopropylethylamine as starting materials.

1H-NMR (500MHz, DMSO-d6) δ: 2.23 (6H, s), 2.39-2.35 (2H, m), 2.72 (3H, s), 2.92-2.8 (2H, m), 3.81 (3H, s) , 5.78-5.74 (1H, dd), 6.30-6.24 (1H, m), 6.48-6.39 (1H, m), 7.02 (1H, s), 7.54-7.49 (2H, m), 7.63-7.58 (1H, m), 8.22 (1H, m), 8.46-8.44 (2H, m), 8.73 (1H, s), 9.09 (1H, bs), 10.07 (1H, s).

ESI-Ms m/z: 447.5 [M+H].

Example 37 N-(2-((2-(1-pyrrolidinyl)ethyl)(methyl)amino)-4-methoxy-5-(4-phenyl-1,3,5-tri Pyrazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, phenylboronic acid, N-methyl-2-(pyrrolidin-1-yl) The title compound was obtained according to the method of Example 1 using ethylamine, allylic acid chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 1.72 (4H, m), 2.50 (6H, m), 2.70 (3H, s), 3.07-3.03 (2H, m), 3.82 (3H, s), 5.77 -5.73(1H,dd),6.29-6.23(1H,m),6.53-6.44(1H,m),7.01(1H,s),7.54-7.49(2H,m),7.63-7.58(1H,m) , 8.22 (1H, m), 8.46-8.43 (2H, m), 8.73 (1H, s), 9.09 (1H, bs), 9.76 (1H, s).

ESI-Ms m/z: 474 [M+H].

Example 38 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-trifluoromethoxyphenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-trifluoromethoxyphenylboronic acid, N,N,N'- The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.25 (6H, s), 2.39-2.35 (2H, m), 2.71 (3H, s), 2.92-2.89 (2H, m), 3.80 (3H, s) , 5.75-5.73 (1H, dd), 6.27-6.24 (1H, m), 6.48-6.42 (1H, m), 7.03 (1H, m), 7.66-7.60 (1H, m), 8.27-8.24 (2H, m), 8.46 (1H, s), 8.77 (1H, s), 8.89-8.88 (1H, s), 9.36 (1H, bs), 10.07 (1H, s).

ESI-Ms m/z: 532.3 [M+H].

Example 39 N-(2-((2-(1-pyrrolidinyl)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-trifluoromethoxybenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-trifluoromethoxybenzeneboronic acid, N-methyl-2- The title compound was obtained according to the procedure of Example 1 using (pyrrolidin-1-yl)ethylamine, allyl chloride and diisopropylethylamine.

1H-NMR (500MHz, DMSO-d6) δ: 1.73 (4H, m), 2.39-2.35 (6H, m), 2.71 (3H, s), 2.98 (2H, m), 3.81 (3H, s), 5.75 -5.73 (1H, dd), 6.27-6.24 (1H, m), 6.50-6.44 (1H, m), 7.03 (1H, m), 7.66-7.61 (2H, m), 8.20 (1H, m), 8.27 (1H, m), 8.46 (1H, s), 8.77 (1H, s), 9.22 (1H, bs), 9.77 (1H, s).

ESI-Ms m/z: 558.3 [M+H].

Example 40 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-4-methoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxy-3-methylbenzeneboronic acid, N,N, The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.21 (9H, s), 2.34-2.31 (2H, m), 2.72 (3H, s), 2.90-2.86 (2H, m), 3.82 (3H, s) , 3.87 (3H, s), 5.78-5.74 (1H, dd), 6.28-6.23 (1H, m), 6.46-6.41 (1H, m), 7.06-7.03 (2H, m), 8.32-8.26 (2H, m), 8.66 (1H, s), 8.85 (2H, m), 10.11 (1H, s).

ESI-Ms m/z: 492.5 [M+H].

Example 41 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-trifluoro)) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-trifluoromethylphenylboronic acid, N,N The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.27 (6H, s), 2.50-2.39 (2H, m), 2.72 (3H, s), 2.93 (2H, m), 3.81 (3H, s), 5.78 -5.74(1H,dd),6.29-6.23(1H,m),6.48-6.39(1H,m),7.04(1H,s),8.02(1H,br),8.14(1H,s),8.45(1H , m), 8.57 (1H, s), 8.81 (1H, s), 9.34 (1H, m), 10.04 (1H, m).

ESI-Ms m/z: 550.2 [M+H].

Example 42 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-chloro-5-trifluoro)) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2-chloro-5-trifluoromethylphenylboronic acid, N,N, The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.27 (6H, s), 2.50-2.39 (2H, m), 2.72 (3H, s), 2.93 (2H, m), 3.81 (3H, s), 5.74 -5.69 (1H, dd), 6.23-6.17 (1H, m), 6.41-6.35 (1H, m), 6.99 (1H, s), 7.86 (2H, m), 8.16-8.10 (1H, m), 8.30 (1H, s), 8.77-8.74 (1H, m), 9.64 (1H, s), 10.04 (1H, m).

ESI-Ms m/z: 550.2 [M+H].

Example 43 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(3-chloro-4-trifluoromethylphenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-trifluoromethylphenylboronic acid, N,N The title compound was obtained according to the procedure of Example 1 using dimethylethanolamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.27 (6H, s), 2.60 (2H, m), 3.81 (3H, s), 4.20 (2H, m), 5.74-5.72 (1H, dd), 6.24 (1H, m), 6.49 (1H, m), 6.95 (1H, s), 8.09-7.98 (1H, m), 8.54-8.41 (3H, m), 8.81 (1H, m), 9.39 (1H, s ), 9.66 (1H, s).

ESI-Ms m/z: 537.2 [M+H].

Example 44 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(3-methyl-4-methoxyphenyl) )-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-methoxy-3-methylbenzeneboronic acid, N,N- The title compound was obtained according to the procedure of Example 1 using dimethylethanolamine, allyl chloride and diisopropylethylamine as starting materials.

1H-NMR (500MHz, DMSO-d6) δ: 2.21 (6H, s), 2.27 (3H, s), 3.79 (2H, m), 3.86 (6H, s), 4.54 (2H, m), 5.67-5.65 (1H, dd), 6.22-6.19 (1H, m), 6.76 (1H, m), 6.94 (1H, s), 7.04 (1H, m), 8.25-8.20 (2H, m), 8.35 (1H, s ), 8.63 (1H, s), 9.05 (1H, br), 10.31 (1H, s).

ESI-Ms m/z: 479.2 [M+H].

Example 45 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2,5-dimethoxybenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2,5-dimethoxyphenylboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.22 (6H, s), 2.39-2.37 (2H, m), 2.70 (3H, s), 2.90-2.86 (2H, m), 3.72 (6H, s) , 3.78 (3H, s), 5.75-5.72 (1H, dd), 6.23-6.17 (1H, m), 6.41-6.35 (1H, m), 7.08-7.04 (2H, m), 7.18-7.17 (1H, m), 8.17 (1H, m), 8.38 (1H, s), 8.65 (1H, s), 9.24 (1H, s), 10.03 (1H, m).

ESI-Ms m/z: 508.2 [M+H].

Example 46 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(2,5-dimethoxyphenyl)-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2,5-dimethoxybenzeneboronic acid, N,N-dimethyl The title compound was obtained according to the procedure of Example 1 using hexanesamine, </RTI> </RTI> <RTIgt;

1H-NMR (500MHz, DMSO-d6) δ: 2.29 (6H, s), 2.72-2.67 (2H, m), 3.72 (6H, s), 3.78 (3H, s), 4.19 (2H, m), 5.75 -5.72(1H,dd),6.23-6.17(1H,m),6.41-6.35(1H,m),7.08-7.04(2H,m),7.18-7.17(1H,m),8.17(1H,m) , 8.38 (1H, s), 8.65 (1H, s), 9.24 (1H, s), 10.03 (1H, m).

ESI-Ms m/z: 495.2 [M+H].

Example 47 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,5-dimethoxybenzene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,5-dimethoxyphenylboronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.33 (6H, s), 2.54 (2H, m), 2.70 (3H, s), 2.98 (2H, m), 3.81 (9H, s), 5.76-5.72 (1H, dd), 6.04 (1H, s), 6.26-6.20 (1H, m), 6.57-6.48 (1H, m), 6.70 (1H, s), 7.01 (1H, s), 7.52 (2H, s ), 8.72 (1H, s), 9.26 (1H, s), 10.01 (1H, s).

ESI-Ms m/z: 508.2 [M+H].

Example 48 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(3,5-dimethoxyphenyl)-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,5-dimethoxybenzeneboronic acid, N,N-dimethyl The title compound was obtained according to the procedure of Example 1 using hexanesamine, </RTI> </RTI> <RTIgt;

1H-NMR (500MHz, DMSO-d6) δ: 2.33 (6H, s), 2.72 (2H, m), 3.80-3.76 (9H, s), 4.23-4.21 (2H, m), 5.73-5.71 (1H, Dd), 6.22-6.19 (1H, m), 6.55-6.50 (1H, m), 6.70 (1H, br), 6.93 (1H, s), 7.48 (2H, m), 8.21 (1H, s), 8.70 (1H, bs), 9.26 (1H, s), 9.70 (1H, m).

ESI-Ms m/z: 495.2 [M+H].

Example 49 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methoxy-4-fluoro) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-fluoro-3-methoxybenzeneboronic acid, N,N,N The title compound was obtained according to the procedure of Example 1 using the crude material of &lt;RTIgt;&lt;/RTI&gt;

1H-NMR (500MHz, DMSO-d6) δ: 2.21 (6H, s), 2.32-2.26 (2H, m), 2.72 (3H, s), 2.88 (2H, m), 3.81 (3H, s), 3.87 (3H, s), 5.77-5.74 (1H, dd), 6.29-6.21 (1H, m), 6.39-6.35 (1H, m), 6.90 (1H, s), 7.37-7.35 (1H, m), 8.06 (2H, m), 8.73-8.67 (2H, m), 9.21-9.12 (1H, br), 10.08 (1H, s).

ESI-Ms m/z: 496.0 [M+H].

Example 50 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-isopropyl-4-)- Oxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-isopropyl-4-methoxybenzeneboronic acid, N,N The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ: 1.16-1.14 (6H, s), 2.23 (6H, s), 2.39-2.37 (2H, m), 2.72 (3H, s), 2.92-2.90 ( 2H,m), 3.28-3.23 (1H, s), 3.81 (3H, s), 3.87 (3H, s), 5.76-5.73 (1H, dd), 6.26-6.20 (1H, m), 6.46-6.37 ( 1H, m), 7.07-7.03 (2H, m), 8.30-8.22 (3H, m), 8.66 (1H, s), 9.01 (1H, s), 10.09 (1H, s).

ESI-Ms m/z: 520.1 [M+H].

Example 51 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-methoxy) -5-methylphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-methoxy-5-methylbenzeneboronic acid, N The title compound was obtained according to the procedure of Example 1 using N, N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.36 (3H, s), 2.50 (6H, s), 2.39-2.37 (2H, m), 2.72 (3H, s), 2.92-2.90 (2H, m) , 3.821 (3H, s), 3.85 (3H, s), 5.73-5.69 (1H, dd), 6.29-6.23 (1H, m), 6.97 (1H, s), 7.18-7.17 (1H, br), 8.26 (2H, m), 8.72 (1H, s), 9.07-9.04 (1H, br), 9.80 (1H, s), 10.60 (1H, s).

ESI-Ms m/z: 526.3 [M+H].

Example 52 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-5-methoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-5-methoxyphenylboronic acid, N,N, The title compound was obtained according to the procedure of Example 1 using N?-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 2.34 (6H, s), 2.56 (2H, m), 2.69 (3H, s), 2.98 (2H, m), 3.82-3.81 (6H, s) , 5.75-5.73 (1H, dd), 6.27-6.23 (1H, m), 6.55-6.50 (1H, m), 7.02 (1H, s), 7.25 (1H, s), 7.83 (1H, s), 7.96 (1H, s), 8.15 (1H, s), 8.74 (1H, s), 9.32-9.28 (1H, br), 9.97 (1H, s).

ESI-Ms m/z: 512.2 [M+H].

Example 53 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-fluoro-4-methoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-fluoro-4-methoxybenzeneboronic acid, N,N,N The title compound was obtained according to the procedure of Example 1 using the crude material of &lt;RTIgt;&lt;/RTI&gt;

1H-NMR (300MHz, DMSO-d6) δ: 10.26 (s, 1H), 9.72 (s, 1H), 8.99 (s, 1H), 8.70 (m, 1H), 8.82-8.19 (m, 2H), 7.29 (m, 1H), 6.98-6.95 (m, 2H), 6.32–6.29 (m, 1H), 5.75–5.72 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.28-3.18 (m, 4H), 2.71 (s, 6H), 2.63 (s, 3H).

ESI-Ms m/z: 496.2 [M+H].

Example 54 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-chloro-4-methoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2-chloro-4-methoxybenzeneboronic acid, N,N,N The title compound was obtained according to the procedure of Example 1 using the crude material of &lt;RTIgt;&lt;/RTI&gt;

1H-NMR (300MHz, DMSO-d6) δ: 9.45 (s, 1H), 9.25 (s, 1H), 8.71 (s, 1H), 8.13 (m, 1H), 7.88-7.86 (m, 1H), 7.10 (s, 1H), 7.03-7.01 (m, 1H), 6.91 (s, 1H), 6.64 - 6.58 (m, 1H), 6.32 - 6.28 (m, 1H), 5.80-5.78 (d, 1H), 3.84 (s, 6H), 3.31-3.25 (m, 4H), 2.81 (s, 6H), 2.62 (s, 3H).

ESI-Ms m/z: 512.2 [M+H].

Example 55 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-chloro-3,5-di) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 4-chloro-3,5-dimethoxyphenylboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (300MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.31 (s, 1H), 9.22 (s, 1H), 8.77 (s, 1H), 7.73 (m, 2H), 7.02 (s) , 1H), 6.65–6.59 (m, 1H), 6.31–6.21 (d, 1H), 5.81-5.79 (d, 1H), 3.90 (s, 6H), 3.85 (s, 3H), 3.31-3.30 (t , 2H), 3.27-3.26 (t, 2H), 2.81 (s, 6H), 2.62 (s, 3H).

ESI-Ms m/z: 543.2 [M+H].

Example 56 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-methyl-)- 5-methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-methyl-5-methoxybenzeneboronic acid, N The title compound was obtained according to the procedure of Example 1 using N, N'-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (300MHz, CDCl3-d6) δ: 10.07 (s, 1H), 9.23 (s, 1H), 8.73 (s, 2H), 8.02 (s, 1H), 7.85 (s, 1H), 7.04 (s) , 1H), 6.44-6.37 (m, 1H), 6.25-6.22 (m, 1H), 5.76-5.74 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.988 (s, 2H) ), 2.72 (s, 3H), 2.33 (t, 2H), 2.27 (s, 3H), 2.22 (s, 6H).

ESI-Ms m/z: 527.2 [M+H].

Example 57 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4,5-di) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4,5-dimethoxyphenylboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, CDCl3-d6) δ: 10.03 (s, 1H), 9.34 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.07 (s) , 1H), 6.99 (s, 1H), 6.39-6.44 (m, 1H), 6.19-6.23 (m, 1H), 5.73-5.75 (m, 1H), 3.83 (s, 3H), 3.79-3.81 (d , 6H), 2.89-2.90 (t, 2H), 2.70 (s, 3H), 2.39 (t, 2H), 2.24 (s, 6H).

ESI-Ms m/z: 542.3 [M+H].

Example 58 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-4-methoxy) Phenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-chloro-4-methoxybenzeneboronic acid, N,N,N The title compound was obtained according to the method of Example 1 using m-triethyldiamine, allylic acid chloride and diisopropylethylamine.

1H-NMR (500MHz, CDCl3-d6) δ: 10.02 (s, 1H), 9.10 (s, 1H), 8.69 (s, 1H), 8.40 (s, 2H), 8.16 (s, 1H), 7.27-7.29 (d, 1H), 7.03 (s, 1H), 6.46-6.52 (m, 1H), 6.25-6.30 (m, 1H), 5.74-5.77 (m, 1H), 3.95 (s, 3H), 3.82 (s , 3H), 2.95 (t, 2H), 2.71 (s, 3H), 2.48 (t, 2H), 2.30 (s, 6H).

ESI-Ms m/z: 512.3 [M+H].

Example 59 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-chloro-thieno[2, 3-B]pyridyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, thieno[2,3-B]pyridine-3-boronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, CDCl3-d6) δ: 10.11 (s, 1H), 9.40 (s, 1H), 9.11-9.16 (d, 1H), 8.75 (s, 1H), 8.62 (s, 2H), 8.27 (s,1H), 7.34(s,1H),7.07(s,1H),6.44-6.49(m,1H),6.21-6.24(m,1H),5.74-5.76(m,1H),3.79(s , 3H), 2.95 (t, 2H), 2.76 (s, 3H), 2.43 (t, 2H), 2.26 (s, 6H).

ESI-Ms m/z: 505.3 [M+H].

Example 60 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(benzo[b]thiophene-3-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, benzothiophene-3-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using methylenediamine, allyl chloride and diisopropylethylamine.

1H-NMR (500MHz, DMSO-d6) δ: 9.94 (s, 1H), 9.36 (s, 1H), 9.03 (s, 1H), 8.73 (s, 2H), 8.48 (s, 1H), 8.07-8.05 (m,1H), 7.42 (s, 2H), 7.04 (s, 1H), 6.70-6.66 (d, 1H), 6.27-6.21 (d, 1H), 5.76-5.72 (d, 1H), 3.81 (s) , 3H), 3.12 (s, 2H), 2.80 (s, 2H), 2.71 (s, 3H), 2.25 (s, 6H).

ESI-Ms m/z: 504.1 [M+H].

Example 61 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,5-dichloro-4-) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,5-dichloro-4-methoxybenzeneboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, CDCl3-d6) δ: 10.07 (s, 1H), 9.69 (s, 1H), 9.42 (s, 1H), 8.76 (s, 1H), 8.40 (s, 2H), 6.70 (s) , 2H), 6.27-6.33 (m, 1H), 5.73-5.76 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.16 (t, 2H), 2.71 (s, 3H), 2.40 (t, 2H), 2.26 (s, 6H).

ESI-Ms m/z: 546.0 [M+H].

Example 62 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methoxy-4-cyclo)) Propylphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-methoxy-4-cyclopropylbenzeneboronic acid, N,N The title compound was obtained according to the method of Example 1 using N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, CDCl3-d6) δ: 9.52 (s, 1H), 9.32 (s, 1H), 9.10 (s, 1H), 8.71 (s, 1H), 7.93-7.95 (d, 1H), 7.87 (s, 1H), 7.09 (m, 1H), 6.92-6.94 (m, 1H), 6.65-6.70 (m, 1H), 6.29-6.32 (m, 1H), 5.79-5.81 (m, 1H), 3.68 (s, 6H), 3.27 (s, 2H), 2.81 (s, 6H), 2.63 (s, 3H), 2.51 (t, 2H), 2.19 (m, 1H), 0.96-1.00 (m, 2H), 0.71-0.72 (m, 2H).

ESI-Ms m/z: 518.2 [M+H].

Example 63 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-trifluoromethyl-4-) Methoxyphenyl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-trifluoromethyl-4-methoxybenzeneboronic acid, N, The title compound was obtained according to the procedure of Example 1 using N,N,-trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, CDCl3-d6) δ: 10.07 (s, 1H), 9.24 (s, 1H), 8.70 (s, 2H), 8.56 (s, 2H), 7.42 (d, 1H), 7.03 (s) , 1H), 6.41-6.47 (m, 1H), 6.21-6.27 (m, 1H), 5.73-5.77 (m, 1H), 3.99 (s, 3H), 3.80 (s, 3H), 2.89-2.92 (t , 2H), 2.72 (s, 3H), 2.38-2.40 (t, 2H), 2.41 (s, 6H).

ESI-Ms m/z: 546.2 [M+H].

Example 64 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(benzo[b]furan-5-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, benzofuran-5-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using methylenediamine, allyl chloride and diisopropylethylamine.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.12 (s, 1H), 8.91 (d, 2H), 8.74 (s, 1H), 8.45 (s, 2H), 8.25 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.05 (s, 1H), 6.43 - 6.45 (m, 1H), 6.32 (d, 1H), 5.78-5.80 (d, 1H), 3.84 (s, 3H) ), 3.36 (t, 2H), 3.13 (s, 3H), 2.35 (t, 2H), 2.23 (s, 6H).

ESI-Ms m/z: 488.3 [M+H].

Example 65 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-benzo[d]-[d Pyrazol-6-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 1-methylcarbazole-6-boronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.13 (s, 1H), 9.06 (s, 1H), 8.78 (s, 1H), 8.70 (s, 1H), 8.23 (s, 2H), 8.13 (s, 1H), 7.86 (s, 1H), 7.05 (s, 1H), 6.42 - 6.47 (m, 1H), 6.23 - 6.26 (d, 1H), 5.76 - 5.78 (d, 1H), 4.11 (s , 3H), 3.84 (s, 3H), 2.91 (t, 2H), 2.73 (s, 3H), 2.37 (t, 2H), 2.24 (s, 6H).

ESI-Ms m/z: 502.2 [M+H].

Example 66 N-(2-((2-(Methoxy)ethyl))(methyl)amino)-4-methoxy-5-((4-(1-methyl-benzo[d]] Pyrazol-6-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 1-methylcarbazole-6-boronic acid, N-methyl-2 The title compound was obtained according to the procedure of Example 1 using methoxyethylamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.29 (s, 2H), 9.05 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.21-8.23 (s, 1H) , 8.14(s,1H), 7.86(s,1H), 7.00(s,1H),6.44–6.49(m,1H),6.23-6.26(d,1H),5.76-5.78(d,1H),4.12 (s, 3H), 3.83 (s, 3H), 3.51 (t, 2H), 3.35 (s, 3H), 2.97 (t, 2H), 2.76 (s, 3H).

ESI-Ms m/z: 489.2 [M+H].

Example 67 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(1-methyl-benzo[d]pyrazole) -6-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 1-methyloxazol-6-boronic acid, N,N-dimethyl The title compound was obtained according to the procedure of Example 1 using hexanesamine, </RTI> </RTI> <RTIgt;

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 9.71 (s, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.47 (s, 2H), 8.18-8.20 (s, 1H) , 8.13 (s, 1H), 7.85 (s, 1H), 6.97 (s, 1H), 6.48-6.53 (m, 1H), 6.21-6.25 (d, 1H), 5.74-5.76 (d, 1H), 4.22 (t, 2H), 4.20 (s, 3H), 3.84 (s, 3H), 2.63 (t, 2H), 2.28 (s, 6H).

ESI-Ms m/z: 489.2 [M+H].

Example 68 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(isoquinolin-6-yl)-) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 6-isoquinolineboronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.10 (s, 1H), 9.42 (s, 1H), 9.39 (s, 1H), 9.29 (s, 1H), 9.16 (s, 1H), 8.86 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.05 (s, 1H), 6.58 (s, 1H), 6.35 ( s, 1H), 5.82 (d, 1H), 3.86 (s, 3H), 2.98 (t, 2H), 2.72 (s, 3H), 2.36 (t, 2H), 2.32 (s, 6H).

ESI-Ms m/z: 499.4 [M+H].

Example 69 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methyl-5-((4-(quinolin-5-yl)-1, 3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, quinoline-5-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.14 (s, 1H), 9.78 (s, 1H), 9.26 (s, 1H), 8.96-8.75 (t, 2H), 8.47-8.38 (m, 2H), 8.20 (s, 2H), 7.23 (s, 1H), 7.21 (s, 1H), 6.49 - 6.44 (m, 1H), 6.28 - 6.24 (d, 1H), 5.79 - 5.78 (d, 1H) , 2.85 (s, 2H), 2.68 (s, 3H), 2.50 (s, 2H), 2.39 (s, 6H), 2.19 (s, 3H).

ESI-Ms m/z: 483.3 [M+H].

Example 70 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-naphthyl)-1,3) ,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2-naphthalene boronic acid, N,N,N'-trimethylethylene The title compound was obtained according to the procedure of Example 1 using EtOAc, EtOAc, EtOAc

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.13 (s, 1H), 9.20 (brs, 2H), 8.80 (s, 1H), 8.52-8.49 (m, 1H), 8.22-8.16 (m, 2H), 8.05–7.99 (m, 2H), 7.66–7.56 (m, 2H), 7.06 (s, 1H), 6.54–6.31 (m, 2H), 5.83-5.80 (d, 1H), 3.86 (s, 3H), 2.93 (t, 2H), 2.73 (s, 3H), 2.41 (t, 2H), 2.26 (s, 6H).

ESI-Ms m/z: 498.4 [M+H].

Example 71 N-(2-((2-(Dimethylamino)ethyl)oxy)-4-methoxy-5-((4-(2-naphthyl)-1,3,5- Triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 2-naphthalene boronic acid, N,N,N'-trimethylethylene The title compound was obtained according to the procedure of Example 1 using EtOAc, EtOAc, EtOAc

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.75 (s, 1H), 9.13 (brs, 2H), 8.77 (s, 1H), 8.48-8.45 (m, 1H), 8.25-8.15 (m, 2H), 8.01–7.99 (m, 2H), 7.66–7.58 (m, 2H), 6.97 (s, 1H), 6.54–6.31 (m, 2H), 5.81-5.79 (m, 1H), 3.90-3.85 ( m, 5H), 2.73-2.63 (m, 2H), 2.30 (s, 6H).

ESI-Ms m/z: 485.3 [M+H].

Example 72 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(7-methoxy-2-naphthalene) 1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 7-methoxy-2-naphthalene boronic acid, N,N,N' The title compound was obtained according to the procedure of Example 1 using trimethylethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 10.15 (s, 1H), 9.14-9.11 (brs, 2H), 8.77 (s, 1H), 8.48-8.45 (m, 1H), 8.30 (s, 1H), 8.14 - 8.12 (m, 1H), 7.92-7.90 (m, 1H), 7.41 (s, 1H), 7.23 - 7.21 (m, 1H), 7.06 (s, 1H), 6.52 - 6.30 (m, 2H), 5.83-5.80 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.91 (t, 2H), 2.74 (s, 3H), 2.34 (t, 2H), 2.22 (s) , 6H).

ESI-Ms m/z: 528.2 [M+H].

Example 73 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(quinoline) -6-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, quinoline-6-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 9.78 (s, 1H), 9.13 (brs, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.47-8.44 (m, 1H) , 8.26-8.15 (m, 2H), 8.01–7.99 (m, 1H), 7.66–7.58 (m, 2H), 6.87 (s, 1H), 6.54–6.34 (m, 2H), 5.81-5.78 (m, 1H), 3.92-3.87 (m, 5H), 2.75-2.65 (s, 3H), 2.41 (t, 2H), 2.30 (s, 6H).

ESI-Ms m/z: 499.3 [M+H].

Example 74 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1H-indol-7-yl)) -1,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, indole-7-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

1H-NMR (500MHz, DMSO-d6) δ: 2.25 (6H, s), 2.40 (2H, m), 2.74 (3H, s), 2.93 (2H, m), 3.86 (3H, s), 5.76-5.73 (1H, dd), 6.26-6.20 (1H, m), 6.49-6.40 (1H, m), 6.60 (1H, s), 7.06 (1H, s), 7.20-7.15 (1H, m), 7.86-7.83 (1H,m), 8.22 (1H, s), 8.34-8.32 (1H, m), 8.64 (1H, s), 8.75 (1H, s), 9.67 (1H, bs), 10.08 (1H, s), 11.83 (1H, s).

ESI-Ms m/z: 487.2 [M+H].

Example 75 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(quinolin-8-yl)-1) ,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, quinoline-8-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d6) δ: 2.22 (6H, s), 2.37 (2H, m), 2.69 (3H, s), 2.87 (2H, m), 3.79 (3H, s), 5.80- 5.73 (1H, dd), 6.25-6.22 (1H, m), 6.43-6.37 (1H, m), 7.02 (1H, s), 7.57 (1H, s), 7.69 (1H, s), 7.91-7.90 ( 1H,m), 8.12-8.10(1H,m),8.49-8.40(2H,m),8.71(1H,s),8.96(1H,s),9.32(1H,s),9.98(1H,s) .

ESI-Ms m/z: 499.2 [M+H].

Example 76 N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(quinolin-7-yl)-1) ,3,5-triazin-2-yl)amino)phenyl)acrylamide

4-fluoro-2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, quinoline-7-boronic acid, N,N,N'-trimethyl The title compound was obtained according to the procedure of Example 1 using ethylenediamine, allyl chloride and diisopropylethylamine as the starting material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 2.20 (6H, s), 2.35 (2H, m), 2.69 (3H, s), 2.87 (2H, m), 3.80 (3H, s), 5.79 -5.71(1H,dd), 6.25-6.22(1H,m),6.43-6.37(1H,m),7.02(1H,s),7.57(1H,s),7.70(1H,s),7.91-7.90 (1H, m), 8.11-8.09 (1H, m), 8.49-8.40 (2H, m), 8.73 (1H, s), 8.95 (1H, s), 9.32 (1H, s), 9.95 (1H, s ).

ESI-Ms m/z: 499.2 [M+H].

Comparative Example 1 N-(3-(((4-(3,4,5-trimethoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxy Phenyl)acrylamide

2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3,4,5-trimethoxyaniline, allyl chloride and diisopropyl The title compound was obtained in a similar manner to Example 1 using the amine as a material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.00 (s, 1H), 9.50 (s, 1H), 8.70 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 7.57 –7.54(d,1H),7.06–7.01(m,3H),6.44-6.35(m,1H),6.23-6.18(m,1H), 5.72-5.68(m,1H),3.75(s,3H) , 3.58 (s, 9H).

ESI-Ms m/z: 453.0 [M+H].

Comparative Example 2 N-(3-(((4-(3-methyl-4-methoxyphenyl)amino)-1,3,5-triazin-2-yl)amino)-4-methoxy Phenyl amide

2-methoxy-5-nitroaniline, 2,4-dichloro-1,3,5-triazine, 3-methyl-4-methoxyaniline, allyl chloride and diisopropyl The title compound was obtained in a similar manner to Example 1 using ethylamine as a material.

^{1 H-NMR (500MHz, DMSO} -d 6) δ: 10.02 (s, 1H), 9.46 (s, 1H), 8.64-8.61 (s, 1H), 8.23 (s, 1H), 7.89 (s, 1H) , 7.56–7.53 (d, 1H), 7.43-7.38 (m, 2H), 7.04-7.01 (d, 1H), 6.74-6.72 (s, 1H), 6.46-6.37 (m, 1H), 6.24-6.18 ( m, 1H), 5.72-5.69 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.02-1.98 (m, 3H).

ESI-Ms m/z: 407.2 [M+H].

Experimental Example 1 Evaluation of in vitro kinase activity

1 experimental material

1.1 enzyme

EGFR ^WT kinase, purchased from Carna Corporation;

EGFR ^T790M/L858R kinase was purchased from Invitrogen.

1.2 reagent

Adenosine triphosphate (ATP), purchased from Sigma;

Dimethyl sulfoxide (DMSO), purchased from Sigma;

Peptide (Peptide FAM-P22), purchased from GL Biochem;

Ethylenediaminetetraacetic acid (EDTA), purchased from Sigma

1.3 instruments

Caliper EZ reader microfluidic chip instrument, purchased from Caliper Life Sciences, Inc.

2 experimental methods

1) Prepare 1× Kinase Base Buffer and Stop Buffer

A.1×kinase base buffer (for EGFR ^WT )

50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl ₂ , 10 mM MnCl ₂ , 2 mM DTT.

B.1×kinase base buffer (for EGFR ^T790M/L858R )

50mM HEPES, pH7.5,0.0015% Brij-35,10mM MgCl 2, 2mM DTT.

C. Stop buffer

100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.

2) Preparing compounds

A. Compounds of the invention:

The compounds prepared according to the above examples were each dissolved to 10 mM with 100% DMSO. Diluted to 50 μM with complete medium, then diluted to 5 μM with complete medium containing 0.1% DMSO, and then diluted 3 times for a total of 10 concentrations (for EGFR ^WT );

The compounds prepared according to the above examples were each dissolved to 10 mM with 100% DMSO. Diluted to 50 μM with complete medium, then diluted to 1 μM with complete medium containing 0.1% DMSO, and then diluted 3 times for a total of 10 concentrations (for EGFR ^T790M/L858R );

B. Add 100 μl of 100% DMSO to the empty wells to prepare a no-kinase-free compound control group and a kinase-free compound control group;

The 96-well plate used for the label is the source plate.

C. Prepare the media board

10 μl of the compound was transferred from the source plate into a new 96-well plate as a media plate.

90 μl of 1×kinase buffer was added to each well of the media plate.

Shake well for 10 min.

3) Prepare the experiment board

A. Transfer 5 μl to 384-well plates per well from a 96-well media plate.

4) Kinase reaction

A. Prepare 2.5×kinase solution

The EGFR ^WT kinase and EGFR ^T790M/L858R kinase stock solutions were separately added to 1× basal buffer to prepare a 2.5×kinase solution.

B. Prepare a 2.5× peptide solution

The FAM-labeled peptide and ATP were added to 1 x basal buffer to prepare a 2.5 x peptide solution.

C. Transfer 10 μl of 2.5× kinase solution to a 384-well assay plate.

D. Incubate for 10 min at room temperature.

E. Transfer 10 μl of 2.5× peptide solution to a 384-well assay plate.

Simultaneously set a no-kinase-free compound control group (containing 2% DMSO, 1×basal buffer and 2.5× peptide solution and a kinase-free compound control group (including 2% DMSO, 2.5×kinase solution and 2.5× peptide solution) ).

F. Kinase reaction and termination

Incubate for a while at 28 °C.

The reaction was stopped by the addition of 25 μl of stop buffer.

5) Caliper instrument readings

Read the data on the Caliper instrument.

6) Fitting curve

A. Obtain each group of conversion data from the Caliper program;

B. Calculate the inhibition rate

Inhibition rate % = (max - com) / (max - min) × 100, wherein "max" represents a kinase-free compound control group, "min" represents a no-kinase-free compound control group, and "com" represents a test compound group.

C. ₅₀ values _are calculated using IC Graphpad 5.0 data processing software. The results are shown in Table 1.

Table 1

Note: "-" means not detected

These results indicate, the compounds of the present invention is a mutant EGFR kinase, e.g. mutant EGFR ^{T790M / L858R} kinases have good inhibitory activity, exhibits excellent selectivity for drug-resistant tumor is expected to be, especially for EGFR mutations lead to drug The tumor has a specific therapeutic effect.

Experimental Example 2 Evaluation of in vitro cell viability

1 experimental material

1.1 cells

Experimental cell line NCI-H1975 (EGFR double mutant cells with L858R and T790M mutations) and A431 (EGFR wild type cells), purchased from ATCC;

1.2 reagent

Cell Titer-Glo luminescent cell viability assay, purchased from Promega;

RPMI1640medium, purchased from Invitrogen;

DMEM medium, purchased from Invitrogen;

Fetal bovine serum, purchased from Invitrogen;

NCI-H1975 cells were cultured in RPMI1640 medium containing 10% inactivated fetal bovine serum (GIBCO), containing penicillin 100 IU/mL and streptomycin 100 μg/mL;

A431 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum (GIBCO) containing penicillin 100 IU/mL and streptomycin 100 μg/mL.

2 experimental methods

1) CTG assay

A. Digest the NCI-H1975 and A431 cells in the logarithmic growth phase, then blow them into a single cell suspension, inoculate them in a 96-well culture plate, 100 μL per well medium, and each of the three cell 96-well plates. Among them, NCI-H1975 cells were inoculated with ³ ×10 ³ cells per well, and A431 cells were inoculated with ⁴ ×10 ³ cells per well; B. 96-well plates were cultured in a 37-degree, 5% CO ₂ incubator for 16-24 hours, After the cells were attached, the test compound was added at the following concentration (the highest test concentration of the compound on NCI-H1975 cells was 4 μM, 3 fold dilution, a total of 9 concentrations; the highest test concentration on A431 cells was 10 μM, 3 times Dilution, a total of 9 concentrations),

C. Incubate for another 72 hours in an incubator;

D. Add 100 μL of CTG solution, shake it in the dark for 2 min, incubate for 10 min;

E. Put the plate in

Multi-mode microplate reader reading plate;

F. Record the luminescence reading results and calculate the inhibition rate according to the following formula:

Inhibition rate (%) = (1-(RLU _{com -} RLU _blank ) / (RLU _{DMSO -} RLU _blank )) × 100%,

RLUcom is the fluorescence value of the compound group, RLU _DMSO is the fluorescence value of the DMSO control group, and RLU _blank is the fluorescence value of the DMSO-free control group.

Using curve-fitting software XLFit pharmacodynamic inhibition curves plotted and _IC50 values calculated IC. The results are shown in Table 2.

Table 2

The above experimental results show that the compound of the present invention has a good inhibitory effect on EGFR mutant cells, and has better selectivity for mutant cells than EGFR wild type cells.

Experimental Example 3 Evaluation of in vitro IGF1R kinase and INSR kinase kinase activity

1 experimental material

1.1 enzyme

IGF1R kinase (insulin-like growth factor 1 receptor), purchased from Invitrogen;

INSR kinase (insulin receptor), purchased from Carna Corporation

1.2 reagent

Adenosine triphosphate (ATP), purchased from Sigma;

Dimethyl sulfoxide (DMSO), purchased from Sigma;

Peptide (Peptide FAM-P22), purchased from GL Biochem;

Peptide (Peptide FAM-P13), purchased from GL Biochem;

Ethylenediaminetetraacetic acid (EDTA), purchased from Sigma

2 experimental methods

1) Prepare 1× Kinase Base Buffer and Stop Buffer

A.1×kinase base buffer (for INSR)

50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl ₂ , 10 mM MnCl ₂ , 2 mM DTT.

B.1×kinase base buffer (for IGF1R)

50mM HEPES, pH7.5,0.0015% Brij-35,10mM MgCl 2, 2mM DTT.

C. Stop buffer

100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.

2) Preparing compounds

A. Compounds of the invention:

For the IGF1R kinase and INSR kinase assays, the compounds prepared according to the above examples of the invention were each dissolved to 10 mM with 100% DMSO. Dilute to 500 μM with complete medium, then dilute to 10 μM with complete medium containing 0.1% DMSO, and then serially dilute 3 times for a total of 10 concentrations;

B. Add 100 μl of 100% DMSO to the empty wells to prepare a no-kinase-free compound control group and a kinase-free compound control group;

The 96-well plate used for the label is the source plate.

C. Prepare the media board

10 μl of the compound was transferred from the source plate into a new 96-well plate as a media plate.

90 μl of 1×kinase buffer was added to each well of the media plate.

Shake well for 10 min.

3) Prepare the experiment board

A. Transfer 5 μl to 384-well plates per well from a 96-well media plate.

4) Kinase reaction

A. Prepare 2.5×kinase solution

The IGF1R kinase and INSR kinase stock solutions were separately added to 1× basal buffer to prepare a 2.5×kinase solution.

B. Prepare a 2.5× peptide solution

The FAM-labeled peptide (Peptide FAM-P22) and ATP were added to 1× base buffer to prepare a 2.5× peptide solution (for INSR);

The FAM-labeled peptide (Peptide FAM-P13) and ATP were added to 1 x basal buffer to prepare a 2.5 x peptide solution (for IGF1R).

C. Transfer 10 μl of 2.5× kinase solution to a 384-well assay plate.

D. Incubate for 10 min at room temperature.

E. Transfer 10 μl of 2.5× peptide solution to a 384-well assay plate.

Simultaneously set a no-kinase-free compound control group (containing 2% DMSO, 1×basal buffer and 2.5× peptide solution and a kinase-free compound control group (including 2% DMSO, 2.5×kinase solution and 2.5×min Acid solution).

F. Kinase reaction and termination

Incubate for a while at 28 °C.

The reaction was stopped by the addition of 25 μl of stop buffer.

5) Caliper instrument readings

Read the data on the Caliper instrument.

6) Fitting curve

A. Get the conversion data from the Caliper program.

B. Calculate the inhibition rate

Inhibition rate % = (max - com) / (max - min) x 100, wherein "max" represents a kinase-free compound control, "min" represents a no-kinase-free compound control, and "com" represents a test compound group.

C. IC ₅₀ values were calculated using Xlfit add 4.3.1 data processing software. The results are shown in Table 3.

table 3

It is known that EGFR inhibitors have strong inhibitory effects on IGF1R and INSR, which may cause side effects such as hyperglycemia and impaired insulin signaling. According to the experimental report, AstraZeneca's irreversible EGFR inhibitor AZD9291 has an IC _{50 of} about 2900 nM for IGF1R kinase (see Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form Of the Receptor, M. Raymond V. Finlay, et al. J Med Chem. 2014 Oct 23; 57(20): 8249-67). The above experimental results of the present invention indicate that the compounds of the present invention have a weak inhibitory effect on the kinases IGF1R and INSR, and the IC ₅₀ value is more than 5000 nM, and the effect on blood glucose is predicted to be weak and the safety is high. In addition, in vivo experiments have also shown that the compounds of the invention have no effect on blood glucose levels in mice.

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims (10)

1. A compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

   

   among them:

   X is selected from the group consisting of hydrogen, halogen, alkyl, amino and alkylamino;

   Each R _{1 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halo, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkane Alkyl acyl group, amino acyl group, alkyl acyl group, alkyl acylamino group, nitro group, cyano group, aryl group and heteroaryl group, wherein m is selected from 1, 2, 3 and 4, and when m is 2, each R ₁ The atoms to which they are attached may together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, which is optionally selected from an alkyl group, Substituted with one or more groups of haloalkyl, alkoxy, amino, hydroxy, halo and oxo;

   Each R _{2 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halo, amino, aminoalkyl, alkylamino, nitro and cyano, wherein n is selected from 1, 2 and 3;

   R _{3 is} selected from the group consisting of an amino group, an alkylamino group and a nitrogen-containing heterocycloalkyl group, and the amino group, the alkylamino group and the nitrogen-containing heterocycloalkyl group are optionally selected from the group consisting of an alkyl group, a halogenated alkyl group, an alkoxy group, an amino group and a hydroxyl group. Substituting one or more groups; and

   Q is selected from the group consisting of O and N(R ₄ ), wherein R _{4 is} selected from the group consisting of hydrogen and alkyl.
2. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   X is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, amino, C _1-6 alkylamino, and (C _1-6 alkyl)(C _1-6 alkyl)amino;

   Each R _{1 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _{1- 6} alkoxy, halogen, amino, amino-C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylamino C _1-6 alkyl, C _1-6 alkylamino acyl, amino Acyl, C _1-6 alkyl acyl, C _1-6 alkyl acylamino, nitro, cyano and phenyl, wherein m is selected from 1, 2, 3 and 4, and when m is 2, each R ₁ is The atoms to which they are attached may together form a C _3-6 cycloalkyl group, a C _3-6 heterocycloalkyl group, a phenyl group or a C _5-6 membered heteroaryl group, said C _3-6 cycloalkyl group, C _{3 - 6} Heterocycloalkyl, phenyl or C _5-6 membered heteroaryl optionally selected from C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, amino, hydroxy, Substituting one or more groups of halogen and oxo;

   Each R _{2 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _{1- 6} alkoxy, halogen, amino, amino C _1-6 alkyl, C _1-6 alkylamino, nitro and cyano, wherein n is selected from 1, 2 and 3;

   R _{3 is} selected from the group consisting of amino, C _1-6 alkylamino, (C _1-6 alkyl)(C _1-6 alkyl)amino, nitrogen-containing five-membered heterocycloalkyl, and nitrogen-containing six-membered heterocycloalkyl; with

   Q is selected from the group consisting of O and N(R ₄ ), wherein R _{4 is} selected from the group consisting of hydrogen and C _1-6 alkyl.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino, methylamino and dimethylamino.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   Each R _{1 is} independently selected from the group consisting of hydrogen, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, cycloheptyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyloxy, fluoro, chloro , bromine, iodine, amino, aminomethyl, aminoethyl, aminopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino, methylaminoacyl, dimethylaminoacyl , ethylamino acyl, diethylamino acyl, amino acyl, methyl acyl, ethyl acyl, methyl acylamino, ethyl acylamino, nitro, cyano and phenyl, wherein m is selected from 1, 2, 3 and 4. When m is 2, each of R ₁ and the atom to which they are bonded may together form a cyclopentyl group, a cyclohexyl group, a tetrahydropyrrolyl group, an oxolyl group, a dioxolyl group, an oxetanyl group, and two. Oxhexyl, phenyl, furyl, pyrazolyl, pyridyl or pyrrolyl, said cyclopentyl, cyclohexyl, tetrahydropyrrolyl, oxolyl, dioxa Cyclopentyl, oxetanyl, dioxolyl, phenyl, furyl, pyrazolyl, pyridyl or pyrrolyl are optionally selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro. Substituting one or more groups of chlorine, bromine and oxo.
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   Each R _{2 is} independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, and fluoro, wherein n is selected from 1, 2, and 3.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

   R _{3 is} selected from the group consisting of amino, methylamino, dimethylamino, tetrahydropyrrolyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, optionally selected from C _1-3 alkyl, halo C One or more groups of _1-3 alkyl, C _1-3 alkoxy, amino and hydroxy are substituted.
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Q is selected from the group consisting of O and N(R ₄ ), wherein R _{4 is} selected From hydrogen, methyl and ethyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound is selected from the group consisting of:

   

   

   

   

   

   
9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or the pharmaceutical composition of claim 9 for use in the treatment and/or Or the use in a drug for preventing tumors, preferably, the tumor is a drug resistant tumor, and more preferably, the tumor is a tumor resistant to an EGFR inhibitor.