CN105272967A - Triazine epidermal growth factor acceptor inhibitor and application thereof - Google Patents

Triazine epidermal growth factor acceptor inhibitor and application thereof Download PDF

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CN105272967A
CN105272967A CN201510320533.2A CN201510320533A CN105272967A CN 105272967 A CN105272967 A CN 105272967A CN 201510320533 A CN201510320533 A CN 201510320533A CN 105272967 A CN105272967 A CN 105272967A
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alkyl
group
amino
base
benzo
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CN105272967B (en
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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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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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

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Abstract

The invention relates to a triazine epidermal growth factor acceptor inhibitor and application thereof. The invention relates to the technical field of medicine and chemistry, and more concretely relates to a kind of compound having epidermal growth factor acceptor inhibition effect, pharmaceutical composition including the compound, and application of the compound and the pharmaceutical composition as medicines for treating cancers. The triazine epidermal growth factor acceptor inhibitor of the invention has good inhibition effect on a mutant type EGFR kinase, expresses an excellent selectivity, and is likely to be a cancer medicine with special therapeutic effect for medicine-resistant tumors, especially medicine-resistant tumors arising from EGFR mutation.

Description

Triazines epidermal growth factor receptor inhibitor and application thereof
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to a class and there is the inhibiting compound of EGF-R ELISA, 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 has the inhibiting compound of EGF-R ELISA or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkylamino;
Y is selected from key ,-C 1-C 6alkylidene group-, NH ,-C 1-C 6alkylidene group-NH-,-NH-C 1-C 6alkylidene group-,-C (O) NH-,-NHC (O)-,-NHC (O) NH-, O, S, S (O) and S (O) 2;
R 1be selected from aryl and heterocyclic radical, described aryl and heterocyclyl are by one or more alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl is amino, aryl, heterocyclic radical, nitro and cyano group replace, wherein, cycloalkyl or Heterocyclylalkyl is formed together with the atom that 2 adjacent substituting groups can connect with them, described cycloalkyl or Heterocyclylalkyl are optionally selected from alkyl further, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, one or more groups of halogen replace,
Each R 2independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl amino, nitro and cyano group, wherein n is selected from 1,2,3 and 4;
Q is selected from N, O, S ,-C 1-C 6alkylidene-,-C 1-C 6alkylidene-N-,-NH-C 1-C 6alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-; With
R a, R bseparately be selected from hydrogen, alkyl, alkylamino, thiazolinyl, amino, alkylaminoalkyl group, cycloalkyl ,-alkyl-cycloalkyl, aryl ,-alkyl-aryl-group, heterocyclic radical ,-alkyl-heterocyclyl groups; described alkyl, cycloalkyl, alkyl-cycloalkyl, aryl and heterocyclyl are replaced by one or more halogen, alkyl, thiazolinyl, amino, alkylamino, haloalkyl, alkyl acyl, alkylaminoacyl, aminoacyl, alkenylacyl, cycloalkyl, cycloalkenyl group and heterocyclic radical; wherein when Q be selected from O, S and-NHC (O)-time, R bdo not exist; Or
R a, R bconnected Q forms heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl together, and described heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl are optionally replaced by one or more halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, cycloalkyl, cycloalkenyl group and heterocyclic radical.
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;
Y is selected from key ,-C 1-C 6alkylidene group-, NH ,-C 1-C 6alkylidene group-NH-,-NH-C 1-C 6alkylidene group-,-C (O) NH-,-NHC (O)-,-NHC (O) NH-, O, S, S (O) and S (O) 2;
R 1be selected from aryl and heterocyclic radical, described aryl and heterocyclyl are by one or more alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl is amino, aryl, heterocyclic radical, nitro and cyano group replace, cycloalkyl or Heterocyclylalkyl is formed together with the atom that 2 wherein adjacent substituting groups can connect with them, described cycloalkyl or Heterocyclylalkyl are optionally selected from alkyl further, haloalkyl, alkoxyl group, halogenated alkoxy, one or more groups of oxo and halogen replace,
Each R 2independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl amino, nitro and cyano group, wherein n is selected from 1,2,3 and 4;
Q is selected from N, O, S ,-C 1-C 6alkylidene-,-C 1-C 6alkylidene-N-,-NH-C 1-C 6alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-; With
R a, R bseparately be selected from hydrogen, alkyl, alkylamino, thiazolinyl, amino, alkylaminoalkyl group, cycloalkyl ,-alkyl-cycloalkyl, aryl ,-alkyl-aryl-group, heterocyclic radical ,-alkyl-heterocyclyl groups; described alkyl, cycloalkyl, alkyl-cycloalkyl, aryl and heterocyclyl are replaced by one or more halogen, alkyl, thiazolinyl, amino, alkylamino, haloalkyl, alkyl acyl, alkylaminoacyl, aminoacyl, alkenylacyl, cycloalkyl, cycloalkenyl group and heterocyclic radical; wherein when Q be selected from O, S and-NHC (O)-time, R bdo not exist; Or
R a, R bconnected Q forms heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl together, and described heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl are optionally replaced by one or more halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, cycloalkyl, cycloalkenyl group and heterocyclic radical.
In some preferred embodiments, X is selected from hydrogen, halogen, C 1-6alkyl and amino, further preferably, X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino.
In some preferred embodiments, Y is selected from key ,-C 1-C 3alkylidene group-, NH ,-C 1-C 3alkylidene group-NH-,-NH-C 1-C 3alkylidene group-,-C (O) NH-,-NHC (O)-and-NHC (O) NH-, more preferably, Y is selected from key, CH 2, NH and O.
In some embodiments, Y is selected from key and NH.In some embodiments, Y is key.
In some preferred embodiments, R 1be selected from monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocyclic radical, tricyclic condensed heterocyclic radical, described monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocyclic radical, tricyclic condensed heterocyclyl are by one or more C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, oxo, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, aryl, C 3-8heterocyclic radical, nitro, cyano group replace, and form C together with the atom that 2 wherein adjacent substituting groups can connect with them 3-6cycloalkyl or C 3-6heterocyclylalkyl, described C 3-6cycloalkyl or C 3-6heterocyclylalkyl is optionally selected from one or more groups replacements of alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, halogen further.
In some preferred embodiments, R 1be selected from monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, bicyclic heteroaryl, Bicyclic-fused heteroaryl and tricyclic condensed heteroaryl, described monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, bicyclic heteroaryl, Bicyclic-fused heteroaryl and tricyclic condensed heteroaryl are optionally by one or more C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, oxo, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, aryl, C 3-8heterocyclic radical, nitro, cyano group replace, and wherein, form C together with the atom that 2 adjacent substituting groups can connect with them 3-6cycloalkyl or C 3-6heterocyclylalkyl, described C 3-6cycloalkyl or C 3-6heterocyclylalkyl can further by C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, oxo, halogen substiuted.In other preferred embodiments, R 1be selected from phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, triazol radical, oxazolyl, isoxazolyl, indyl, pseudoindoyl, benzo ring thiazolinyl, benzo oxaheterocyclenyl groups, benzo dioxane thiazolinyl, benzo-aza cycloalkenyl group, benzodiazepine heterocycloalkenyl, benzimidazole thiophanate heterocycloalkenyl, benzo dithia cycloalkenyl group, benzo oxygen thia cycloalkenyl group, benzo oxaza thiazolinyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzothienyl, purine radicals, acridyl, carbazyl, chromene ketone group, quinoxalinyl, benzoxazolyl, described phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, triazol radical, oxazolyl, isoxazolyl, indyl, pseudoindoyl, benzo ring thiazolinyl, benzo oxaheterocyclenyl groups, benzo dioxane thiazolinyl, benzo-aza cycloalkenyl group, benzodiazepine heterocycloalkenyl, benzimidazole thiophanate heterocycloalkenyl, benzo dithia cycloalkenyl group, benzo oxygen thia cycloalkenyl group, benzo oxaza thiazolinyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzothienyl, purine radicals, acridyl, carbazyl, chromene ketone group, quinoxalinyl, benzoxazolyl is optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace.Such as, in some specific embodiments, R 1be selected from benzocyclobutane thiazolinyl, benzo ring pentenyl, benzo ring hexenyl, benzocyclohepta thiazolinyl, benzo oxole base, benzo oxinyl, benzo oxepane thiazolinyl, benzodioxole base, Ben Bing oxane, benzodioxepins base, benzodiazepine cycloheptenyl, benzimidazole thiophanate heterocycle amyl group, benzimidazole thiophanate heterocycle hexenyl, benzothiepines base, benzo dithia cyclopentyl, benzo dithia cyclohexenyl, benzo dithia cycloheptenyl, benzo oxygen thia cyclopentenyl, benzo oxathiene base, benzo oxygen thia cycloheptenyl, benzo oxaza heptenyl, wherein these groups are optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, nitro, cyano group replace.In some specific embodiments, R 1be selected from phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzo [d] [1, 3] dioxa cyclopentenyl, pyrazolo [1, 5-a] pyridine, 1, 4-Ben Bing oxane, described phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzo [d] [1, 3] dioxa cyclopentenyl, pyrazolo [1, 5-a] pyridine, 1, 4-Ben Bing oxane is optionally by one or more methyl, ethyl, propyl group, trifluoromethyl, methoxyl group, oxyethyl group, propoxy-, oxo, fluorine, chlorine, amino, methylamino-, ethylamino, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, methylacyl is amino, ethyl acyl amino, vinyl acyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace.
In other preferred embodiments, R 1be selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl, described phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl are optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1 is formed together with the atom that 2 wherein adjacent substituting groups can connect with them, 3-dioxolanes base or 1,4-dioxocyclohex alkyl, described cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1,3-dioxolanes base and Isosorbide-5-Nitrae-dioxocyclohex alkyl are optionally selected from C further 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6one or more groups of alkoxyl group, oxo, halogen replace.
In some preferred embodiments, each R 2independently selected from hydrogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, nitro, cyano group, wherein n is selected from 1,2,3 and 4; Further preferably, each R 2independently selected from hydrogen, C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, nitro, cyano group, wherein n is selected from 1,2 and 3.
In some embodiments, each R 2independently selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, methylacyl amino, ethyl acyl amino, vinyl acyl amino, nitro, cyano group, wherein n is selected from 1,2 and 3.
In some specific embodiments, each R 2in must have one for vinyl acyl amino, all the other each R 2be selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, nitro, cyano group, wherein n is selected from 2 and 3.
In some specific embodiments, each R 2in must have one for vinyl acyl amino, and with adjacent, all the other each R 2be selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, nitro, cyano group, wherein n is selected from 2 and 3.
In some preferred embodiments, Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-6alkyl, C 1-6alkylamino, C 2-6alkenyl, amino, C 1-6alkylamino C 1-6alkyl, C 3-8cycloalkyl ,-C 1-6alkyl-C 3-8cycloalkyl, aryl ,-C 1-6alkyl-aryl-group, C 3-10heterocyclic radical ,-C 1-6alkyl-C 3-10heterocyclic radical, described C 1-6alkyl, C 2-6alkenyl, C 3-8cycloalkyl ,-C 1-6alkyl-C 3-8cycloalkyl, aryl, C 3-10heterocyclic radical ,-C 1-6alkyl-C 3-10heterocyclyl is by one or more halogen, C 1-6alkyl, C 2-6alkenyl, amino, C 1-6alkylamino, halo C 1-6alkyl, C 1-6alkyl acyl, C 1-6alkylaminoacyl, aminoacyl, C 2-6alkenylacyl, C 3-8cycloalkyl, C 3-8cycloalkenyl group, C 3-8heterocyclic radical replaces, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist; Or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N or CH form quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclic radical together, described quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclyl be by one or more halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 3-8cycloalkyl, C 3-8cycloalkenyl group, C 3-8heterocyclic radical replaces.In some embodiments, Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-3alkyl, C 1-3alkylamino, C 2-4alkenyl, amino, C 1-3alkylamino C 1-3alkyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl ,-C 1-3alkyl-aryl-group, C 3-6heterocyclic radical ,-C 1-3alkyl-C 3-6heterocyclic radical, described C 1-3alkyl, C 2-4alkenyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl, C 3-6heterocyclic radical ,-C 1-3alkyl-C 3-6heterocyclyl is by one or more halogen, C 1-3alkyl, C 2-4alkenyl, amino, C 1-3alkylamino, halo C 1-3alkyl, C 1-3alkyl acyl, C 1-3alkylaminoacyl, aminoacyl, C 2-3alkenylacyl, C 3-6cycloalkyl, C 3-6cycloalkenyl group, C 3-6heterocyclic radical replaces, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist; Or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N or CH form quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclic radical together, described quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclyl be by one or more halogen, C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-3alkenylacyl, C 1-3alkyl acylamino, C 3-6cycloalkyl, C 3-6cycloalkenyl group, C 3-6heterocyclic radical replaces.
In some embodiments, Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-3alkyl, C 1-3alkylamino, C 2-4alkenyl, amino, C 1-3alkylamino C 1-3alkyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl ,-C 1-3alkyl-aryl-group, C 4-8azacycloalkyl, C 4-8diazacyclo alkyl ,-C 1-3alkyl-C 4-8azacycloalkyl ,-C 1-3alkyl-C 4-8diazacyclo alkyl, C 4-8nitrogen heterocyclic thiazolinyl, C 4-8diazacyclo thiazolinyl ,-C 1-3alkyl-C 4-8nitrogen heterocyclic thiazolinyl ,-C 1-3alkyl-C 4-8diazacyclo thiazolinyl, described C 1-3alkyl, C 2-4alkenyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl, C 4-8azacycloalkyl, C 4-8diazacyclo alkyl ,-C 1-3alkyl-C 4-8azacycloalkyl ,-C 1-3alkyl-C 4-8diazacyclo alkyl, C 4-8nitrogen heterocyclic thiazolinyl, C 4-8diazacyclo thiazolinyl ,-C 1-3alkyl-C 4-8nitrogen heterocyclic thiazolinyl ,-C 1-3alkyl-C 4-8diazacyclo thiazolinyl is optionally by one or more halogen, C 1-3alkyl, C 2-4alkenyl, amino, C 1-3alkylamino, halo C 1-3alkyl, C 1-3alkyl acyl, C 1-3alkylaminoacyl, aminoacyl, C 2-3alkenylacyl, C 3-6cycloalkyl, C 3-6heterocyclic radical replaces, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist; Or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N or CH form quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, azacycloalkyl, nitrogen heterocyclic thiazolinyl, diazacyclo alkyl or diazacyclo thiazolinyl together, described quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, azacycloalkyl, nitrogen heterocyclic thiazolinyl, diazacyclo alkyl or diazacyclo thiazolinyl be optionally by one or more halogen, C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-3alkenylacyl, C 1-3alkyl acylamino, C 3-6cycloalkyl, C 3-6cycloalkenyl group, C 3-6heterocyclic radical replaces.
In some preferred embodiments, Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-6alkyl, piperazinyl, piperidyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base, described C 1-6alkyl, piperazinyl, piperidyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base is optionally by one or more halogen, amino, C 1-6alkyl, C 1-6alkylamino, halo C 1-6alkyl, C 1-6alkyl acyl, C 1-6alkylaminoacyl, aminoacyl, C 2-6alkenylacyl, piperazinyl, N-alkylpiperazinyl replace, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist; Or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N forms piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine or R together a, R bconnected CH forms pyrazole ring together, and described piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine, pyrazole ring are optionally by one or more halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, heterocyclic radical replace;
In other embodiments, Q is selected from N, O, CH, R a, R bseparately be selected from hydrogen, C 1-6alkyl, piperazinyl, piperidyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base, described C 1-6alkyl, piperazinyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base is optionally by one or more halogen, amino, C 1-3alkyl, C 1-3alkylamino, halo C 1-3alkyl, C 1-3alkyl acyl, C 1-3alkylaminoacyl, aminoacyl, C 2-4alkenylacyl, piperazinyl, N-alkylpiperazinyl replace, wherein when Q is selected from O, and R bdo not exist; Or
Q is selected from N and CH, R a, R bconnected atom N forms piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine or R together a, R bconnected CH forms pyrazole ring together, and described piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine, pyrazole ring are optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, piperazinyl, N-alkylpiperazinyl replace.
In other specific embodiments, Q is selected from N and O, R abe selected from-C 1-3alkylamino ,-C 1-3alkylamino C 1-3alkyl ,-C 1-3alkylamino (C 1-3alkyl) (C 1-3alkyl) ,-C 1-3alkyl oxy C 1-3alkyl ,-C 1-3alkyl-C 4-8azacycloalkyl ,-C 1-3alkyl-C 4-8diazacyclo alkyl, R bbe selected from hydrogen, C 1-6alkyl, wherein when Q is selected from O, R bdo not exist.
In other specific embodiments, Q is selected from N and O, R abe selected from-ethyleneimino ,-ethylidene-methylamino-,-ethylidene-dimethylamino ,-ethylenemethoxy ,-ethylidene oxyethyl group ,-ethylidene Pyrrolidine base ,-ethylidene piperidyl ,-ethylidene piperazinyl ,-ethylidene methylpiperazine base, R bbe selected from hydrogen, C 1-6alkyl, wherein when Q is selected from O, R bdo not exist.
According to the present invention, in some preferred embodiments, compound of the present invention is compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino;
Y is key;
R 1be selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl, described phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl are optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace, wherein, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1 is formed together with the atom that 2 adjacent substituting groups can connect with them, 3-dioxolanes base or 1,4-dioxocyclohex alkyl, described cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1,3-dioxolanes base or Isosorbide-5-Nitrae-dioxocyclohex alkyl are optionally selected from C further 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6one or more groups of alkoxyl group, oxo and halogen replace,
Each R 2in must have one for vinyl acyl amino, and with adjacent, all the other each R 2be selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, nitro, cyano group, wherein n is selected from 2 and 3;
Q is selected from N and O, R abe selected from-ethyleneimino ,-ethylidene-methylamino-,-ethylidene-dimethylamino ,-ethylenemethoxy ,-ethylidene oxyethyl group ,-ethylidene Pyrrolidine base ,-ethylidene piperidyl ,-ethylidene piperazinyl ,-ethylidene methylpiperazine base, R bbe selected from hydrogen, C 1-6alkyl, wherein when Q is selected from O, R bdo not exist.
In some preferred embodiments, the invention provides compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein said general formula I is general formula I a,
Wherein:
X is selected from hydrogen, halogen, C 1-6alkyl and amino;
R 1be selected from aryl and heteroaryl, described aryl and heteroaryl are optionally by one or more C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, oxo, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, nitro, cyano group replace, and wherein, 2 adjacent substituting groups can form C by connected atom together 3-6cycloalkyl or C 3-6heterocyclylalkyl, described C 3-6cycloalkyl or C 3-6heterocyclylalkyl is optionally selected from C further 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6one or more groups of alkoxyl group, oxo and halogen replace;
Each R 2independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, alkylamino, nitro and cyano group, wherein n is selected from 1,2 and 3;
Q is selected from N and O, R abe selected from-C 1-6alkylamino ,-C 1-6alkylamino C 1-6alkyl ,-C 1-6alkylamino (C 1-6alkyl) (C 1-6alkyl) ,-C 1-6alkyl oxy C 1-6alkyl ,-C 1-6alkyl C 3-8heterocyclylalkyl, R bbe selected from hydrogen, C 1-6alkyl, wherein when Q is selected from O, R bdo not exist.
In some preferred embodiments, the compound of general formula I a of the present invention 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.
In some preferred embodiments, the compound of general formula I a of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein R 1be selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl, described phenyl, naphthyl, pyridyl, pyrimidyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, indyl, pseudoindoyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzopyrazoles base, benzothienyl and benzoxazolyl are optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, nitro, cyano group replace, wherein, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1 is formed together with the atom that 2 adjacent substituting groups can connect with them, 3-dioxolanes base, 1, 4-dioxocyclohex alkyl, described cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1,3-dioxolanes base, Isosorbide-5-Nitrae-dioxocyclohex alkyl are optionally selected from C further 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3one or more groups of alkoxyl group, oxo, halogen replace.
In some preferred embodiments, the compound of general formula I a of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein each R 2independently selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, nitro, cyano group, wherein n is selected from 1,2 and 3;
In some preferred embodiments, the compound of general formula I a of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein Q is selected from N and O, R abe selected from-C 1-3alkylamino ,-C 1-3alkylamino C 1-3alkyl ,-C 1-3alkylamino (C 1-3alkyl) (C 1-3alkyl) ,-C 1-3alkyl oxy C 1-3alkyl ,-C 1-3alkyl C 3-6nitrogen heterocyclic ring alkyl, R bbe selected from hydrogen, C 1-3alkyl, wherein when Q is selected from O, R bdo not exist;
Further preferably, Q is selected from N and O, R abe selected from-ethyleneimino ,-ethylidene-methylamino-,-ethylidene-dimethylamino ,-ethylenemethoxy ,-ethylidene oxyethyl group ,-ethylidene Pyrrolidine base ,-ethylidene piperidyl ,-ethylidene piperazinyl ,-ethylidene methylpiperazine base, R bbe selected from hydrogen, C 1-3alkyl, wherein when Q is selected from O, R bdo not exist.
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.The preparation method of the compound of general formula I comprises the steps:
The raw material of A formula 1 and the raw material generation nucleophilic reaction of formula 2 obtain the intermediate of formula 3;
The intermediate of B formula 3 and the raw material reaction of formula 4 obtain the intermediate of formula 5;
The intermediate of C formula 5 and the raw material reaction of formula 6 obtain the compound of general formula I.
Above-mentioned X, Y, R 1, R 2, Q, R a, R bthere 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.
" thiazolinyl " of the present invention refers to the straight or branched unsaturated alkyl containing one or more carbon-carbon double bond (C=C)." C of the present invention 2-6thiazolinyl " to refer to containing 1 or 2 carbon-carbon double bonds and containing the unsaturated alkyl of 2 to 6 carbon atoms." C of the present invention 2-4thiazolinyl " to refer to containing 1 or 2 carbon-carbon double bonds and containing the unsaturated alkyl of 2 to 4 carbon atoms.
" 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.
" aryl " of the present invention comprises mononuclear aromatics and polycyclic aromatic hydrocarbons.Containing a phenyl ring in monocyclic aromatic hydrocarbon group, concrete as benzene,toluene,xylene, halogeno-benzene, vinylbenzene etc.; Containing plural phenyl ring in polycyclic aromatic group, as biphenyl, naphthalene, anthracene etc.
" heteroaryl " of the present invention refers at least containing 1 heteroatomic aryl.
" heterocyclic radical " of the present invention refers to that wherein heteroatoms is N, O or S, comprises single heterocyclic radical and fused heterocycle base, and total annular atoms number of preferred described heterocyclic radical is 5-15 at least containing heteroatomic saturated a, fractional saturation and complete undersaturated cyclic group.Suitable single heterocyclic radical includes but not limited to furans, thiophene, pyrroles, thiazole, imidazoles, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazoles ， oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran (THF), Pyrrolidine, piperidines, piperazine, morpholine, isoxazoline etc.Suitable fused heterocycle base includes but not limited to quinoline, isoquinoline 99.9, indoles, benzodioxole base, benzo dioxine base, cumarone, thionaphthene, purine, acridine, carbazole, fluorenes, chromene ketone, Fluorenone, quinoxaline, 3,4-dihydro naphthalenones, diphenylene-oxide, hydrogenated dibenzofurans, benzoxazolyl etc.
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-(1-skatole-4-base)-1,3,5-triazine-2-is amino) phenyl) allyl acid amides
The synthesis of the chloro-N-of step a4-(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), DIPEA (8.32g, 64.5mmol) and 60ml tetrahydrofuran (THF) successively, dissolve, be cooled to 0-2 DEG C, add 2,4-bis-chloro-1 in batches, 3,5-triazine (3.14g, 21.08mmol), finish, continue 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 bN-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-skatole-4-base)-1,3,5-triazines-2-amine
In 30ml microwave reaction bottle, add 1-skatole-4-boric acid ester (800mg successively, 3.11mmol), the chloro-N-of step a gains 4-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-1,3,5-triazine-2-amine (965mg, 3.11mmol), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex (110mg, 0.04eq), x-phos (237mg, 0.16eq), cesium carbonate (3.0g, 9.33mmol) with Isosorbide-5-Nitrae-dioxane/H 2o (15ml/2.5ml), dissolves, argon replaces, 105 DEG C of microwave reaction 90min, and concentrated, column chromatography purification obtains title compound.
The synthesis of step cN-(4-((2-(dimethylamino) ethyl) (methyl) is amino)-2-methoxyl group-5-nitrophenyl)-4-(1-skatole-4-base)-1,3,5-triazines-2-amine
In 50ml single port bottle, add step b gains N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-skatole-4-base)-1,3 successively, 5-triazine-2-amine (52mg, 0.13mmol), N, N, N '-trimethylammonium quadrol (20.0mg, 0.19mmol), DIPEA (50mg, 0.39mg) and 10ml dioxane, dissolve, 110 DEG C of back flow reaction 3h, stopped reaction, concentrated, column chromatography purification obtains title compound.
The synthesis of steps d N-(4-((2-(dimethylamino) ethyl) (methyl) is amino)-2-methoxyl group-5-aminophenyl)-4-(1-skatole-4-base)-1,3,5-triazines-2-amine
In 50ml single port bottle, add step c gains N-(4-((2-(dimethylamino) ethyl) (methyl) is amino)-2-methoxyl group-5-nitrophenyl)-4-(1-skatole-4-base)-1 successively, 3,5-triazine-2-amine (54mg, 0.11mmol), 10%Pd-C (5mg) and 10ml methyl alcohol, 1 standard atmosphere pressure, H 2reduction 1h, stopped reaction, filters, and concentrated title compound, obtains title compound, be directly used in next step.
Step eN-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(1-skatole-4-base)-1,3,5 triazine-2-are amino) phenyl) synthesis of allyl acid amides
In 50ml single port bottle, add steps d gains N-(4-((2-(dimethylamino) ethyl) (methyl) is amino)-2-methoxyl group-5-aminophenyl)-4-(1-skatole-4-base)-1,3,5-triazine-2-amine (41mg, 0.09mmol), diisopropylethylamine (35.0mg, 0.27mmol), 15ml anhydrous methylene chloride, dissolve, instillation allyl group acyl chlorides (10mg, methylene dichloride (1ml) solution 0.11mmol), 10min reacts completely, and concentrated, column chromatography purification obtains title compound.
1H-NMR(500MHz,DMSO-d 6)δ:2.23(6H,d),2.34-2.36(2H,t),2.73(3H,s),2.89-2.91(2H,t),3.84(6H,s),5.72-5.76(1H,d),6.20-6.25(1H,d),6.36-6.41(1H,mt),7.04(1H,s),7.23-7.28(2H,m),7.66-7.68(1H,d),8.29-8.35(2H,m),8.49(1H,s),8.70(1H,s),9.2(1H,s),10.09(1H,s)。
ESI-Msm/z:501.4[M+H]。
Embodiment 2N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(1-skatole-2 base)-1,3,5-triazine-2-is amino) phenyl) allyl acid amides
The synthesis of step aN-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-skatole-2-base)-1,3,5-triazines-2-amine
With the chloro-N-of embodiment 1 step a gains 4-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-1,3,5-triazines-2-amine and 1-skatole-2-boric acid for raw material, obtain title compound according to the method for embodiment 1 step b.
Step b2N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(1-skatole-2 base)-1,3,5-triazine-2-is amino) phenyl) synthesis of allyl acid amides
With step a gains N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-skatole-2-base)-1,3,5-triazine-2-amine, N, N, N '-trimethylammonium quadrol and allyl group acyl chlorides are raw material, obtain title compound according to the method for embodiment 1 step c, steps d and step e.
1H-NMR(300MHz,DMSO-d 6)δ:2.50-2.73(8H,m),3.09-3.21(5H,m),3.83(3H,s),4.06-4.22(3H,m),5.73-5.77(1H,d),6.25-6.30(1H,d),6.99(1H,s),7.08-7.13(1H,t),7.27-7.32(1H,t),7.51-7.66(3H,m),8.36(1H,s),8.68(1H,s),9.27(1H,s),9.83,(1H,s)，10.16(1H,s)。
ESI-Msm/z:501.3[M+H]。
Embodiment 3N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(3-(1-methylcarbamoylphenyl))-1; 3,5-triazine-2-is amino) phenyl) allyl acid amides
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2,4-bis-chloro-1,3,5-triazines, 3-(methyl-carbamoyl) borate ester, N, N, N '-trimethylammonium quadrol and 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),2.37-2.41(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 4N-(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 5N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(1-skatole-5-base)-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, 1-skatole-5-boric 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(500MHz,DMSO-d 6)δ:2.23(6H,d),2.34-2.36(2H,t),2.73(3H,s),2.89-2.91(2H,t),3.84(6H,s),5.78-5.79(1H,d),6.29-6.32(1H,d),6.42-6.48(1H,mt),6.57(1H,s),7.04(1H,s),7.40-7.41(1H,d),7.50-7.52(1H,d),8.22(1H,s),8.28-8.30(1H,d),8.68(1H,s),8.83(2H,s),10.09(1H,s)。
ESI-Msm/z:501.4[M+H]。
Embodiment 6N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(1H-indol-3-yl)-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, 1H-indoles-3-boric 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(500MHz,DMSO-d 6)δ:2.22(6H,d),2.34-2.37(2H,t),2.75(3H,s),2.89-2.91(2H,t),3.81(3H,s),5.75-5.77(1H,d),6.27-6.30(1H,d),6.40-6.45(1H,m),6.57(1H,s),7.06(1H,s),7.16-7.17(1H,m),7.44-7.46(1H,d),8.29(2H,s),8.57(2H,s),8.77(1H,s),10.16(1H,s),11.93(1H,s)。
ESI-Msm/z:487.3[M+H]。
Embodiment 7N-(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 8N-(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 9N-(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 10N-(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 11N-(2-((2-(4-methylpiperazine-1-yl) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1H-indol-3-yl)-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, 1H-indoles-3-boric 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:11.90(s,1H),9.36(s,1H),8.71(s,1H),8.54(s,2H),8.48(s,1H),8.13(s,1H),7.47-7.44(d,1H),7.19-7.08(m,2H),6.997(s,1H),6.69-6.60(m,1H),6.31-6.25(d,1H),5.78–5.75(d,1H),3.82(s,3H),3.05(m,5H),2.54–2.50(m,8H),2.41-2.21(m,5H)。
ESI-Msm/z:542.4[M+H]。
Embodiment 12N-(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 13N-(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 14N-(3-((4-((4-(4-Acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
Step aN-(3-((4-chloro-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
Take 0.165g2,4-bis-chloro-1,3,5-triazine, in reaction flask, is dissolved with 5mLTHF, is slowly added dropwise to 0.155gDIPEA at 0 DEG C, after stirring 10min, be slowly added dropwise to the THF solution that 5ml is dissolved with 0.216gN-(3-amino-benzene) acrylamide, stir 30min, stopped reaction, adds 30mL frozen water, extraction into ethyl acetate (3 × 15mL), merge organic layer, saturated common salt water washing once, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain title compound.
ESI-MSm/z:276[M+H]。
Step bN-(3-((4-((4-(4-Acetylpiperazine-1-base)-2-p-methoxy-phenyl) is amino)-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
Take 0.26g step a gains N-(3-((4-chloro-1,3,5-triazine-2-base) amino) benzene) acrylamide and 0.5g1-(4-(4-amino-3-p-methoxy-phenyl) piperazine-1-base) ethyl ketone be in reaction flask, after dissolving with 10mLTHF, be added dropwise to 5 trifluoroacetic acids, after 50 DEG C of stirring 20min, stopped reaction, adds 30mL frozen water, extraction into ethyl acetate (3 × 15mL), merge organic layer, once, anhydrous sodium sulfate drying, filters in saturated common salt water washing, concentrated, column chromatography purification obtains title compound.
1HNMR(300MHz,DMSO-d 6):δ10.05(s,1H),9.71(s,1H),8.43(s,1H),8.25(s,1H),7.85(s,1H),7.55-7.53(d,1H),7.42-7.36(m,2H),7.20-7.15(t,1H),6.67(s,1H),6.51-6.42(m,2H),6.29-6.22(d,1H),5.76-5.73(d,1H),3.80(s,3H),3.58(s,4H),3.16-3.10(m,4H),2.05(s,3H)。
ESI-MSm/z:489[M+H]。
Embodiment 15N-(3-((4-((4-(4-methylpiperazine-1-yl)-3-trifluoromethyl) is amino)-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
With N-(3-amino-benzene) acrylamide, 2,4-bis-chloro-1,3,5-triazines and 3-trifluoromethyl-4-(4-methylpiperazine-1-yl methyl), aniline is for raw material, and the method with embodiment 14 obtains title compound.
1HNMR(300MHz,DMSO-d 6):δ10.17(s,1H),10.03(s,1H),9.86(s,1H),8.39(s,1H),8.13-8.11(m,1H),8.03(s,1H),7.89(s,1H),7.60-7.57(d,1H),7.44-7.42(m,2H),7.26-7.21(t,1H),6.52-6.43(m,1H),6.27-6.21(d,1H),5.76-5.73(d,1H),3.61(s,2H),3.12-3.05(m,4H),2.7(m,4H),2.05(s,3H)。
ESI-MSm/z:513.3[M+H]。
Embodiment 16N-(3-((4-((4-(4-ethyl piperazidine-1-base)-2-p-methoxy-phenyl) is amino)-1,3,5-triazines-2-base) is amino) phenyl) acrylamide
With N-(3-amino-benzene) acrylamide, 2,4-bis-chloro-1,3,5-triazines and 2-methoxyl group-4-(4-ethyl piperazidine-1-base), aniline is for raw material, and the method with embodiment 14 obtains title compound.
1HNMR(300MHz,DMSO-d 6):δ10.17(s,1H),9.95-9.90(s,1H),8.74(m,1H),8.28(s,1H),7.85-7.82(bs,1H),7.54-7.51(m,1H),7.41-7.39(m,2H),7.20-7.18(m,1H),6.71(s,1H),6.54-6.45(m,2H),6.29-6.22(d,1H),5.77-5.73(d,1H),3.86(m,2H),3.81(s,3H),3.21-3.17(m,4H),3.10-3.03(m,4H),1.32-1.27(t,3H)。
ESI-MSm/z:475.3[M+H]。
Embodiment 17N-(5-((4-amino-6-(1-Methyl-1H-indole-3-base)-1,3,5-triazine-2-base) amino)-4-methoxyl group-2-((2-(4-methylpiperazine-1-yl) ethyl) (methyl) is amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2, the chloro-6-of 4-bis-amino-1,3,5-triazine, 1-Methyl-1H-indole-3-boric acid, N-methyl-2-(4-methylpiperazine-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:9.41(s,1H),9.25(s,1H),8.78(s,1H),8.56–8.53(d,1H),8.18(s,1H),7.52–7.49(d,2H),7.25–7.12(m,2H),6.98(s,1H),6.81(m,2H),6.36–6.31(d,1H),5.83–5.79(d,1H),3.92(s,3H),3.87(s,3H),2.68(m,4H),2.36(m,8H),2.16(s,6H).
ESI-Msm/z:571.3[M+H]。
Embodiment 18N-(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 19N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-(4-(pyridin-3-yl)-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, pyridine-3-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:2.23(6H,d),2.36-2.37(2H,t),2.72(3H,s),2.91(2H,t),3.80(3H,s),5.75-5.77(1H,d),6.25-6.28(1H,d),6.40-6.45(1H,m),7.03(1H,s),7.54-7.56(1H,m),8.19(2H,s),8.72-8.81(3H,s),9.47(1H,s),10.08(1H,s)。
ESI-Msm/z:449.3[M+H]。
Embodiment 20N-(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 21N-(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 22N-(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 23N-(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 24N-(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 25N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the fluoro-1H-indoles of 5--2-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, the fluoro-indoles of 5--2-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:11.71(s,1H),10.37(s,1H),8.89(s,1H),8.74(s,1H),8.25(s,1H),7.40-7.60(m,3H),7.06-7.17(m,2H),6.36-6.55(m,2H),5.85-5.88(s,1H),3.88(s,3H),3.30(t,2H),2.90(s,3H),2.35(t,2H),2.31(s,6H)。
ESI-Msm/z:505.2[M+H]。
Embodiment 26N-(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 27N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(9,9-dimethyl fluorene-2-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, 9,9-dimethyl fluorene-2-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:10.15(s,1H),9.08(s,1H),8.75(s,1H),8.54(s,1H),8.48(d,1H),7.90-7.97(m,4H),7.58-7.61(m,1H),7.39-7.40(m,1H),7.06(s,1H),6.25-6.48(m,2H),5.77-5.80(m,1H),3.84(s,3H),2.91(t,2H),2.74(s,3H),2.35(t,2H),2.23(s,6H),1.472.23(s,6H)。
ESI-Msm/z:564.2[M+H]。
Embodiment 28N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(isoquinoline 99.9-4-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, 4-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:10.04(s,1H),9.61(s,1H),9.44(s,1H),9.18(s,1H),8.92(s,1H),8.92(s,1H),8.24(s,1H),7.96(s,1H),7.72(s,2H),7.05(s,1H),6.40-6.45(m,1H),6.21-6.24(m,1H),5.73-5.75(d,1H),3.80(s,3H),2.91(t,2H),2.73(s,3H),2.37(t,2H),2.22(s,6H)。
ESI-Msm/z:499.4[M+H]。
Embodiment 29N-(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 30N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(benzo [b] furans-3-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-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(300MHz,DMSO-d 6)δ:10.19(s,1H),9.78(s,1H),9.30(s,1H),8.99(s,1H),8.70(s,1H),8.14-8.50(m,2H),7.68-7.70(d,1H),7.37-7.39(m,2H),7.00(s,1H),6.23-6.29(d,1H),5.72-5.76(d,1H),3.84(s,3H),3.34(t,2H),3.28(t,2H),2.80(s,6H),2.53(s,3H)。
ESI-Msm/z:488.4[M+H]。
Embodiment 31N-(2-((2-(dimethylamino) ethyl) (methyl) is amino) the chloro-5-of-4-((4-(benzo [b] thiene-3-yl-)-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the chloro-5-N-methyl-p-nitroaniline of the fluoro-2-of 4-, 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(300MHz,CDCl 3-d 6)δ:12.69(s,1H),9.79(s,1H),9.53(s,1H),9.36(s,1H),9.06-9.09(d,1H),8.87(s,1H),7.88-7.91(d,1H),7.62(s,1H),7.31-7.51(m,2H),7.15(s,1H),6.50-6.55(d,1H),5.78-5.82(d,1H),3.41(t,2H),3.28(t,2H),2.83(s,6H),2.73(s,3H)。
ESI-Msm/z:509.0[M+H]。
Embodiment 32N-(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 33N-(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 34N-(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 35N-(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 36N-(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 37N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(quinoline-3-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-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:10.18(s,1H),9.76(s,1H),9.16–9.05(d,1H),8.85(s,1H),8.31–8.21(m,3H),8.12–8.11(m,1H),7.91–7.69(m,1H),7.72–7.69(m,1H),7.07(s,1H),6.47(s,1H),6.33–6.23(m,1H),5.82(s,1H),3.82(s,3H),3.04(s,2H),2.75(s,3H),2.36(s,2H),2.23(s,6H).
ESI-Msm/z:499.2[M+H]。
Embodiment 38N-(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 39N-(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 40N-(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 41N-(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 42N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1 – methylpyrazole base-4-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-methyl isophthalic acid H-pyrazoles-4-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:10.15(s,1H),8.80-8.59(m,4H),8.29(s,1H),7.03(s,1H),6.48-6.39(m,1H),6.32-6.27(s,1H),5.80-5.76(s,1H),3.93(s,3H),3.84(s,3H),2.90-2.86(m,2H),2.71(s,3H),2.34-2.31(m,2H),2.21(s,6H).
ESI-Msm/z:452.2[M+H]。
Embodiment 43N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(quinolyl-4)-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-4-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:10.06(s,1H),9.67(s,1H),9.05(s,1H),8.86–8.81(m,2H),8.44(s,1H),8.25(s,1H),8.09(s,2H),7.83–7.80(m,1H),7.05(s,1H),6.46–6.37(m,1H),6.22–6.21(d,1H),5.78–5.75(d,1H),3.84(s,3H),2.88(s,2H),2.73(s,3H),2.33(s,2H),2.20(s,6H).
ESI-Msm/z:499.0[M+H]。
Embodiment 44N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-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:9.50(s,1H),8.92(s,1H),8.82(s,1H),8.39–8.29(m,3H),8.20(s,2H),7.88(s,1H),7.53(s,1H),7.04–7.01(d,1H),6.46–6.43(d,1H),6.28–6.22(d,1H),5.79–5.75(d,1H),3.82(s,3H),2.95–2.93(m,2H),2.71-2.67(m,3H),2.41(s,2H),2.23(s,6H).
ESI-Msm/z:498.9.[M+H]。
Embodiment 45N-(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 46N-(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 47N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methyl-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-d 6)δ:10.22(s,1H),9.81(s,1H),8.91(s,1H),8.73(s,1H),8.53(s,1H),8.44(s,1H),8.03(s,1H),7.47(s,1H),7.35(s,1H),7.14(s,1H),6.44–6.39(m,1H),6.23–6.19(d,1H),5.77–5.75(d,1H),2.88(s,2H),2.74(s,3H),2.50(s,2H),2.22(s,6H),2.19(s,3H).
ESI-Msm/z:488.0[M+H]。
Embodiment 48N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(5-tolylthiophene-2-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, 5-phenyl-2-thiophene phenyl 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:2.48(6H,s),2.67(2H,m),2.72(3H,s),3.07(2H,m),3.92(3H,s),5.75-5.74(1H,dd),6.39(1H,m),6.64(1H,m),6.90(1H,s),7.37-7.35(1H,m),7.45-7.42(2H,m),7.50-7.49(1H,m),7.73-7.69(2H,m),8.00(1H,s),8.47-8.39(1H,m),8.62(1H,s),9.39(1H,br),10.12(1H,s)。
ESI-Msm/z:530.3[M+H]。
Embodiment 49N-(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 50N-(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 51N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(the chloro-benzo of 5-[b] furans-3-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, the chloro-cumarone of 5--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-d 6)δ:10.07(s,1H),9.36(s,1H),9.08(s,1H),8.70(s,2H),8.33(s,1H),7.75–7.72(m,1H),7.43(s,1H),7.07(s,1H),6.46-6.37(m,1H),6.24-6.19(d,1H),5.76-5.72(d,1H),3.80(s,3H),2.90(s,2H),2.75(s,3H),2.36(s,2H),2.22(s,6H).
ESI-Msm/z:522.2[M+H]。
Embodiment 52N-(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 53N-(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 54N-(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 55N-(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 56N-(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 57N-(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 58N-(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 59N-(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 60N-(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 61N-(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 62N-(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 63N-(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 64N-(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 65N-(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 66N-(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 67N-(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 68N-(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 69N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1-Methyl-1H-indole-3-base)-6-amino-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methoxyl group-5-N-methyl-p-nitroaniline, 2,4-bis-chloro-6-amino-1,3,5-triazine, N-skatole-2-boric 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:2.22(6H,s),2.31-2.27(2H,m),2.70(3H,s),2.90-2.87(2H,m),3.87(3H,s),3.93(3H,s),5.83-5.79(1H,d),6.47-6.31(2H,m),6.80(2H,bs),7.03(1H,s),7.16-7.11(1H,m),7.25-7.20(1H,m),7.51-7.49(2H,m),8.28(1H,s),8.85-8.82(1H,m),9.42(1H,bs),10.20(1H,s)。
ESI-Msm/z:515.6[M+H]。
Embodiment 70N-(2-((2-(piperidino) ethyl) (methyl) is amino)-4-methoxyl group-5-((4-(1-Methyl-1H-indole-3-base)-6-amino-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline, 2, the chloro-6-of 4-bis-amino-1,3,5-triazine, N-skatole-2-boric acid, N-methyl-2-(piperidin-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:1.36(2H,m),1.49(4H,m),2.36-2.31(6H,m),2.68(3H,s),2.98-2.95(2H,m),3.87(3H,s),3.92(3H,s),5.81-5.80(1H,m),6.35-6.31(1H,m),6.68-6.63(1H,m),6.83-6.81(2H,bs),6.99(1H,s),7.16-7.13(1H,m),7.24-7.21(1H,m),7.53-7.49(2H,m),8.33(1H,s),8.55-8.54(1H,dd),8.78(1H,bs),9.47(1H,s)。
ESI-Msm/z:556.6[M+H]。
Embodiment 71N-(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 72N-(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 73N-(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 74N-(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 75N-(2-((2-(dimethylamino) ethyl) (methyl) is amino)-4-methyl-5-((4-(1-Methyl-1H-indole-3-base)-6-amino-1,3,5-triazine-2-base) amino) phenyl) acrylamide
With 4-fluoro-2-methyl-5-nitro aniline, 2,4-bis-chloro-6-amino-1,3,5-triazines, N-skatole-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:2.21(3H,s),2.22(6H,s),2.37-2.35(2H,m),2.70(3H,s),2.86(2H,m),3.85(3H,s),5.77-5.74(1H,d),6.35-6.31(1H,m),6.47-6.41(2H,m),6.61(2H,bs),7.06-7.01(1H,m),7.20-7.17(1H,m),7.47-7.44(1H,m),8.21(2H,s),8.51-8.38(2H,m),10.13(1H,s)。
ESI-Msm/z:500.5[M+H]。
Embodiment 76N-(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 77N-(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 78N-(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 79N-(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 80N-(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 81N-(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 82N-(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 83N-(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 84N-(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 85N-(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 86N-(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 87N-(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]。
Embodiment 88N-(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 89N-(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 90N-(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 91N-(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 92N-(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 93N-(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 94N-(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 95N-(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 96N-(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 97N-(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 98N-(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 99N-(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 100N-(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 101N-(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]。
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, and " min " represents without kinases without compound control, 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) and 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 in containing 10% deactivation foetal calf serum (GIBCO) RPMI1640 substratum in, 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 perfect medium, after being then diluted to 10 μMs with the perfect medium containing 0.1%DMSO, 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 50much 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 prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkylamino;
Y is selected from key ,-C 1-C 6alkylidene group-, NH ,-C 1-C 6alkylidene group-NH-,-NH-C 1-C 6alkylidene group-,-C (O) NH-,-NHC (O)-,-NHC (O) NH-, O, S, S (O) and S (O) 2;
R 1be selected from aryl and heterocyclic radical, described aryl and heterocyclyl are by one or more alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl is amino, aryl, heterocyclic radical, nitro and cyano group replace, cycloalkyl or Heterocyclylalkyl is formed together with the atom that 2 wherein adjacent substituting groups can connect with them, described cycloalkyl or Heterocyclylalkyl are optionally selected from alkyl further, haloalkyl, alkoxyl group, halogenated alkoxy, one or more groups of oxo and halogen replace,
Each R 2independently selected from hydrogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halogen, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl amino, nitro and cyano group, wherein n is selected from 1,2,3 and 4;
Q is selected from N, O, S ,-C 1-C 6alkylidene-,-C 1-C 6alkylidene-N-,-NH-C 1-C 6alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-; With
R a, R bseparately be selected from hydrogen, alkyl, alkylamino, thiazolinyl, amino, alkylaminoalkyl group, cycloalkyl ,-alkyl-cycloalkyl, aryl ,-alkyl-aryl-group, heterocyclic radical ,-alkyl-heterocyclyl groups; described alkyl, cycloalkyl ,-alkyl-cycloalkyl, aryl and heterocyclyl are replaced by one or more halogen, alkyl, thiazolinyl, amino, alkylamino, haloalkyl, alkyl acyl, alkylaminoacyl, aminoacyl, alkenylacyl, cycloalkyl, cycloalkenyl group and heterocyclic radical; wherein when Q be selected from O, S and-NHC (O)-time, R bdo not exist; Or
R a, R bconnected Q forms heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl together, and described heterocyclic radical, cycloalkyl, cycloalkenyl group or aryl are optionally replaced by one or more halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, cycloalkyl, cycloalkenyl group and heterocyclic radical.
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, be preferably selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl group, sec.-propyl, amino.
3., according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of claim 1 or 2, wherein Y is selected from key ,-C 1-C 3alkylidene group-, NH ,-C 1-C 3alkylidene group-NH-,-NH-C 1-C 3alkylidene group-,-C (O) NH-,-NHC (O)-and-NHC (O) NH-.
4. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, the wherein R of any one of claim 1-3 1be selected from monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocyclic radical, tricyclic condensed heterocyclic radical, described monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocyclic radical, tricyclic condensed heterocyclyl are by one or more C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, oxo, halo C 1-6alkoxyl group, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, aryl, C 3-8heterocyclic radical, nitro, cyano group replace, and form C together with the atom that 2 wherein adjacent substituting groups can connect with them 3-6cycloalkyl or C 3-6heterocyclylalkyl, described C 3-6cycloalkyl or C 3-6heterocyclylalkyl is optionally selected from one or more groups replacements of alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, oxo, halogen further;
Preferably, R 1be selected from phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, triazol radical, oxazolyl, isoxazolyl, indyl, pseudoindoyl, benzo ring thiazolinyl, benzo oxaheterocyclenyl groups, benzo dioxane thiazolinyl, benzo-aza cycloalkenyl group, benzodiazepine heterocycloalkenyl, benzimidazole thiophanate heterocycloalkenyl, benzo dithia cycloalkenyl group, benzo oxygen thia cycloalkenyl group, benzo oxaza thiazolinyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzothienyl, purine radicals, acridyl, carbazyl, chromene ketone group, quinoxalinyl, benzoxazolyl, described phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrazolyl, furyl, thienyl, thiazolyl, imidazolyl, triazol radical, oxazolyl, isoxazolyl, indyl, pseudoindoyl, benzo ring thiazolinyl, benzo oxaheterocyclenyl groups, benzo dioxane thiazolinyl, benzo-aza cycloalkenyl group, benzodiazepine heterocycloalkenyl, benzimidazole thiophanate heterocycloalkenyl, benzo dithia cycloalkenyl group, benzo oxygen thia cycloalkenyl group, benzo oxaza thiazolinyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuryl, benzothienyl, purine radicals, acridyl, carbazyl, chromene ketone group, quinoxalinyl, benzoxazolyl is optionally by one or more C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, oxo, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1 is formed together with the atom that 2 wherein adjacent substituting groups can connect with them, 3-dioxolanes base or 1,4-dioxocyclohex alkyl, described cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1,3-dioxolanes base and Isosorbide-5-Nitrae-dioxocyclohex alkyl are optionally selected from C further 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6one or more groups of alkoxyl group, oxo, halogen replace,
Further preferably, R 1be selected from phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzocyclobutane thiazolinyl, benzo ring pentenyl, benzo ring hexenyl, benzocyclohepta thiazolinyl, benzo oxole base, benzo oxinyl, benzo oxepane thiazolinyl, benzodioxepins base, benzodiazepine cycloheptenyl, benzimidazole thiophanate heterocycle amyl group, benzimidazole thiophanate heterocycle hexenyl, benzothiepines base, benzo dithia cyclopentyl, benzo dithia cyclohexenyl, benzo dithia cycloheptenyl, benzo oxygen thia cyclopentenyl, benzo oxathiene base, benzo oxygen thia cycloheptenyl, benzo oxaza heptenyl, benzodioxole base, Pyrazolopyridine, Ben Bing oxane, described phenyl, naphthyl, tetrahydrofuran base, Pyrrolidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzocyclobutane thiazolinyl, benzo ring pentenyl, benzo ring hexenyl, benzocyclohepta thiazolinyl, benzo oxole base, benzo oxinyl, benzo oxepane thiazolinyl, benzodioxepins base, benzodiazepine cycloheptenyl, benzimidazole thiophanate heterocycle amyl group, benzimidazole thiophanate heterocycle hexenyl, benzothiepines base, benzo dithia cyclopentyl, benzo dithia cyclohexenyl, benzo dithia cycloheptenyl, benzo oxygen thia cyclopentenyl, benzo oxathiene base, benzo oxygen thia cycloheptenyl, benzo oxaza heptenyl, benzodioxole base, Pyrazolopyridine, Ben Bing oxane is optionally by one or more methyl, ethyl, propyl group, trifluoromethyl, methoxyl group, oxyethyl group, propoxy-, oxo, fluorine, chlorine, amino, methylamino-, ethylamino, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, methylacyl is amino, ethyl acyl amino, vinyl acyl amino, phenyl, C 3-8heterocyclylalkyl, C 3-8heteroaryl, nitro, cyano group replace, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1 is formed together with the atom that 2 wherein adjacent substituting groups can connect with them, 3-dioxolanes base or 1,4-dioxocyclohex alkyl, described cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, 1,3-dioxolanes base and Isosorbide-5-Nitrae-dioxocyclohex alkyl are optionally selected from C further 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3one or more groups of alkoxyl group, oxo, halogen replace.
5. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of any one of Claims 1-4, wherein each R 2independently selected from hydrogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, halogen, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 2-6alkenylacyl amino, nitro, cyano group, n is selected from 1,2,3 and 4;
Preferably, each R 2independently selected from hydrogen, C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, halogen, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-4alkenylacyl, C 1-3alkyl acylamino, C 2-4alkenylacyl amino, nitro, cyano group, n is selected from 1,2 and 3;
Further preferably, R 2be selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, fluorine, chlorine, amino, methylamino-, dimethylamino, ethylamino, diethylin, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, methylacyl amino, ethyl acyl amino, vinyl acyl amino, nitro, cyano group, n is selected from 1,2 and 3.
6. according to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of any one of claim 1 to 5, wherein:
Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-6alkyl, C 1-6alkylamino, C 2-6thiazolinyl, amino, C 1-6alkylamino C 1-6alkyl, C 3-8cycloalkyl ,-C 1-6alkyl-C 3-8cycloalkyl, aryl ,-C 1-6alkyl-aryl-group, C 3-10heterocyclic radical ,-C 1-6alkyl-C 3-10heterocyclic radical, described C 1-6alkyl, C 2-6thiazolinyl, C 3-8cycloalkyl ,-C 1-6alkyl-C 3-8cycloalkyl, aryl, C 3-10heterocyclic radical ,-C 1-6alkyl-C 3-10heterocyclyl is by one or more halogen, C 1-6alkyl, C 2-6alkenyl, amino, C 1-6alkylamino, halo C 1-6alkyl, C 1-6alkyl acyl, C 1-6alkylaminoacyl, aminoacyl, C 2-6alkenylacyl, C 3-8cycloalkyl, C 3-8heterocyclic radical replaces, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist, or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N or CH form quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclic radical together, described quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, cycloalkenyl group or heterocyclyl be by one or more halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 3-8cycloalkyl, C 3-8cycloalkenyl group, C 3-8heterocyclic radical replaces; Preferably, Q is selected from N, O ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-,-NHC (O)-and-NHC (O) N-, R a, R bseparately be selected from hydrogen, C 1-3alkyl, C 1-3alkylamino, C 2-4alkenyl, amino, C 1-3alkylamino C 1-3alkyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl ,-C 1-3alkyl-aryl-group, C 4-8azacycloalkyl, C 4-8diazacyclo alkyl ,-C 1-3alkyl-C 4-8azacycloalkyl ,-C 1-3alkyl-C 4-8diazacyclo alkyl, C 4-8nitrogen heterocyclic thiazolinyl, C 4-8diazacyclo thiazolinyl ,-C 1-3alkyl-C 4-8nitrogen heterocyclic thiazolinyl ,-C 1-3alkyl-C 4-8diazacyclo thiazolinyl, described C 1-3alkyl, C 2-4alkenyl, C 3-6cycloalkyl ,-C 1-3alkyl-C 3-6cycloalkyl, aryl, C 4-8azacycloalkyl, C 4-8diazacyclo alkyl ,-C 1-3alkyl-C 4-8azacycloalkyl ,-C 1-3alkyl-C 4-8diazacyclo alkyl, C 4-8nitrogen heterocyclic thiazolinyl, C 4-8diazacyclo thiazolinyl ,-C 1-3alkyl-C 4-8nitrogen heterocyclic thiazolinyl ,-C 1-3alkyl-C 4-8diazacyclo thiazolinyl is optionally by one or more halogen, C 1-3alkyl, C 2-4alkenyl, amino, C 1-3alkylamino, halo C 1-3alkyl, C 1-3alkyl acyl, C 1-3alkylaminoacyl, aminoacyl, C 2-3alkenylacyl, C 3-6cycloalkyl, C 3-6cycloalkenyl group, C 3-6heterocyclic radical replaces, wherein when Q be selected from O and-NHC (O)-time, R bdo not exist, or
Q is selected from N ,-C 1-C 3alkylidene-,-C 1-C 3alkylidene-N-,-NH-C 1-C 3alkylidene-,-C (O) N-and-NHC (O) N, R a, R bconnected atom N or CH form quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, azacycloalkyl, nitrogen heterocyclic thiazolinyl, diazacyclo alkyl or diazacyclo thiazolinyl together, described quaternary, five yuan, hexa-atomic or seven-membered ring alkyl, azacycloalkyl, nitrogen heterocyclic thiazolinyl, diazacyclo alkyl or diazacyclo thiazolinyl be optionally by one or more halogen, C 1-3alkyl, halo C 1-3alkyl, C 1-3alkoxyl group, halo C 1-3alkoxyl group, amino, C 1-3alkylamino, C 1-3alkylaminoacyl, aminoacyl, C 1-3alkyl acyl, C 2-3alkenylacyl, C 1-3alkyl acylamino, C 3-6cycloalkyl, C 3-6cycloalkenyl group, C 3-6heterocyclic radical replaces.
7. compound according to claim 6 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
Q is selected from N, O and CH, R a, R bseparately be selected from hydrogen, C 1-6alkyl, piperazinyl, piperidyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base, described C 1-6alkyl, piperazinyl, piperidyl, N-azetidinyl, Pyrrolidine base, C 1-6alkyl-piperazinyl, C 1-6alkyl-piperidinyl, C 1-6alkyl-N-heterocycle butane group, C 1-6alkyl-Pyrrolidine base is optionally by one or more halogen, amino, C 1-6alkyl, C 1-6alkylamino, halo C 1-6alkyl, C 1-6alkyl acyl, C 1-6alkylaminoacyl, aminoacyl, C 2-6alkenylacyl, piperazinyl, N-alkylpiperazinyl replace, wherein when Q is selected from O, and R bdo not exist; Or
Q is selected from N and CH, R a, R bconnected atom N forms piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine or R together a, R bconnected CH forms pyrazole ring together, and described piperazine ring, Pyrrolidine ring, piperidine ring, N-azetidine, pyrazole ring are optionally by one or more halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkoxyl group, amino, C 1-6alkylamino, C 1-6alkylaminoacyl, aminoacyl, C 1-6alkyl acyl, C 2-6alkenylacyl, C 1-6alkyl acylamino, C 3-8heterocyclic radical replaces.
8. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, described compound is following compound:
9. a pharmaceutical composition, it comprises the compound of any one of claim 1-8 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
10. the compound of any one of claim 1-8 or the composition of claim 9 are for the preparation of the application treated and/or prevented in the medicine of tumour, preferably, wherein said tumour is for having drug-fast tumour, and more preferably, described tumour is for have drug-fast tumour to EGFR inhibitor.
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