CN105175349A - Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof - Google Patents

Phenyl substituted triazine compounds adopted as EGFR inhibitor, and applications thereof Download PDF

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Publication number
CN105175349A
CN105175349A CN201510317908.XA CN201510317908A CN105175349A CN 105175349 A CN105175349 A CN 105175349A CN 201510317908 A CN201510317908 A CN 201510317908A CN 105175349 A CN105175349 A CN 105175349A
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amino
alkyl
group
methyl
phenyl
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王勇
徐信
项仪宾
王小伟
张小猛
蔡建峰
廖文辉
黄丹丹
张仓
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a class of phenyl substituted triazine compounds having epidermal growth factor receptor inhibition effects, a pharmaceutical composition containing the compound, and uses of the compounds or the pharmaceutical composition as cancer treatment drugs. According to the present invention, the compounds have good inhibition activity on mutant EGFR kinase, exhibit excellent selectivity, and are expected to be the drugs providing specific treatment effects on drug resistance tumors, especially EGFR mutation-causing drug resistance tumors.

Description

The compound in triazine class replaced as the phenyl of EGFR inhibitor and application thereof
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to a class and there is compound in triazine class that the inhibiting phenyl of EGF-R ELISA replaces, pharmaceutical composition containing this compound, and described compound or pharmaceutical composition are as the purposes of cancer treatment drugs.
Background technology
EGF-R ELISA (EpidermalGrowthFactorReceptor, EGFR) is the expression product of proto-oncogene C-erbB-1, is one of EGFR family member.EGFR family comprises EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3) and ERBB4 (HER-4) four members.EGFR is divided into extracellular region, cross-film district and intracellular region 3 part, extracellular region is by the ligand binding domain of N-terminal 621 Amino acid profiles, when with ligand binding after, there is dimerization effect, there is crosslinked phosphorylation further in the acceptor of dimerization, activate the TK subprovince of intracellular region, cause change in a series of cell, finally make cell break up, breed and transform.
Cause the continuous activation etc. of EGFR after the enhancing that downstream signal can be caused to conduct when EGFR high expression level or unconventionality expression or sudden change, finally promote cell proliferation, intrusion, transfer, vasculogenesis etc., developing of cause cancer.EGFR-tyrosine kinase inhibitor (TKI) is adopted to treat the gold standard become in Treatment for Non-small Cell Lung field for EGFR.But, Clinical practice finds, the EGFR inhibitor such as Gefitinib, Tarceva mean treatment is after 10 months, and patient can produce resistance, and research display resistance is suddenlyd change relevant with MET oncogene with EGFR gene T790M, L858R.Meanwhile, first-generation EGFR inhibitor lacks the selectivity of Wild type EGFR and mutant egf R.
Therefore, the effective medicine of tumour patient, particularly exploitation developed producing resistance because of EGFR sudden change can improve further to Wild type EGFR and mutant egf R selectivity, heightens the effect of a treatment, reduces the medicine of side effect, will have a good application prospect.
Summary of the invention
What the object of this invention is to provide general formula I of the present invention has the inhibiting compound of EGF-R ELISA or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.
Another object of the present invention is to provide the method for the compound of preparing general formula I of the present invention or its isomer, pharmacologically acceptable salts, hydrate, solvate or crystallization.
Another object of the present invention is to provide the pharmaceutical composition of compound or its isomer, pharmacologically acceptable salts, hydrate, solvate or crystallization and the drug effect acceptable carrier comprising general formula I of the present invention and comprises the compound of general formula I of the present invention or the pharmaceutical composition of its isomer, pharmacologically acceptable salts, hydrate, solvate or crystallization and another kind of antiviral drug.
Also object of the present invention is to provide the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and treats and/or prevents the method for cancer and the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug for the preparation of the application treated and/or prevented in the medicine of cancer.
For foregoing invention object, the invention provides following technical scheme:
First aspect, the invention provides the compound shown in general formula I or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkylamino;
Each R 1independently selected from hydrogen, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, aminoalkyl group, alkylamino, alkylaminoalkyl group, alkylaminoacyl, aminoacyl, alkyl acyl, alkyl acylamino, nitro, cyano group, aryl and heteroaryl; wherein m is selected from 1,2,3 and 4; when m is 2, each R 1connected atom can form cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl together, and one or more groups that described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from alkyl, haloalkyl, alkoxyl group, amino, hydroxyl, halogen and oxo replace;
Each R 2independently selected from hydrogen, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, aminoalkyl group, alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3;
R 3be selected from amino, alkylamino and nitrogen heterocyclic ring alkyl, its one or more groups being optionally selected from alkyl, haloalkyl, alkoxyl group, amino and hydroxyl replace; With
Q is selected from O and N (R 4), wherein R 4be selected from hydrogen and alkyl.
In some preferred embodiments, X is selected from hydrogen, halogen, C 1-6alkyl, amino, C 1-6alkylamino and (C 1-6alkyl) (C 1-6alkyl) amino, further preferably, X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino, methylamino-and dimethylamino.
In some preferred embodiments, each R 1independently selected from hydrogen, phenyl, hydroxyl, carboxyl, C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, amino-C 1-6alkyl, C 1-6alkylamino, C 1-6alkylamino C 1-6alkyl, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 1-6alkyl acylamino, nitro and cyano group, wherein m is selected from 1,2,3 and 4, when m is 2, each R 1connected atom can form C together 3-6cycloalkyl, C 3-6heterocyclylalkyl, phenyl or C 5-6unit's heteroaryl, described C 3-6cycloalkyl, C 3-6heterocyclylalkyl, phenyl or C 5-6unit's heteroaryl is optionally selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6one or more groups of alkoxyl group, amino, hydroxyl, halogen and oxo replace;
Further preferably, each R 1independently selected from hydrogen, phenyl, hydroxyl, carboxyl, C 1-6alkyl, halo C 1-3alkyl, hydroxyl C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, halogen, amino, amino-C 1-3alkyl, C 1-3alkylamino, C 1-3alkylamino C 1-3alkyl, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 1-3alkyl acylamino, nitro and cyano group, wherein m is selected from 1,2,3 and 4, when m is 2, each R 1connected atom can form C together 3-6cycloalkyl, C 3-6oxacycloalkyl, phenyl or C 5-6unit's heteroaryl, described C 3-6cycloalkyl, C 3-6oxacycloalkyl, phenyl or C 5-6unit's heteroaryl is optionally selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6one or more groups of alkoxyl group, amino, hydroxyl, halogen and oxo replace.
In some specific embodiments, each R 1independently selected from hydrogen, phenyl, hydroxyl, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, trifluoromethyl, methylol, hydroxyethyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, trifluoromethyl oxygen base, fluorine, chlorine, bromine, iodine, amino, amino methyl, amino-ethyl, aminopropyl, methylamino-, ethylamino, third is amino, dimethylamino, diethylin, methylethylamine, methylamino-acyl group, dimethylamino acyl group, ethylamino acyl group, diethylin acyl group, aminoacyl, methylacyl, ethyl acyl group, methylacyl is amino, ethyl acyl amino, nitro and cyano group, wherein m is selected from 1, 2, 3 and 4, when m is 2, each R 1connected atom can form cyclopentyl together, cyclohexyl, Pyrrolidine base, oxocyclopentyl, dioxolyl (such as 1, 3-dioxy cyclopentyl), oxacyclohexyl or dioxacyclohexyl (such as 1, 4-dioxocyclohex base), phenyl, furyl, pyrazolyl, pyridyl or pyrryl, described cyclopentyl, cyclohexyl, Pyrrolidine base, oxocyclopentyl, dioxolyl, oxacyclohexyl, dioxacyclohexyl, phenyl, furyl, pyrazolyl, pyridyl or pyrryl are optionally selected from methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, one or more groups of bromine and oxo replace.
In some preferred embodiments, each R 2independently selected from hydrogen, hydroxyl, carboxyl, C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, amino C 1-6alkyl, C 1-6alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3;
Further preferably, each R 2independently selected from hydrogen, hydroxyl, carboxyl, C 1-3alkyl, halo C 1-3alkyl, hydroxyl C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, halogen, amino, amino C 1-3alkyl, C 1-3alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3.
In some specific embodiments, each R 2independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, wherein n is selected from 1,2 and 3.
In some preferred embodiments, R 3be selected from amino, C 1-6alkylamino, (C 1-6alkyl) (C 1-6alkyl) amino, nitrogenous five-membered ring alkyl and nitrogenous hexa-member heterocycle alkyl, it is optionally selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6one or more groups of alkoxyl group, amino, hydroxyl replace;
Further preferably, R 3be selected from amino, methylamino-, dimethylamino, Pyrrolidine base, piperidyl, piperazinyl, 4-methylpiperazine base, it is optionally selected from C 1-3alkyl, halo C 1-3alkyl, C 1-3one or more groups of alkoxyl group, amino and hydroxyl replace.
In some specific embodiments, R 3for dimethylamino.
In some preferred embodiments, Q is selected from O and N (R 4), wherein R 4be selected from hydrogen and C 1-6alkyl; Further preferably, R 4be selected from hydrogen and C 1-3alkyl; Still more preferably, R 4be selected from hydrogen, methyl and ethyl.
In some specific embodiments, Q is N (R 4), wherein R 4be selected from hydrogen and methyl.
In some specific embodiments, compound of the present invention is compound or its steric isomer, pharmacologically acceptable salts, hydrate, solvate or the crystallization of general formula I, wherein:
X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino, methylamino-and dimethylamino;
Each R 1independently selected from hydrogen, phenyl, hydroxyl, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, trifluoromethyl, methylol, hydroxyethyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, trifluoromethyl oxygen base, fluorine, chlorine, bromine, iodine, amino, amino methyl, amino-ethyl, aminopropyl, methylamino-, ethylamino, third is amino, dimethylamino, diethylin, methylethylamine, methylamino-acyl group, dimethylamino acyl group, ethylamino acyl group, diethylin acyl group, aminoacyl, methylacyl, ethyl acyl group, methylacyl is amino, ethyl acyl amino, nitro and cyano group, wherein m is selected from 1, 2, 3 and 4,
Each R 2independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, wherein n is selected from 1,2 and 3;
R 3for dimethylamino; With
Q is N (R 4), wherein R 4be selected from hydrogen and methyl.
In some specific embodiments, compound of the present invention is compound or its steric isomer, pharmacologically acceptable salts, hydrate, solvate or the crystallization of general formula I, wherein:
X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino, methylamino-and dimethylamino;
M is 2, two R 1connected atom can form cyclopentyl, cyclohexyl, Pyrrolidine base, 1 together, 3-dioxy cyclopentyl, 1,4-dioxocyclohex base, phenyl, furyl, pyrazolyl, pyridyl or pyrryl, described cyclopentyl, cyclohexyl, Pyrrolidine base, 1, one or more groups that 3-dioxy cyclopentyl, Isosorbide-5-Nitrae-dioxocyclohex base, phenyl, furyl, pyrazolyl, pyridyl or pyrryl is optionally selected from methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine and oxo replace;
Each R 2independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, wherein n is selected from 1,2 and 3;
R 3be selected from amino, methylamino-, dimethylamino, Pyrrolidine base, piperidyl, piperazinyl, 4-methylpiperazine base;
Q is N (R 4), wherein R 4be selected from hydrogen and methyl.
In a specific embodiment, the invention provides following compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug:
On the other hand, the invention provides the preparation method of the compound of general formula I of the present invention, comprise the steps:
Wherein:
The raw material of formula 1 and the raw material generation nucleophilic reaction of formula 2 obtain the intermediate of formula 3;
The intermediate of formula 3 and the raw material reaction of formula 4 obtain the intermediate of formula 5;
The intermediate of formula 5 and the raw material reaction of formula 6 obtain the intermediate of formula 7;
The intermediate of formula 7 obtains the intermediate of formula 8 through nitro-reduction reaction;
The intermediate of formula 8 and acryloyl chloride react the compound of obtained general formula I;
Above-mentioned X, R 1, R 2, m, n, Q, R 3there is the definition in general formula I.
The third aspect, the invention provides pharmaceutical composition, and it comprises compound of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.
In some embodiments, the invention provides pharmaceutical composition, it comprises compound of the present invention, isomer, solvate, crystallization or prodrug, also comprises one or more compounds being selected from following composition: how Gefitinib, Tarceva, lapatinibditosylate, Ah method replace Buddhist nun (dacomitinib), training profit for Buddhist nun (pelitinib), WZ4002, AG-490, AZD8931 etc. for Buddhist nun, Ah handkerchief for Buddhist nun, Dacca for Buddhist nun, ZD6474, card.
Compound of the present invention, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, thinner or mixed with excipients can be prepared into pharmaceutical preparation, to be suitable for per os or parenteral admin.Medication includes, but are not limited to intracutaneous, intramuscular, intraperitoneal, intravenously, subcutaneous, nose interior and peroral route.Described preparation can be used by any approach, such as, by infusion or inject, is used by the approach absorbed through epithelium or mucocutaneous (such as oral mucosa or rectum etc.).Administration can be whole body or local.The example of oral administration preparation comprises solid or liquid dosage form, specifically, comprises tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspensoid etc.Described preparation is prepared by methods known in the art, and comprises conventional carrier, thinner or the vehicle used of field of pharmaceutical preparations.
Fourth aspect, the invention provides the method for compound of the present invention, isomer, solvate, crystallization or prodrug or medicine composite for curing of the present invention and/or prophylaxis of tumours and preparing the application treated and/or prevented in tumour medicine, comprise and easily send out the pharmaceutical composition that crowd or tumour patient use compound of the present invention, isomer, solvate, crystallization or prodrug or comprise compound of the present invention, isomer, solvate, crystallization or prodrug, effectively to reduce Tumor incidence, to extend tumour patient life to tumour.
In some embodiments, the invention provides the method that the compound of general formula I of the present invention, isomer, solvate, crystallization or prodrug or medicine composite for curing of the present invention have drug-fast tumour, comprise to the compound of the present invention with drug-fast tumour patient administering therapeutic significant quantity, isomer, solvate, crystallization or prodrug or the pharmaceutical composition comprising compound of the present invention, isomer, solvate, crystallization or prodrug.In other embodiments, the invention provides the compound of general formula I of the present invention, isomer, solvate, crystallization or prodrug or pharmaceutical composition of the present invention and treat the application had in the medicine of drug-fast tumour in preparation.It is described that to have drug-fast tumour can be have drug-fast tumour to multi-medicament, preferably to EGFR inhibitor, there is drug-fast tumour, such as to first, second, third generation EGFR inhibitor, such as to Gefitinib, Tarceva and lapatinibditosylate, there is drug-fast tumour.Described tumour includes but not limited to solid tumor, is preferably lung cancer, tumor of head and neck, colorectal cancer, bladder cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, cancer of the stomach, oral carcinoma, liver cancer, ovarian cancer.More preferably, described tumour is nonsmall-cell lung cancer.In some embodiments, the invention provides the method that the compound of general formula I of the present invention, isomer, solvate, crystallization or prodrug treatment have drug-fast tumour, wherein said tumour carries EGFR mutator gene.In one embodiment, the EGFR mutator gene that described tumour is carried is that the 20th exon exists T790M sudden change.In another embodiment, the EGFR mutator gene that described tumour is carried is that the 21st exon exists L858R sudden change and/or disappearance/insertion mutation.In another embodiment, the EGFR mutator gene that described tumour is carried is T790M and L858R double mutations.In other embodiments, the invention provides the compound of the general formula I of the present invention being used for the treatment of tumour, isomer, solvate, crystallization or prodrug or pharmaceutical composition of the present invention, wherein treat function of tumor and show outstanding curative effect, the selectivity of height and/or less side effect.In some embodiments again, the invention provides the method for the compound of general formula I of the present invention, isomer, solvate, crystallization or prodrug or medicine composite for curing tumour of the present invention, described method comprises the compound of the general formula I of the present invention of the bacterium needing it, isomer, solvate, crystallization or prodrug or pharmaceutical composition of the present invention, the effect of the treatment tumour aspect produced shows outstanding curative effect, the selectivity of height and/or less side effect.
Term definition
Unless otherwise defined, all technology used herein and scientific terminology have the identical implication usually understood with those skilled in the art.
" isomer " of the present invention comprises compound along configuration structure body, conformer and enantiomer.Configurational isomer refers to the cis-trans-isomer of cis or transconfiguration.Conformer refers to because singly-bound rotates the steric isomer produced.
" pharmacologically acceptable salts " of the present invention refers to the pharmacy acceptable salt that compound of the present invention is formed with acid, and described acid can be selected from: phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, tosic acid, oxysuccinic acid, methanesulfonic etc.
" solvate " of the present invention refer to solute (as active compound of the present invention, as described in the salt of active compound) and the mixture that is combined to form of solvent (as water).Solvent refers to solvent that is known to those of skill in the art or that easily determine.If water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc.
" crystallization " of the present invention refers to the various solid form of compound formation of the present invention, comprises crystal formation, amorphous.
" prodrug " of the present invention refers under the physiological condition of organism, change into the compound of compound of the present invention owing to reacting with enzyme, hydrochloric acid in gastric juice etc., namely change into the compound of compound of the present invention by the oxidation, reduction, hydrolysis etc. of enzyme and/or changed into the compound of compound of the present invention by the hydrolysis reaction etc. of hydrochloric acid in gastric juice etc.
" pharmaceutical composition " of the present invention refers to and comprises any one compound as herein described, comprises the protection form of isomer, prodrug, solvate, pharmacy acceptable salt or its chemistry, and the mixture of one or more pharmaceutically acceptable carriers.
" for the preparation of the application treated and/or prevented in the medicine of tumour " of the present invention refer to can the growth of Tumor suppression, development and/or transfer, mainly to required human or animal to controlling the compound of the present invention that gives treatment effective dose to suppress, to slow down or to reverse the growth of curee's tumour, development or expanding.
" alkyl " of the present invention refers to the saturated hydrocarbyl of straight chain, side chain or ring-type, the alkyl preferably below 12 carbon atoms, the alkyl more preferably below 6 carbon atoms.The embodiment of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, cyclobutyl, n-pentyl, isopentyl, neo-pentyl, cyclohexyl, n-hexyl, isohexyl, 2,2,-methyl butyl and 2,3-dimethylbutyl." C of the present invention 1-6alkyl " refer to the saturated hydrocarbyl of straight chain, side chain or ring-type containing 1-6 carbon atom." C of the present invention 1-3alkyl " refer to the saturated hydrocarbyl of straight chain, side chain or ring-type containing 1-3 carbon atom.This term comprises substituted or unsubstituted alkyl, and described alkyl can be optionally selected from following group replace by one or more: alkyl, alkoxyl group, aryloxy, alkylamino, arylamino, halogen, hydroxyl, amino, nitro, cyano group, alkyl acyl, aminoacyl, alkylamino acyl group, alkylsulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl.
" alkoxyl group " of the present invention refers to-O-alkyl.
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine.
" haloalkyl " of the present invention refers at least by the alkyl of a halogen atom replacement.
" halogenated alkoxy " of the present invention refers at least by the alkoxyl group of a halogen substiuted, is preferably at least by the C of a halogen substiuted 1-6alkoxyl group, more preferably halo C 1-3alkoxyl group, suitable halo C 1-3alkoxyl group is chlorine methoxyl group, fluorine methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy; Two chloroethoxies, difluoroethoxy, tri-chloroethoxy base, trifluoro ethoxy.
" alkylamino " of the present invention refers to the amino replaced by alkyl, comprises alkyl monosubstituted amino, two alkylamino.
" aminoalkyl group " of the present invention refers to the alkyl replaced by amino.
" alkylaminoalkyl group " of the present invention refers to the alkyl replaced by alkylamino.
" alkylaminoacyl " of the present invention refer to alkylamino-C (O)-.
" alkyl acylamino " of the present invention refer to alkyl-C (O)-amino-.
" cycloalkyl " of the present invention refers to the alkyl of ring-type, includes but not limited to cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl.
" Heterocyclylalkyl " of the present invention refers to the alkyl at least containing a heteroatomic ring-type, and described heteroatoms is selected from N, O and S." nitrogen heterocyclic ring alkyl " of the present invention refers to the alkyl of the ring-type at least containing an atom N." oxacycloalkyl " of the present invention refers to the alkyl of the ring-type at least containing an O atom.
" aryl " of the present invention refers to phenyl, xenyl or naphthyl, preferred phenyl.This term comprises replacement and unsubstituted group.Described aryl can be optionally selected from following group replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, aryloxy, halogen, haloalkyl, halogenated alkoxy, hydroxyl, nitro, amino, single alkylamino, two alkylamino, arylamino, alkyl acyl, aminoacyl, alkylamino acyl group, amido ,-CN, aryl or heteroaryl.
" heteroaryl " of the present invention refers to the heteroatomic 3-10 unit heteroaromatic ring system being selected from N, O and S containing 1-4, preferred C 3-7unit's heteroaromatic ring system, as thiophene, pyridine, imidazoles, furans, pyrroles, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazoles ， oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole etc., suitable hetero-aromatic ring includes but not limited to thiophene, pyridine, imidazoles.This term comprises replacement and unsubstituted group.Described hetero-aromatic ring can be optionally selected from following group replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, aryloxy, halogen, haloalkyl, halogenated alkoxy, hydroxyl, nitro, amino, single alkylamino, two alkylamino, arylamino, alkyl acyl, aminoacyl, alkylamino acyl group, amido ,-CN, aryl or heteroaryl.
Embodiment
Representational embodiment is to better the present invention is described below, but not for limiting the scope of the invention.
Embodiment 1N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(3-(1-methylcarbamoylphenyl))-1; 3,5-triazine-2-is amino) phenyl) acrylamide
The synthesis of the chloro-N-of step 1:4-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-1,3,5-triazines-2-amine
In 100ml reaction flask, add 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline (4.0g, 21.5mmol) and DIPEA (8.32g, 64.5mmol) successively, dissolve with 60ml tetrahydrofuran (THF), be cooled to 0-2 DEG C, add 2,4-bis-chloro-1 in batches, 3,5-triazine (3.14g, 21.08mmol), finish, reaction 5h, stopped reaction, add 60ml water, stir, filter, filter cake washes with water, and dry title compound, is directly used in next step.
The synthesis of step 2:N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-3-(1-N-Methyl-benzoyl)-1,3,5-triazines-2-amine
In 30ml microwave reaction bottle, add 3-(N-methyl formyl ammonia) phenyl-boron dihydroxide (900mg successively, 5.03mmol), the chloro-N-of step 1 gains 4-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-1,3,5-triazine-2-amine (1.50g, 5.03mmol), tetra-triphenylphosphine palladium (231mg, 0.04eq) with cesium carbonate (4.9g, 15mmol), with Isosorbide-5-Nitrae-dioxane/H 2o (8ml/1ml) dissolves, argon replaces, 110 DEG C of microwave reaction 45min, and concentrated, column chromatography purification obtains title compound.
Step 3:3-(4-((4-((2-(dimethylamino) ethyl (methyl) is amino)-2-methoxyl group-5-nitrophenyl) is amino)-1,3,5-triazine-2-base) synthesis of-N-methyl-benzamide
Step 2 gains N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-3-(1-N-Methyl-benzoyl)-1 is added successively in 50ml single port bottle; 3,5-triazine-2-amine (230mg, 0.58mmol), N; N; N '-trimethylammonium quadrol (117.0mg, 1.16mmol) and DIPEA (224mg, 1.74mmol); dissolve with 10ml dioxane; 110 DEG C of back flow reaction 3h, concentrated, column chromatography purification obtains title compound.
Step 4:3-(4-((4-((2-(dimethylamino) ethyl (methyl) is amino)-2-methoxyl group-5-aminophenyl) is amino)-1,3,5-triazine-2-base) synthesis of-N-methyl-benzamide
Step 3 gains 3-(4-((4-((2-(dimethylamino) ethyl (methyl) is amino)-2-methoxyl group-5-nitrophenyl) is amino)-1 is added successively in 50ml single port bottle, 3,5-triazine-2-base)-N-methyl-benzamide (146mg, 0.30mmol), 10%Pd-C (15mg, 0.1eq) with 10ml methyl alcohol, 1 standard atmosphere pressure, H 2reduction 1h, filters, obtains title compound.
Step 5:N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(3-(1-methylcarbamoylphenyl))-1; 3,5-triazine-2-is amino) phenyl) synthesis of acrylamide:
In 50ml single port bottle, add step 4 gains 3-(4-((4-((2-(dimethylamino) ethyl (methyl) is amino)-2-methoxyl group-5-aminophenyl) is amino)-1,3,5-triazine-2-base)-N-methyl-benzamide (98mg, 0.22mmol) with diisopropylethylamine (71.0mg, 0.55mmol), dissolve with 15ml anhydrous methylene chloride, instillation allyl group acyl chlorides (22mg, methylene dichloride (1ml) solution 0.24mmol), reaction 10min, concentrated, column chromatography purification obtains title compound.
1H-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-Msm/z:505.3[M+H]。
Embodiment 2N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(3,4-(methylenedioxy) phenyl))-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,4-(methylenedioxy) borate ester, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:492.3[M+H]。
Embodiment 3N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4-p-methoxy-phenyl)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyphenylboronic acid ester, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:478.3[M+H]。
Embodiment 4N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-Carbamoylphenyl)-1; 3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-formamyl borate ester, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:491.4[M+H]。
Embodiment 5N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2,3-dihydrobenzo [1,4] dioxin-6-bases)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, phendioxin-6-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:506.3[M+H]。
Embodiment 6N-(2-((2-(4-methylpiperazine-1-yl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4-p-methoxy-phenyl)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyphenylboronic acid, N-methyl-2-(4-methylpiperazine-1-yl) ethamine, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:533.4[M+H]。
Embodiment 7N-(2-((2-(piperidin-1-yl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2,3-dihydrobenzo [1,4] dioxin-6-bases)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, phendioxin, 4-dioxane-6-boric acid, N-methyl-2-(piperidin-1-yl) ethamine, allyl group acyl chlorides are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:546.5[M+H]。
Embodiment 8N-(2-((2-(piperidin-1-yl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4-p-methoxy-phenyl)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyphenylboronic acid, N-methyl-2-(piperidin-1-yl) ethamine, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1. 1H-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-Msm/z:518.4[M+H]。
Embodiment 9N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(the fluoro-3-aminomethyl phenyl of 4-)-1,3,5-triazine-2-base is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-methyl-4-fluorobenzoic boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:480.4[M+H]。
Embodiment 10N-(2-((2-(piperidin-1-yl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2,3-bihydrogen-1-indenone-5-base)-1,3,5-triazine-2-is amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the bromo-1-indone of 5-, N-methyl-2-(piperidin-1-yl) ethamine, allyl group acyl chlorides for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:541.64[M+H]。
Embodiment 11N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-methyl-5-tert-butyl-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the 3-tertiary butyl-5-methyl-phenylo boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:518.3[M+H]。
Embodiment 12N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2,2-bis-fluoro-1, luxuriant-5-base disliked by 3-benzo two)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3, luxuriant, N disliked by bromo-2,2-bis-fluoro-1, the 3-benzos two of 5-triazine, 5-, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
1H-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-Msm/z:528.0[M+H]。
Embodiment 13N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-fluoro-4,5-Dimethoxyphenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3, fluoro-4, the 5-dimethoxyphenylboronic of 5-triazine, 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:526.1[M+H]。
Embodiment 14N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3, the fluoro-4-p-methoxy-phenyl of 5-bis-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, bromo-2, the 6-difluoroanisoles of 4-, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:514.3[M+H]。
Embodiment 15N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-4-aminomethyl phenyl of 3-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-4-methylphenylboronic acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:496.4[M+H]。
Embodiment 16N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-4 – fluorophenyls of 3-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-4-fluorobenzoic boric acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:500.2[M+H]。
Embodiment 17N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3,4 – Dimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,4-dimethoxyphenylboronic, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:508.2[M+H]。
Embodiment 18N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4 – xenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-biphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:524.2[M+H]。
Embodiment 19N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3,4 – 3,5-dimethylphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,4-dimethylphenyl boronic acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:476.2[M+H]。
Embodiment 20N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3,4,5 – trimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,4,5-trimethoxy phenylo boric acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:538.0[M+H]。
Embodiment 21N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the fluoro-4 – aminomethyl phenyls of 3-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the fluoro-4-methylphenylboronic acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:480.0[M+H]。
Embodiment 22N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2-chloro-3,4,5 – trimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3, chloro-3,4, the 5-trimethoxy phenylo boric acids of 5-triazine, 2-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
1H-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-Msm/z:571.9[M+H]。
Embodiment 23N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-methoxyphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:478.3[M+H]。
Embodiment 24N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(4 – p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyphenylboronic acid, N, N ,-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:465.2[M+H]。
Embodiment 25N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – methyl-5-chloro-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-5-methylphenylboronic acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:496.2[M+H]。
Embodiment 26N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-phenyl of the fluoro-5-of 3 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-5-fluorobenzoic boric acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:500.2[M+H]。
Embodiment 27N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(the chloro-phenyl of the fluoro-5-of 3 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-5-fluorobenzoic boric acid of 3-, N, N ,-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:487.2[M+H]。
Embodiment 28N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-phenyl of 3 – trifluoromethyl-5-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-5-trifluoromethylbenzene boronic acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:550.2[M+H]。
Embodiment 29N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-aminomethyl phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-methylphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:462.3[M+H]。
Embodiment 30N-(2-((2-(1-pyrrolidyl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – (N; N-formyl-dimethylamino) phenyl)-1; 3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2; 4-bis-chloro-1; 3; 5-triazine, 3-(N; N-dimethylamino formyl radical) phenylo boric acid, N-methyl-(2-pyrrolidin-1-yl-ethyl)-amine, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
1H-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-Msm/z:545.4[M+H]。
Embodiment 31N-(2-((2-(1-pyrrolidyl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4 – p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 4-methoxyphenylboronic acid, N-methyl-(2-pyrrolidin-1-yl-ethyl)-amine, allyl group acyl chlorides and diisopropylethylamine is raw material, obtains title compound according to the method for embodiment 1.
1H-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-Msm/z:504.3[M+H]。
Embodiment 32N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – (N; N-formyl-dimethylamino) phenyl)-1; 3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3; 5-triazine, 3-(N, N-dimethylamino formyl radical) phenylo boric acid, N, N; N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:519.4[M+H]。
Embodiment 33N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – (N, N-dimethylamino) phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-(N, N dimethylamine base) phenylo boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:491.2[M+H]。
Embodiment 34N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methyl-5-((4-(3,4-Dimethoxyphenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methyl-5-nitro aniline, 2,4-bis-chloro-1,3,5-triazines, 3,4-dimethoxyphenylboronic, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:492.3[M+H]。
Embodiment 35N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methyl-5-((4-(3,4,5 – trimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methyl-5-nitro aniline, 2,4-bis-chloro-1,3,5-triazines, 3,4,5-trimethoxy phenylo boric acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:522.0[M+H]。
Embodiment 36N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-phenyl-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, phenylo boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:447.5[M+H]。
Embodiment 37N-(2-((2-(1-pyrrolidyl) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-phenyl-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, phenylo boric acid, N-methyl-2-(pyrrolidin-1-yl) ethamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:474[M+H]。
Embodiment 38N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – Trifluoromethoxyphen-l)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-trifluoromethoxy phenylo boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:532.3[M+H]。
Embodiment 39N-(2-((2-(1-pyrrolidyl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – Trifluoromethoxyphen-l)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-trifluoromethoxy phenylo boric acid, N-methyl-2-(pyrrolidin-1-yl) ethamine, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:558.3[M+H]。
Embodiment 40N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – methyl-4-p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyl group-3-methylphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:492.5[M+H]。
Embodiment 41N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-4-trifluoromethyl of 3 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3, the chloro-4-trifluoromethyl phenyl boronic acid of 5-triazine, 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
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-Msm/z:550.2[M+H]。
Embodiment 42N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-5-trifluoromethyl of 2 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-5-trifluoromethylbenzene boronic acid of 2-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:550.2[M+H]。
Embodiment 43N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(the chloro-4-trifluoromethyl of 3 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the chloro-4-trifluoromethyl phenyl boronic acid of 3-, N, N-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:537.2[M+H]。
Embodiment 44N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(3 – methyl-4-p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 4-methoxyl group-3-methylphenylboronic acid, N, N-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:479.2[M+H]。
Embodiment 45N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2,5 – Dimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 2,5-dimethoxyphenylboronic, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:508.2[M+H]。
Embodiment 46N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(2,5 – Dimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 2,5-dimethoxyphenylboronic, N, N-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:495.2[M+H]。
Embodiment 47N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3,5 – Dimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,5-dimethoxyphenylboronic, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:508.2[M+H]。
Embodiment 48N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(3,5 – Dimethoxyphenyls)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,5-dimethoxyphenylboronic, N, N-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:495.2[M+H]。
Embodiment 49N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-methoxyl group-4 – fluorophenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the fluoro-3-methoxyphenylboronic acid of 4-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:496.0[M+H]。
Embodiment 50N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-sec.-propyl-4 – p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-sec.-propyl-4-methoxyphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
1H-NMR(500MHz,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-Msm/z:520.1[M+H]。
Embodiment 51N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-4 – methoxyl group-5-aminomethyl phenyls of 3-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-chlorine 4-methoxyl group-5-methylphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
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-Msm/z:526.3[M+H]。
Embodiment 52N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-5 – p-methoxy-phenyls of 3-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-chloro-5-methoxyl phenyl-boron dihydroxide, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:512.2[M+H]。
Embodiment 53N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the fluoro-4-p-methoxy-phenyl of 3 –)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, the fluoro-4-methoxyphenylboronic acid of 3-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:496.2[M+H]。
Embodiment 54N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2 – chloro-4-methoxy phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 2-chloro-4-methoxy phenylo boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:512.2[M+H]。
Embodiment 55N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(4 – chloro-3,5-Dimethoxyphenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3, chloro-3, the 5-dimethoxyphenylboronic of 5-triazine, 4-, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:543.2[M+H]。
Embodiment 56N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-4-methyl of 3 –-5-p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-chloro-4-methyl-5 methoxyphenylboronic acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine be raw material, obtains title compound according to the method for embodiment 1.
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-Msm/z:527.2[M+H]。
Embodiment 57N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – chloro-4,5-Dimethoxyphenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, chloro-4, the 5-dimethoxyphenylboronic of 3-, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:542.3[M+H]。
Embodiment 58N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3 – chloro-4-methoxy phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-chloro-4-methoxy phenylo boric acid, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:512.3[M+H]。
Embodiment 59N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-thieno-[2 of 3-, 3-B] pyridyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, thieno-[2,3-B] pyridine-3-boric acid, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:505.3[M+H]。
Embodiment 60N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(benzo [b] thiene-3-yl-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, thionaphthene-3-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:504.1[M+H]。
Embodiment 61N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3, the chloro-4-p-methoxy-phenyl of 5 – bis-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,5-bis-chloro-4-methoxyphenylboronic acids, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:546.0[M+H]。
Embodiment 62N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-methoxyl group-4-cyclopropyl phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-methoxyl group-4-cyclopropyl-phenyl boric acid, N, N, N ,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:518.2[M+H]。
Embodiment 63N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(3-trifluoromethyl-4-p-methoxy-phenyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazine, 3-trifluoromethyl-4-methoxyphenylboronic acid, N, N, N,-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine are raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:546.2[M+H]。
Embodiment 64N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(benzo [b] furans-5-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, cumarone-5-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:488.3[M+H]。
Embodiment 65N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1-methyl-benzo [d] pyrazoles-6-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 1-methylindazole-6-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:502.2[M+H]。
Embodiment 66N-(2-((2-(methoxyl group) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1-methyl-benzo [d] pyrazoles-6-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 1-methylindazole-6-boric acid, N-methyl-2-methoxyethyl amine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:489.2[M+H]。
Embodiment 67N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(1-methyl-benzo [d] pyrazoles-6-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 1-methylindazole-6-boric acid, N, N-dimethylethanolamine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:489.2[M+H]。
Embodiment 68N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(isoquinoline 99.9-6-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 6-isoquinoline 99.9 boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:499.4[M+H]。
Embodiment 69N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methyl-5-((4-(quinoline-5-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, quinoline-5-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:483.3[M+H]。
Embodiment 70N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(2 – naphthyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 2-naphthalene boronic acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:498.4[M+H]。
Embodiment 71N-(2-((2-(dimethylamino) ethyl) oxygen base)-4-methoxyl group-5-((4-(2 – naphthyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 2-naphthalene boronic acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:485.3[M+H]。
Embodiment 72N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(7-methoxyl group-2 – naphthyl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 7-methoxyl group-2-naphthalene boronic acids, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:528.2[M+H]。
Embodiment 73N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(quinoline-6-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, quinoline-6-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:499.3[M+H]。
Embodiment 74N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1H-indoles-7-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, indoles-7-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
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-Msm/z:487.2[M+H]。
Embodiment 75N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(quinoline-8-yl)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, quinoline-8-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:499.2[M+H]。
Embodiment 76N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(quinoline-7-base)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, quinoline-7-boric acid, N, N, N '-trimethylammonium quadrol, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method for embodiment 1.
1H-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-Msm/z:499.2[M+H]。
Comparative example 1N-(3-(((4-(3,4,5 – trimethoxyphenyl) is amino)-1,3,5-triazines-2-base) is amino)-4-p-methoxy-phenyl) acrylamide
With 2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3,4,5-trimethoxy-anilines, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method being similar to embodiment 1.
1H-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-Msm/z:453.0[M+H]。
Comparative example 2N-(3-(((4-(3-methyl-4 – p-methoxy-phenyl) is amino)-1,3,5-triazines-2-base) is amino)-4-p-methoxy-phenyl) acrylamide
With 2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-methyl-4-anisidine, allyl group acyl chlorides and diisopropylethylamine for raw material, obtain title compound according to the method being similar to embodiment 1.
1H-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-Msm/z:407.2[M+H]。
The evaluation of experimental example 1 vitro kinase activity
1 experiment material
1.1 enzyme
EGFR wTkinases, is purchased from Carna company;
EGFR t790M/L858Rkinases, is purchased from Invitrogen company.
1.2 reagent
Triphosaden (ATP), is purchased from Sigma company;
Dimethyl sulfoxide (DMSO) (Dimethylsulfoxide, DMSO), is purchased from Sigma company;
Peptide (PeptideFAM-P22), is purchased from GLBiochem company;
Ethylenediamine tetraacetic acid (EDTA) (EDTA), is purchased from Sigma company
1.3 instrument
CaliperEZreader micro-fluidic chip instrument, is purchased from CaliperLifeSciences, Inc.
2 experimental techniques
1) 1 × kinases basis buffer and stop buffer is prepared
A.1 × kinases basis buffer is (for EGFR wT)
50mMHEPES，pH7.5，0.0015％Brij-35，10mMMgCl 2，10mMMnCl 2，2mMDTT。
B.1 × kinases basis buffer is (for EGFR t790M/L858R)
50mMHEPES，pH7.5，0.0015％Brij-35，10mMMgCl 2，2mMDTT。
C. stop buffer
100mMHEPES，pH7.5，0.0015％Brij-35，0.2％CoatingReagent#3，50mMEDTA。
2) compound is prepared
A. compound of the present invention:
With 100%DMSO, the compound prepared according to above embodiment is dissolved to 10mM respectively.Be diluted to 50 μMs with perfect medium, after being then diluted to 5 μMs with the perfect medium containing 0.1%DMSO, 3 times of dilutions successively, totally 10 concentration are (for EGFR wT);
With 100%DMSO, the compound prepared according to above embodiment is dissolved to 10mM respectively.Be diluted to 50 μMs with perfect medium, after being then diluted to 1 μM with the perfect medium containing 0.1%DMSO, 3 times of dilutions successively, totally 10 concentration are (for EGFR t790M/L858R);
B. in the hole of sky, 100 μ l100%DMSO are added for preparing without kinases without compound control group and have kinases without compound control group;
Mark 96 orifice plates used for carrying out source plate.
C. medium plate is prepared
Always shift 10 μ l compounds in source plate in 96 new orifice plates, as medium plate.
90 μ l1 × kinase buffer liquid are added in the every hole of medium plate.
Vibration mixing 10min.
3) preparing experiment plate
A. from 96 hole medium plates, every hole transferase 45 μ l is in 384 orifice plates.
4) kinase reaction
A. 2.5 × kinase solution is prepared
By EGFR wTkinases and EGFR t790M/L858Rkinases stoste adds in 1 × basis buffer respectively, is mixed with 2.5 × kinase solution.
B. 2.5 × peptide solution is prepared
The peptide mark FAM and ATP are added in 1 × basis buffer, are mixed with 2.5 × peptide solution.
C. 10 μ l2.5 × kinase solution are shifted in 384 hole brassboards.
D. incubated at room 10min.
E. 10 μ l2.5 × peptide solution are shifted in 384 hole brassboards.
Arrange simultaneously and without compound control group without kinases (comprise 2%DMSO, 1 × basis buffer and 2.5 × peptide solution and have kinases without compound control group (comprising 2%DMSO, 2.5 × kinase solution and 2.5 × peptide solution).
F. kinase reaction and termination
For some time is hatched under 28 DEG C of conditions.
Add 25 μ l stop buffer termination reactions.
5) Caliper instrument readings
Reading of data on Caliper instrument.
6) matched curve
A. from Caliper program, each group of conversion data are obtained;
B. inhibiting rate is calculated
Inhibiting rate %=(max-com)/(max-min) × 100, wherein " max " representative has kinases without compound control group, and " min " represents without kinases without compound control group, and " com " represents test-compound group.
C. Graphpad5.0 data processing software is adopted to calculate IC 50value.The results are shown in Table 1.
Table 1
Note: "-" expression does not detect
Above experimental result shows, compound of the present invention such as, to mutant egf R kinases, mutant egf R t790M/L858Rkinases has good inhibit activities, shows excellent selectivity, and being expected to becomes antagonism property of medicine tumour, especially causes the tumour of resistance to have the medicine of special curative effect to EGFR sudden change.
Experimental example 2 cell in vitro activity rating
1 experiment material
1.1 cell
Experiment cell strain NCI-H1975 (the two mutant cell of EGFR, has L858R and T790M sudden change)
With A431 (EGFR wild-type cell), purchased from ATCC;
1.2 reagent
CellTiter-Gloluminescentcellviabilityassay, purchased from Promega company;
RPMI1640medium, purchased from Invitrogen company;
DMEMmedium, purchased from Invitrogen company;
Foetal calf serum, purchased from Invitrogen company;
NCI-H1975 cell cultures is in the RPMI1640 training of the foetal calf serum (GIBCO) containing 10% deactivation
Support in base, containing penicillin 100IU/mL and Streptomycin sulphate 100 μ g/mL;
A431 cell cultures in containing 10% deactivation foetal calf serum (GIBCO) DMEM substratum in,
Containing penicillin 100IU/mL and Streptomycin sulphate 100 μ g/mL.
2 experimental techniques
1) CTG assay method
A. after NCI-H1975 and the A431 cell of logarithmic phase being digested respectively, blow and beat into single cell suspension, be inoculated in 96 well culture plates, every hole substratum 100 μ L, various 3 piece of 96 orifice plate of each cell strain, wherein NCI-H1975 cell per well inoculation 3X10 3individual cell, A431 cell per well inoculation 4X10 3individual cell; B. by 96 orifice plates at 37 degree, 5%CO 2cultivate 16-24 hour in incubator, after cell attachment, (the highest test concentrations of compound on NCI-H1975 cell is 4 μMs, 3 times of dilutions, totally 9 concentration to add test-compound by following concentration requirement; The highest test concentrations on A431 cell is 10 μMs, 3 times of dilutions, totally 9 concentration),
C. in incubator, 72 hours are cultivated again;
D. add the CTG solution of 100 μ L, lucifuge vibration 2min, hatches 10min;
E. culture plate is put into multi-mode microwell plate detector reads plate;
F. record fluorescence (luminescence) and read value result, by following formulae discovery inhibiting rate:
Inhibiting rate (%)=(1-(RLU com-RLU blank)/(RLU dMSO– RLU blank)) × 100%,
Wherein RLUcom is the fluorescent value of compound group, RLU dMSOfor the fluorescent value of DMSO control group, RLU blankfor the fluorescent value without DMSO control group.
XLFit curve fitting software is utilized to draw drug effect inhibiting rate curve and calculate IC 50value.The results are shown in Table 2.
Table 2
Above experimental result shows, compound of the present invention is good to the restraining effect of EGFR mutant cell, relative to EGFR wild-type cell, has good selectivity to mutant cell.
The external IGF1R kinases of experimental example 3 and INSR kinase activity are evaluated
1 experiment material
1.1 enzyme
IGF1R kinases (type-1 insulin like growth factor acceptor), is purchased from Invitrogen company;
INSR kinases (insulin receptor), is purchased from Carna company
1.2 reagent
Triphosaden (ATP), is purchased from Sigma company;
Dimethyl sulfoxide (DMSO) (Dimethylsulfoxide, DMSO), is purchased from Sigma company;
Peptide (PeptideFAM-P22), is purchased from GLBiochem company;
Peptide (PeptideFAM-P13), is purchased from GLBiochem company;
Ethylenediamine tetraacetic acid (EDTA) (EDTA), is purchased from Sigma company
2 experimental techniques
1) 1 × kinases basis buffer and stop buffer is prepared
A.1 × kinases basis buffer (for INSR)
50mMHEPES，pH7.5，0.0015％Brij-35，10mMMgCl 2，10mMMnCl 2，2mMDTT。
B.1 × kinases basis buffer (for IGF1R)
50mMHEPES，pH7.5，0.0015％Brij-35，10mMMgCl 2，2mMDTT。
C. stop buffer
100mMHEPES，pH7.5，0.0015％Brij-35，0.2％CoatingReagent#3，50mMEDTA。
2) compound is prepared
A. compound of the present invention:
For IGF1R kinases and INSR kinase assays, with 100%DMSO, the compound prepared according to the above embodiment of the present invention is dissolved to 10mM respectively.500 μMs are diluted to, then with containing 0.1% with perfect medium
After the perfect medium of DMSO is diluted to 10 μMs, 3 times of dilutions, totally 10 concentration successively;
B. in the hole of sky, 100 μ l100%DMSO are added for preparing without kinases without compound control group and have kinases without compound control group;
Mark 96 orifice plates used for carrying out source plate.
C. medium plate is prepared
Always shift 10 μ l compounds in source plate in 96 new orifice plates, as medium plate.
90 μ l1 × kinase buffer liquid are added in the every hole of medium plate.
Vibration mixing 10min.
3) preparing experiment plate
A. from 96 hole medium plates, every hole transferase 45 μ l is in 384 orifice plates.
4) kinase reaction
A. 2.5 × kinase solution is prepared
IGF1R kinases and INSR kinases stoste are added in 1 × basis buffer respectively, is mixed with 2.5 × kinase solution.
B. 2.5 × peptide solution is prepared
The peptide (PeptideFAM-P22) mark FAM and ATP are added in 1 × basis buffer, are mixed with 2.5 × peptide solution (for INSR);
The peptide (PeptideFAM-P13) mark FAM and ATP are added in 1 × basis buffer, are mixed with 2.5 × peptide solution (for IGF1R).
C. 10 μ l2.5 × kinase solution are shifted in 384 hole brassboards.
D. incubated at room 10min.
E. 10 μ l2.5 × peptide solution are shifted in 384 hole brassboards.
Arrange simultaneously and without compound control group without kinases (comprise 2%DMSO, 1 × basis buffer and 2.5 × peptide solution and have kinases without compound control group (comprising 2%DMSO, 2.5 × kinase solution and 2.5 × peptide solution).
F. kinase reaction and termination
For some time is hatched under 28 DEG C of conditions.
Add 25 μ l stop buffer termination reactions.
5) Caliper instrument readings
Reading of data on Caliper instrument.
6) matched curve
A. from Caliper program, conversion data are obtained.
B. inhibiting rate is calculated
Inhibiting rate %=(max-com)/(max-min) × 100, wherein " max " representative has kinases without compound control, and " min " represents without kinases without compound control, and " com " represents test-compound group.
C. Xlfitadd4.3.1 data processing software is adopted to calculate IC 50value.The results are shown in Table 3.
Table 3
Known EGFR inhibitor is strong to the restraining effect of IGF1R and INSR, may cause in side effects such as height blood sugar and impaired insulin signal transduction.Experimentally report, the non-reversibility EGFR inhibitor AZD9291 of Astrazeneca AB is to the kinase whose IC of IGF1R 50be about 2900nM (see DiscoveryofaPotentandSelectiveEGFRInhibitor (AZD9291) ofBothSensitizingandT790MResistanceMutationsThatSparesth eWildTypeFormoftheReceptor, M.RaymondV.Finlay, etal.JMedChem.2014Oct23; 57 (20): 8249-67).Above experimental result of the present invention shows, the restraining effect of compound of the present invention to kinases IGF1R and INSR is more weak, IC 50be worth much in 5000nM, predict that it is more weak to blood sugar influence, security is higher.In addition, experiments in vivo also shows, compound of the present invention on mouse blood sugar level without impact.
Although be below described in detail the present invention, it will be appreciated by those skilled in the art that and can carry out various amendment and change to the present invention under prerequisite without departing from the spirit and scope of the present invention.Interest field of the present invention is not limited to done detailed description above, and should belong to claims.

Claims (10)

1. the compound shown in general formula I or its pharmacologically acceptable salts, isomer, solvate, crystallization or a prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkylamino;
Each R 1independently selected from hydrogen, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, aminoalkyl group, alkylamino, alkylaminoalkyl group, alkylaminoacyl, aminoacyl, alkyl acyl, alkyl acylamino, nitro, cyano group, aryl and heteroaryl; wherein m is selected from 1,2,3 and 4; when m is 2, each R 1the atom connected with them can together with form cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, one or more groups that described cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are optionally selected from alkyl, haloalkyl, alkoxyl group, amino, hydroxyl, halogen and oxo replace;
Each R 2independently selected from hydrogen, hydroxyl, carboxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, aminoalkyl group, alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3;
R 3be selected from amino, alkylamino and nitrogen heterocyclic ring alkyl, one or more groups that described amino, alkylamino and nitrogen heterocyclic ring alkyl are optionally selected from alkyl, haloalkyl, alkoxyl group, amino and hydroxyl replace; With
Q is selected from O and N (R 4), wherein R 4be selected from hydrogen and alkyl.
2. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
X is selected from hydrogen, halogen, C 1-6alkyl, amino, C 1-6alkylamino and (C 1-6alkyl) (C 1-6alkyl) amino;
Each R 1independently selected from hydrogen, hydroxyl, carboxyl, C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, amino-C 1-6alkyl, C 1-6alkylamino, C 1-6alkylamino C 1-6alkyl, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 1-6alkyl acylamino, nitro, cyano group and phenyl, wherein m is selected from 1,2,3 and 4, when m is 2, each R 1the atom connected with them can together with form C 3-6cycloalkyl, C 3-6heterocyclylalkyl, phenyl or C 5-6unit's heteroaryl, described C 3-6cycloalkyl, C 3-6heterocyclylalkyl, phenyl or C 5-6unit's heteroaryl is optionally selected from C 1-6alkyl, halo C 1-6alkyl, C 1-6one or more groups of alkoxyl group, amino, hydroxyl, halogen and oxo replace;
Each R 2independently selected from hydrogen, hydroxyl, carboxyl, C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, amino C 1-6alkyl, C 1-6alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3;
R 3be selected from amino, C 1-6alkylamino, (C 1-6alkyl) (C 1-6alkyl) amino, nitrogenous five-membered ring alkyl and nitrogenous hexa-member heterocycle alkyl; With
Q is selected from O and N (R 4), wherein R 4be selected from hydrogen and C 1-6alkyl.
3. compound according to claim 1 and 2 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino, methylamino-and dimethylamino.
4. the compound according to any one of claims 1 to 3 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
Each R 1independently selected from hydrogen, hydroxyl, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, trifluoromethyl, methylol, hydroxyethyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, trifluoromethyl oxygen base, fluorine, chlorine, bromine, iodine, amino, amino methyl, amino-ethyl, aminopropyl, methylamino-, ethylamino, third is amino, dimethylamino, diethylin, methylethylamine, methylamino-acyl group, dimethylamino acyl group, ethylamino acyl group, diethylin acyl group, aminoacyl, methylacyl, ethyl acyl group, methylacyl is amino, ethyl acyl amino, nitro, cyano group and phenyl, wherein m is selected from 1, 2, 3 and 4, when m is 2, each R 1the atom connected with them can together with form cyclopentyl, cyclohexyl, Pyrrolidine base, oxocyclopentyl, dioxolyl, oxacyclohexyl, dioxacyclohexyl, phenyl, furyl, pyrazolyl, pyridyl or pyrryl, one or more groups that described cyclopentyl, cyclohexyl, Pyrrolidine base, oxocyclopentyl, dioxolyl, oxacyclohexyl, dioxacyclohexyl, phenyl, furyl, pyrazolyl, pyridyl or pyrryl are optionally selected from methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine and oxo replace.
5. the compound according to any one of Claims 1-4 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
Each R 2independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, trifluoromethyl, methoxyl group, oxyethyl group and fluorine, wherein n is selected from 1,2 and 3.
6. the compound according to any one of claim 1 to 5 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
R 3be selected from amino, methylamino-, dimethylamino, Pyrrolidine base, piperidyl, piperazinyl, 4-methylpiperazine base, it is optionally selected from C 1-3alkyl, halo C 1-3alkyl, C 1-3one or more groups of alkoxyl group, amino and hydroxyl replace.
7. the compound according to any one of claim 1 to 6 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein Q is selected from O and N (R 4), wherein R 4be selected from hydrogen, methyl and ethyl.
8. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein said compound is selected from following compound:
9. a pharmaceutical composition, it comprises compound described in any one of claim 1 to 8 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
10. the compound described in any one of claim 1-8 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug or pharmaceutical composition according to claim 9 are for the preparation of the application treated and/or prevented in the medicine of tumour, preferably, described tumour is for having drug-fast tumour, more preferably, described tumour is for have drug-fast tumour to EGFR inhibitor.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106132957A (en) * 2015-08-31 2016-11-16 无锡双良生物科技有限公司 2 aryl amine pyridines, pyrimidine or pyrrolotriazine derivatives and its production and use
CN106928200A (en) * 2015-12-30 2017-07-07 湖南福沃药业有限公司 For the pyrrolotriazine derivatives for the treatment of cancer
WO2018210246A1 (en) * 2017-05-15 2018-11-22 朱程刚 Triazine compound and pharmaceutically acceptable salt thereof
CN110256367A (en) * 2019-06-26 2019-09-20 中国药科大学 1,3,5-triazines class compound or its pharmaceutical salt and its preparation method and application
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CN114026090A (en) * 2019-07-04 2022-02-08 微境生物医药科技(上海)有限公司 Compound for inhibiting EGFR kinase and preparation method and application thereof
JP2022529616A (en) * 2019-03-29 2022-06-23 深▲せん▼福沃薬業有限公司 Nitrogen-containing aromatic heterocyclic amide derivative for treating cancer

Families Citing this family (6)

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Publication number Priority date Publication date Assignee Title
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083653A1 (en) * 2001-04-11 2002-10-24 Amgen Inc. Triazinyl acrylamide derivatives as kinase inhibitors
WO2011103196A1 (en) * 2010-02-17 2011-08-25 Amgen Inc. Aryl carboxamide derivatives as sodium channel inhibitors for treatment of pain
CN102448462A (en) * 2009-04-20 2012-05-09 阿维拉制药公司 Heteroaryl compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083653A1 (en) * 2001-04-11 2002-10-24 Amgen Inc. Triazinyl acrylamide derivatives as kinase inhibitors
CN102448462A (en) * 2009-04-20 2012-05-09 阿维拉制药公司 Heteroaryl compounds and uses thereof
WO2011103196A1 (en) * 2010-02-17 2011-08-25 Amgen Inc. Aryl carboxamide derivatives as sodium channel inhibitors for treatment of pain

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* Cited by examiner, † Cited by third party
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WO2017035753A1 (en) * 2015-08-31 2017-03-09 无锡双良生物科技有限公司 2-arylamino pyridine, pyridine or triazine derivative, preparation method and use thereof
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CN108864079A (en) * 2017-05-15 2018-11-23 深圳福沃药业有限公司 A kind of triaizine compounds and its pharmaceutically acceptable salt
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