CN105272967B - Triazines epidermal growth factor receptor inhibitor and its application - Google Patents

Triazines epidermal growth factor receptor inhibitor and its application Download PDF

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CN105272967B
CN105272967B CN201510320533.2A CN201510320533A CN105272967B CN 105272967 B CN105272967 B CN 105272967B CN 201510320533 A CN201510320533 A CN 201510320533A CN 105272967 B CN105272967 B CN 105272967B
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amino
alkyl
base
triazine
methoxyl group
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CN105272967A (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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Nanjing Sanhome Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Triazines epidermal growth factor receptor inhibitor and its application.The invention belongs to medicinal chemistry arts, and in particular to one kind has the purposes of the compound, the pharmaceutical composition containing the compound and the compound or pharmaceutical composition of EGF-R ELISA inhibiting effect as cancer treatment drugs.Compound provided by the invention has good inhibitory activity to mutant egf R kinases, shows excellent selectivity, is expected to become confrontation pharmacological property tumour, especially leads to drug of the drug resistant tumour with special curative effect to EGFR mutation.

Description

Triazines epidermal growth factor receptor inhibitor and its application
Technical field
The invention belongs to medicinal chemistry arts, and in particular to one kind has the chemical combination of EGF-R ELISA inhibiting effect The purposes of object, the pharmaceutical composition containing the compound and the compound or pharmaceutical composition as cancer treatment drugs.
Background technique
EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) is proto-oncogene C- The expression product of erbB-1 is one of EGFR family member.EGFR family include EGFR (HER-1), ERBB2 (HER-2), Four members of ERBB3 (HER-3) and ERBB4 (HER-4).EGFR points are 3 part of extracellular region, transmembrane region and intracellular region, extracellular region It is that after with ligand binding, dimerization effect, dimerization occurs by the ligand binding domain of 621 Amino acid profiles of aminoterminal Receptor further occurrence be crosslinked phosphorylation, activate the subprovince TK of intracellular region, cause a series of intracellular variations, finally make cell Differentiation, proliferation and conversion occurs.
Cause holding for EGFR after causing the enhancing or mutation of downstream signal transduction when EGFR high expression or unconventionality expression Continuous activation etc., finally promotes cell Proliferation, intrusion, transfer, angiogenesis etc., causes the occurrence and development of cancer.It is adopted for EGFR Have become the goldstandard in Treatment for Non-small Cell Lung field with EGFR- tyrosine kinase inhibitor (TKI) treatment.No It crosses, clinical use discovery, after the EGFR inhibitors such as Gefitinib, Tarceva mean treatment 10 months, patient can generate drug resistance Property, it is related with the mutation of EGFR gene T790M, L858R and MET oncogene that researches show that drug resistances.Meanwhile first generation EGFR inhibitor Lack the selectivity of Wild type EGFR and mutant egf R.
Therefore, exploitation generates the drug resistant effective drug of tumor patient to because of EGFR mutation, and especially exploitation can be further It improves to Wild type EGFR and mutant egf R selectivity, heightens the effect of a treatment, reduce the drug of side effect, will have good application Prospect.
Summary of the invention
The object of the present invention is to provide the compounds or its pharmacy with EGF-R ELISA inhibiting effect of general formula I Acceptable salt, isomers, solvate, crystallization or prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkyl amino；
Y is selected from key ,-C1-C6Alkylidene-, NH ,-C1-C6Alkylidene-NH- ,-NH-C1-C6Alkylidene-,-C (O) NH- ,- NHC (O)-,-NHC (O) NH-, O, S, S (O) and S (O)2；
R1Selected from aryl and heterocycle, the aryl and heterocycle are optionally by one or more alkyl, halogenated alkyl, alkane Oxygroup, halogenated alkoxy, oxo, halogen, amino, alkyl amino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenyl acyl Base, alkyl acylamino, alkenylacyl amino, aryl, heterocycle, nitro and cyano replace, wherein 2 adjacent substituent groups Atom that can be in connection constitutes naphthenic base or Heterocyclylalkyl together, and the naphthenic base or Heterocyclylalkyl are optionally further Replaced by one or more groups selected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, oxo, halogen；
Each R2Independently selected from hydrogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, alkyl amino, Alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl amino, nitro and cyano, Wherein n is selected from 1,2,3 and 4；
Q is selected from N, O, S ,-C1-C6Alkylidene radical-,-C1-C6Alkylidene radical-N- ,-NH-C1-C6Alkylidene radical-,-C (O) N- ,-NHC (O)-and-NHC (O) N-；With
Ra、RbSeparately it is selected from hydrogen, alkyl, alkyl amino, alkenyl, amino, alkylaminoalkyl group, naphthenic base ,-alkane Base-naphthenic base, aryl ,-alkyl-aryl-group, heterocycle ,-alkyl-heterocyclyl groups, the alkyl, naphthenic base, alkyl-cycloalkyl, Aryl and heterocycle are optionally by one or more halogens, alkyl, alkenyl, amino, alkyl amino, halogenated alkyl, alkyl acyl, alkane Base aminoacyl, aminoacyl, alkenylacyl, naphthenic base, cycloalkenyl and heterocycle replace, wherein when Q is selected from O, S and-NHC (O)-when, RbIt is not present；Or
Ra、RbQ connected to it constitutes heterocycle, naphthenic base, cycloalkenyl or aryl, the heterocycle, cycloalkanes together Base, cycloalkenyl or aryl are optionally by one or more halogens, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, amino, alkyl Amino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, naphthenic base, cycloalkenyl and heterocycle Base replaces.
It is a further object to provide the compounds of formula I or its isomers, pharmacy that prepare of the invention to connect The method of salt, hydrate, solvate or the crystallization received.
It is also another object of the present invention to provide can connect comprising compounds of formula I of the invention or its isomers, pharmacy The pharmaceutical composition of salt, hydrate, solvate or the crystallization received and the acceptable carrier of drug effect and comprising of the invention logical The compound of Formulas I or its isomers, pharmaceutically acceptable salt, hydrate, solvate or crystallization and another antiviral agent Pharmaceutical composition.
Of the invention a further object is provides compounds of formula I or its pharmaceutically acceptable salt, isomery of the invention The method and compounds of formula I of the invention or its medicine of body, solvate, crystallization or prodrug treatment and/or pre- anti-cancer Learn acceptable salt, isomers, solvate, crystallization or prodrug preparation for treat and/or the drug of pre- anti-cancer in Using.
For foregoing invention purpose, the present invention the following technical schemes are provided:
In a first aspect, the present invention provides general formula I compound represented or its pharmaceutically acceptable salt, isomers, solvent close Object, crystallization or prodrug,
Wherein:
X is selected from hydrogen, halogen, alkyl, amino and alkyl amino；
Y is selected from key ,-C1-C6Alkylidene-, NH ,-C1-C6Alkylidene-NH- ,-NH-C1-C6Alkylidene-,-C (O) NH- ,- NHC (O)-,-NHC (O) NH-, O, S, S (O) and S (O)2；
R1Selected from aryl and heterocycle, the aryl and heterocycle are optionally by one or more alkyl, halogenated alkyl, alkane Oxygroup, halogenated alkoxy, oxo, halogen, amino, alkyl amino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenyl acyl Base, alkyl acylamino, alkenylacyl amino, aryl, heterocycle, nitro and cyano replace, wherein 2 adjacent substituent groups can Constituted naphthenic base or Heterocyclylalkyl together with atom in connection, the naphthenic base or Heterocyclylalkyl optionally further by One or more groups selected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, oxo and halogen replace；
Each R2Independently selected from hydrogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, alkyl amino, Alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, alkenylacyl amino, nitro and cyano, Wherein n is selected from 1,2,3 and 4；
Q is selected from N, O, S ,-C1-C6Alkylidene radical-,-C1-C6Alkylidene radical-N- ,-NH-C1-C6Alkylidene radical-,-C (O) N- ,-NHC (O)-and-NHC (O) N-；With
Ra、RbSeparately it is selected from hydrogen, alkyl, alkyl amino, alkenyl, amino, alkylaminoalkyl group, naphthenic base ,-alkane Base-naphthenic base, aryl ,-alkyl-aryl-group, heterocycle ,-alkyl-heterocyclyl groups, the alkyl, naphthenic base, alkyl-cycloalkyl, Aryl and heterocycle are optionally by one or more halogens, alkyl, alkenyl, amino, alkyl amino, halogenated alkyl, alkyl acyl, alkane Base aminoacyl, aminoacyl, alkenylacyl, naphthenic base, cycloalkenyl and heterocycle replace, wherein when Q is selected from O, S and-NHC (O)-when, RbIt is not present；Or
Ra、RbQ connected to it constitutes heterocycle, naphthenic base, cycloalkenyl or aryl, the heterocycle, cycloalkanes together Base, cycloalkenyl or aryl are optionally by one or more halogens, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, amino, alkyl Amino, alkylaminoacyl, aminoacyl, alkyl acyl, alkenylacyl, alkyl acylamino, naphthenic base, cycloalkenyl and heterocycle Base replaces.
In some preferred embodiments, X is selected from hydrogen, halogen, C1-6Alkyl and amino, it is further preferred that X is selected from Hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino.
In some preferred embodiments, Y is selected from key ,-C1-C3Alkylidene-, NH ,-C1-C3Alkylidene-NH- ,-NH- C1-C3Alkylidene-,-C (O) NH- ,-NHC (O)-and-NHC (O) NH-, it is highly preferred that Y is selected from key, CH2, NH and O.
In some embodiments, Y is selected from key and NH.In some embodiments, Y is key.
In some preferred embodiments, R1Selected from monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle Saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocycle, tricyclic condensed heterocycle, the monocyclic aryl, two rings It is fused-aryl, tricyclic condensed aryl, monocycle saturated heterocyclyl, monocycle unsaturated heterocycle base, Bicyclic-fused heterocycle, tricyclic condensed Heterocycle is optionally by one or more C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, oxo, halogen, Amino, C1-6Alkyl amino, C1-6Alkylaminoacyl, aminoacyl, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acyl Amino, C2-6Alkenylacyl amino, aryl, C3-8Heterocycle, nitro, cyano replace, wherein 2 adjacent substituent groups can be with it The atom that connects constitute C together3-6Naphthenic base or C3-6Heterocyclylalkyl, the C3-6Naphthenic base or C3-6Heterocyclylalkyl optionally into One step is replaced by one or more groups selected from alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, oxo, halogen.
In some preferred embodiments, R1Selected from monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed aryl, monocycle Heteroaryl, Bicyclic-fused heteroaryl and tricyclic condensed heteroaryl, the monocyclic aryl, Bicyclic-fused aryl, tricyclic condensed virtue Base, bicyclic heteroaryl, Bicyclic-fused heteroaryl and tricyclic condensed heteroaryl are optionally by one or more C1-6Alkyl, halogenated C1-6Alkane Base, C1-6Alkoxy, halogenated C1-6Alkoxy, oxo, halogen, amino, C1-6Alkyl amino, C1-6Alkylaminoacyl, aminoacyl Base, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acylamino, C2-6Alkenylacyl amino, aryl, C3-8Heterocycle, nitre Base, cyano replace, wherein 2 adjacent substituent groups can atom in connection constitute C together3-6Naphthenic base or C3-6It is miscellaneous Naphthenic base, the C3-6Naphthenic base or C3-6Heterocyclylalkyl can be further by C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, Halogenated C1-6Alkoxy, oxo, halogen replace.In other preferred embodiments, R1Selected from phenyl, naphthalene, tetrahydrofuran Base, nafoxidine base, piperidyl, piperazinyl, morpholinyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrole radicals, pyrazolyl, Furyl, thienyl, thiazolyl, imidazole radicals, triazol radical, oxazolyl, isoxazolyl, indyl, isoindolyl, Benzocycloalkene Base, benzo oxaheterocyclenyl groups, benzo dioxane alkenyl, benzo-aza cycloalkenyl, benzodiazepine * heterocycloalkenyl, benzimidazole thiophanate heterocycle It is alkenyl, benzo dithia cycloalkenyl, benzo oxygen thia cycloalkenyl, benzo oxaza alkenyl, Pyrazolopyridine, quinolyl, different Quinolyl, benzofuranyl, benzothienyl, purine radicals, acridinyl, carbazyl, chromene ketone group, quinoxalinyl, benzoxazoles Base, the phenyl, naphthalene, tetrahydrofuran base, nafoxidine base, piperidyl, piperazinyl, morpholinyl, pyridyl group, pyrimidine radicals, Pyrazinyl, pyridazinyl, pyrrole radicals, pyrazolyl, furyl, thienyl, thiazolyl, imidazole radicals, triazol radical, oxazolyl, different evil Oxazolyl, indyl, isoindolyl, benzo ring alkenyl, benzo oxaheterocyclenyl groups, benzo dioxane alkenyl, benzo-aza cyclenes Base, benzodiazepine * heterocycloalkenyl, benzimidazole thiophanate heterocycloalkenyl, benzo dithia cycloalkenyl, benzo oxygen thia cycloalkenyl, benzo oxygen nitrogen Heterocycloalkenyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, purine radicals, acridinyl, carbazole Base, chromene ketone group, quinoxalinyl, benzoxazolyl are optionally by one or more C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, Halogenated C1-3Alkoxy, oxo, halogen, amino, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl Base, C2-4Alkenylacyl, C1-3Alkyl acylamino, C2-4Alkenylacyl amino, phenyl, C3-8Heterocyclylalkyl, C3-8Heteroaryl, nitre Base, cyano replace.For example, in some specific embodiments, R1Selected from benzocyclobutane alkenyl, benzo cyclopentenyl, benzo Cyclohexenyl group, benzocyclohepta alkenyl, benzo oxole base, benzo oxinyl, benzo oxepane alkenyl, benzo Dioxa cyclopentenyl, benzo oxane, benzodioxepins base, benzodiazepine cycloheptenyl, benzimidazole thiophanate heterocycle amyl, Benzimidazole thiophanate heterocycle hexenyl, benzothiepines base, benzo dithia cyclopenta, benzo dithia cyclohexenyl group, benzo two Thia cycloheptenyl, benzo oxygen thia cyclopentenyl, benzo oxathiene base, benzo oxygen thia cycloheptenyl, benzo oxygen Azepine base, wherein these groups are optionally by one or more C1-3Alkyl, halogenated C1-3Alkyl, C1-3It is alkoxy, halogenated C1-3Alkoxy, oxo, halogen, amino, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-4 Alkenylacyl, C1-3Alkyl acylamino, C2-4Alkenylacyl amino, nitro, cyano replace.In some specific embodiments In, R1Selected from phenyl, naphthalene, tetrahydrofuran base, nafoxidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzo [d] [1,3] dioxa cyclopentenyl, pyrazolo [1,5-a] pyridine, Isosorbide-5-Nitrae-benzo oxane, the phenyl, naphthalene, tetrahydro furan It mutters base, nafoxidine base, pyrazolyl, oxazolyl, isoxazolyl, indyl, benzo [d] [1,3] dioxa cyclopentenyl, pyrazoles And [1,5-a] pyridine, 1,4- benzo oxane are optionally by one or more methyl, ethyl, propyl, trifluoromethyl, methoxyl group, ethoxy Base, propoxyl group, oxo, fluorine, chlorine, amino, methylamino, ethylamino, methylamino acyl group, ethylamino acyl group, aminoacyl, first Base acyl group, ethyl acyl group, vinyl acyl group, methylacyl amino, ethyl acyl amino, vinyl acyl amino, phenyl, C3-8 Heterocyclylalkyl, C3-8Heteroaryl, nitro, cyano replace.
In other preferred embodiments, R1Selected from phenyl, naphthalene, pyridyl group, pyrimidine radicals, pyrrole radicals, pyrazolyl, Furyl, thienyl, thiazolyl, imidazole radicals, oxazolyl, isoxazolyl, indyl, isoindolyl, Pyrazolopyridine, quinoline Base, isoquinolyl, benzofuranyl, benzopyrene oxazolyl, benzothienyl and benzoxazolyl, the phenyl, naphthalene, pyridine It is base, pyrimidine radicals, pyrrole radicals, pyrazolyl, furyl, thienyl, thiazolyl, imidazole radicals, oxazolyl, isoxazolyl, indyl, different Indyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuranyl, benzopyrene oxazolyl, benzothienyl and benzoxazoles Base is optionally by one or more C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, oxo, halogen, amino, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-4Alkenylacyl, C1-3Alkyl acylamino, C2-4Alkenylacyl amino, phenyl, C3-8Heterocyclylalkyl, C3-8Heteroaryl, nitro, cyano replace, wherein 2 adjacent substituent groups Atom that can be in connection constitutes cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxy ring penta together Alkyl or Isosorbide-5-Nitrae-dioxocyclohex alkyl, the cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxy ring penta Alkyl and 1,4- dioxocyclohex alkyl are optionally further selected from C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkane One or more groups substitution of oxygroup, oxo, halogen.
In some preferred embodiments, each R2Independently selected from hydrogen, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alcoxyl Base, halogenated C1-6Alkoxy, halogen, amino, C1-6Alkyl amino, C1-6Alkylaminoacyl, aminoacyl, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acylamino, C2-6Alkenylacyl amino, nitro, cyano, wherein n is selected from 1,2,3 and 4；Into one It walks preferably, each R2Independently selected from hydrogen, C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, halogen, ammonia Base, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-4Alkenylacyl, C1-3Alkyl acyl ammonia Base, C2-4Alkenylacyl amino, nitro, cyano, wherein n is selected from 1,2 and 3.
In some embodiments, each R2Independently selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, Fluorine, chlorine, amino, methylamino, dimethylamino, ethylamino, lignocaine, methylethylamine, methylamino acyl group, ethylamino Acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, methylacyl amino, ethyl acyl amino, vinyl acyl Base amino, nitro, cyano, wherein n is selected from 1,2 and 3.
In some specific embodiments, each R2In must have one for vinyl acyl amino, remaining each R2Selected from hydrogen, Methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, fluorine, chlorine, amino, methylamino, dimethylamino, ethylamino, lignocaine, Methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, Nitro, cyano, wherein n is selected from 2 and 3.
In some specific embodiments, each R2In must have one for vinyl acyl amino, and withIt is adjacent, Remaining each R2Selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, fluorine, chlorine, amino, methylamino, dimethylamino, second Amino, lignocaine, methylethylamine, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl Base, vinyl acyl group, nitro, cyano, wherein n is selected from 2 and 3.
In some preferred embodiments, Q is selected from N, O ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3 Alkylidene radical-,-C (O) N- ,-NHC (O)-and-NHC (O) N-, Ra、RbSeparately it is selected from hydrogen, C1-6Alkyl, C1-6Alkyl amino, C2-6Alkenyl, amino, C1-6Alkyl amino C1-6Alkyl, C3-8Naphthenic base ,-C1-6Alkyl-C3-8Naphthenic base, aryl ,-C1-6Alkyl- Aryl, C3-10Heterocycle ,-C1-6Alkyl-C3-10Heterocycle, the C1-6Alkyl, C2-6Alkenyl, C3-8Naphthenic base ,-C1-6Alkane Base-C3-8Naphthenic base, aryl, C3-10Heterocycle ,-C1-6Alkyl-C3-10Heterocycle is optionally by one or more halogens, C1-6Alkyl, C2-6Alkenyl, amino, C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkylaminoacyl, aminoacyl, C2-6Alkenylacyl, C3-8Naphthenic base, C3-8Cycloalkenyl, C3-8Heterocycle replaces, wherein when Q is selected from O and-NHC (O)-, RbIt does not deposit ?；Or
Q is selected from N ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene radical-,-C (O) N- and-NHC (O) N, Ra、RbN atom or CH connected to it constitute quaternary, five-, six- or seven-membered naphthenic base, cycloalkenyl or heterocycle, institute together Quaternary, five-, six- or seven-membered naphthenic base, cycloalkenyl or the heterocycle stated are optionally by one or more halogens, C1-6Alkyl, halogen For C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, amino, C1-6Alkyl amino, C1-6Alkylaminoacyl, aminoacyl, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acylamino, C3-8Naphthenic base, C3-8Cycloalkenyl, C3-8Heterocycle replaces.? In some embodiments, Q is selected from N, O ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene radical-,-C (O) N- ,-NHC (O)-and-NHC (O) N-, Ra、RbSeparately it is selected from hydrogen, C1-3Alkyl, C1-3Alkyl amino, C2-4Alkenyl, ammonia Base, C1-3Alkyl amino C1-3Alkyl, C3-6Naphthenic base ,-C1-3Alkyl-C3-6Naphthenic base, aryl ,-C1-3Alkyl-aryl-group, C3-6Heterocycle Base ,-C1-3Alkyl-C3-6Heterocycle, the C1-3Alkyl, C2-4Alkenyl, C3-6Naphthenic base ,-C1-3Alkyl-C3-6Naphthenic base, virtue Base, C3-6Heterocycle ,-C1-3Alkyl-C3-6Heterocycle is optionally by one or more halogens, C1-3Alkyl, C2-4Alkenyl, amino, C1-3Alkyl amino, halogenated C1-3Alkyl, C1-3Alkyl acyl, C1-3Alkylaminoacyl, aminoacyl, C2-3Alkenylacyl, C3-6 Naphthenic base, C3-6Cycloalkenyl, C3-6Heterocycle replaces, wherein when Q is selected from O and-NHC (O)-, RbIt is not present；Or
Q is selected from N ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene radical-,-C (O) N- and-NHC (O) N, Ra、RbN atom or CH connected to it constitute quaternary, five-, six- or seven-membered naphthenic base, cycloalkenyl or heterocycle, institute together Quaternary, five-, six- or seven-membered naphthenic base, cycloalkenyl or the heterocycle stated are optionally by one or more halogens, C1-3Alkyl, halogen For C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, amino, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-3Alkenylacyl, C1-3Alkyl acylamino, C3-6Naphthenic base, C3-6Cycloalkenyl, C3-6Heterocycle replaces.
In some embodiments, Q is selected from N, O ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene Base-,-C (O) N- ,-NHC (O)-and-NHC (O) N-, Ra、RbSeparately it is selected from hydrogen, C1-3Alkyl, C1-3Alkyl amino, C2-4 Alkenyl, amino, C1-3Alkyl amino C1-3Alkyl, C3-6Naphthenic base ,-C1-3Alkyl-C3-6Naphthenic base, aryl ,-C1-3Alkyl-virtue Base, C4-8Azacycloalkyl, C4-8Diazacyclo alkyl ,-C1-3Alkyl-C4-8Azacycloalkyl ,-C1-3Alkyl-C4-8Diazacyclo Alkyl, C4-8Azepine cycloalkenyl, C4-8Diazacyclo alkenyl ,-C1-3Alkyl-C4-8Azepine cycloalkenyl ,-C1-3Alkyl-C4-8Diaza Cycloalkenyl, the C1-3Alkyl, C2-4Alkenyl, C3-6Naphthenic base ,-C1-3Alkyl-C3-6Naphthenic base, aryl, C4-8Azacycloalkyl Base, C4-8Diazacyclo alkyl ,-C1-3Alkyl-C4-8Azacycloalkyl ,-C1-3Alkyl-C4-8Diazacyclo alkyl, C4-8Azacyclo- Alkenyl, C4-8Diazacyclo alkenyl ,-C1-3Alkyl-C4-8Azepine cycloalkenyl ,-C1-3Alkyl-C4-8Diazacyclo alkenyl is optionally by one A or multiple halogens, C1-3Alkyl, C2-4Alkenyl, amino, C1-3Alkyl amino, halogenated C1-3Alkyl, C1-3Alkyl acyl, C1-3Alkane Base aminoacyl, aminoacyl, C2-3Alkenylacyl, C3-6Naphthenic base, C3-6Heterocycle replaces, wherein when Q is selected from O and-NHC (O)-when, RbIt is not present；Or
Q is selected from N ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene radical-,-C (O) N- and-NHC (O) N, Ra、RbN atom or CH connected to it constitute quaternary, five-, six- or seven-membered naphthenic base, azacycloalkyl, azacyclo- together Alkenyl, diazacyclo alkyl or diazacyclo alkenyl, the quaternary, five-, six- or seven-membered naphthenic base, azacycloalkyl, Azepine cycloalkenyl, diazacyclo alkyl or diazacyclo alkenyl are optionally by one or more halogens, C1-3Alkyl, halogenated C1-3Alkane Base, C1-3Alkoxy, halogenated C1-3Alkoxy, amino, C1-3Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl Acyl group, C2-3Alkenylacyl, C1-3Alkyl acylamino, C3-6Naphthenic base, C3-6Cycloalkenyl, C3-6Heterocycle replaces.
In some preferred embodiments, Q is selected from N, O ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3 Alkylidene radical-,-C (O) N- ,-NHC (O)-and-NHC (O) N-, Ra、RbSeparately it is selected from hydrogen, C1-6Alkyl, piperazinyl, piperidines Base, N- azetidinyl, nafoxidine base, C1-6Alkyl-piperazinyl, C1-6Alkyl-piperidinyl, C1-6Alkyl-N-heterocycle butane Base, C1-6Alkyl-nafoxidine base, the C1-6Alkyl, piperazinyl, piperidyl, N- azetidinyl, nafoxidine base, C1-6 Alkyl-piperazinyl, C1-6Alkyl-piperidinyl, C1-6Alkyl-N-heterocycle butane group, C1-6Alkyl-nafoxidine base is optionally by one Or multiple halogens, amino, C1-6Alkyl, C1-6Alkyl amino, halogenated C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkylaminoacyl, Aminoacyl, C2-6Alkenylacyl, piperazinyl, N- alkylpiperazinyl replace, wherein when Q is selected from O and-NHC (O)-, RbIt does not deposit ?；Or
Q is selected from N ,-C1-C3Alkylidene radical-,-C1-C3Alkylidene radical-N- ,-NH-C1-C3Alkylidene radical-,-C (O) N- and-NHC (O) N, Ra、RbN atom connected to it constitutes piperazine ring, nafoxidine ring, piperidine ring, N- azetidine or R togethera、RbConnect with it The CH connect constitutes pyrazole ring together, and the piperazine ring, nafoxidine ring, piperidine ring, N- azetidine, pyrazole ring are optionally by one A or multiple halogens, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, amino, C1-6Alkyl amino, C1-6 Alkylaminoacyl, aminoacyl, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acylamino, heterocycle replace；
In other embodiments, Q is selected from N, O, CH, Ra、RbSeparately it is selected from hydrogen, C1-6Alkyl, piperazinyl, piperazine Piperidinyl, N- azetidinyl, nafoxidine base, C1-6Alkyl-piperazinyl, C1-6Alkyl-piperidinyl, C1-6Alkyl-N-heterocycle butane Base, C1-6Alkyl-nafoxidine base, the C1-6Alkyl, piperazinyl, N- azetidinyl, nafoxidine base, C1-6Alkyl-piperazine Piperazine base, C1-6Alkyl-piperidinyl, C1-6Alkyl-N-heterocycle butane group, C1-6Alkyl-nafoxidine base is optionally by one or more halogen Element, amino, C1-3Alkyl, C1-3Alkyl amino, halogenated C1-3Alkyl, C1-3Alkyl acyl, C1-3Alkylaminoacyl, aminoacyl, C2-4Alkenylacyl, piperazinyl, N- alkylpiperazinyl replace, wherein when Q is selected from O, RbIt is not present；Or
Q is selected from N and CH, Ra、RbN atom connected to it constitutes piperazine ring, nafoxidine ring, piperidine ring, N- heterocycle together Butane or Ra、RbCH connected to it constitutes pyrazole ring, the piperazine ring, nafoxidine ring, piperidine ring, N- heterocycle fourth together Alkane, pyrazole ring are optionally by one or more C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, amino, C1-3 Alkyl amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-4Alkenylacyl, C1-3Alkyl acylamino, piperazine Piperazine base, N- alkylpiperazinyl replace.
In other specific embodiments, Q is selected from N and O, RaSelected from-C1-3Alkyl amino ,-C1-3Alkyl amino C1-3 Alkyl ,-C1-3Alkyl amino (C1-3Alkyl) (C1-3Alkyl) ,-C1-3Alkyl oxy C1-3Alkyl ,-C1-3Alkyl-C4-8Azacycloalkyl Base ,-C1-3Alkyl-C4-8Diazacyclo alkyl, RbSelected from hydrogen, C1-6Alkyl, wherein when Q is selected from O, RbIt is not present.
In other specific embodiments, Q is selected from N and O, RaSelected from-ethyleneimino ,-ethylidene-methylamino ,- Ethylidene-dimethylamino ,-ethylenemethoxy ,-ethylidene ethyoxyl ,-ethylidene nafoxidine base ,-ethylidene piperidyl ,- Ethylidene piperazinyl ,-ethylidene methyl piperazine base, RbSelected from hydrogen, C1-6Alkyl, wherein when Q is selected from O, RbIt is not present.
According to the present invention, in some preferred embodiments, the compound of the present invention is compounds of formula I or its medicine Learn acceptable salt, isomers, solvate, crystallization or prodrug, in which:
X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino；
Y is key；
R1Selected from phenyl, naphthalene, pyridyl group, pyrimidine radicals, pyrrole radicals, pyrazolyl, furyl, thienyl, thiazolyl, imidazoles Base, oxazolyl, isoxazolyl, indyl, isoindolyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuranyl, benzo Pyrazolyl, benzothienyl and benzoxazolyl, the phenyl, naphthalene, pyridyl group, pyrimidine radicals, pyrrole radicals, pyrazolyl, furan Mutter base, thienyl, thiazolyl, imidazole radicals, oxazolyl, isoxazolyl, indyl, isoindolyl, Pyrazolopyridine, quinolyl, Isoquinolyl, benzofuranyl, benzopyrene oxazolyl, benzothienyl and benzoxazolyl are optionally by one or more C1-3Alkyl, Halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, oxo, halogen, amino, C1-3Alkyl amino, C1-3Alkyl amino acyl Base, aminoacyl, C1-3Alkyl acyl, C2-4Alkenylacyl, C1-3Alkyl acylamino, C2-4Alkenylacyl amino, phenyl, C3-8 Heterocyclylalkyl, C3-8Heteroaryl, nitro, cyano replace, wherein the atom that 2 adjacent substituent groups can be in connection is together Constitute cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxolanes base or Isosorbide-5-Nitrae-dioxocyclohex alkyl, institute Cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxolanes base or the 1,4- dioxocyclohex alkyl stated are appointed Choosing is further selected from C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, one of oxo and halogen or Multiple groups replace；
Each R2In must have one for vinyl acyl amino, and withIt is adjacent, remaining each R2Selected from hydrogen, methyl, second Base, trifluoromethyl, methoxyl group, ethyoxyl, fluorine, chlorine, amino, methylamino, dimethylamino, ethylamino, lignocaine, Methylethyl Amino, methylamino acyl group, ethylamino acyl group, aminoacyl, methylacyl, ethyl acyl group, vinyl acyl group, nitro, cyanogen Base, wherein n is selected from 2 and 3；
Q is selected from N and O, RaSelected from-ethyleneimino ,-ethylidene-methylamino ,-ethylidene-dimethylamino ,-ethylidene first Oxygroup ,-ethylidene ethyoxyl ,-ethylidene nafoxidine base ,-ethylidene piperidyl ,-ethylidene piperazinyl ,-ethylidene methyl Piperazinyl, RbSelected from hydrogen, C1-6Alkyl, wherein when Q is selected from O, RbIt is not present.
In some preferred embodiments, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug, wherein the general formula I is general formula Ia,
Wherein:
X is selected from hydrogen, halogen, C1-6Alkyl and amino；
R1Selected from aryl and heteroaryl, the aryl and heteroaryl are optionally by one or more C1-6Alkyl, halogenated C1-6 Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, oxo, halogen, amino, C1-6Alkyl amino, C1-6Alkylaminoacyl, amino Acyl group, C1-6Alkyl acyl, C2-6Alkenylacyl, C1-6Alkyl acylamino, C2-6Alkenylacyl amino, nitro, cyano replace, In, 2 adjacent substituent groups can be constituted together C with atom connected to it3-6Naphthenic base or C3-6Heterocyclylalkyl, the C3-6 Naphthenic base or C3-6Heterocyclylalkyl is optionally further selected from C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alcoxyl One or more groups of base, oxo and halogen replace；
Each R2Independently selected from hydrogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, alkyl amino, Nitro and cyano, wherein n is selected from 1,2 and 3；
Q is selected from N and O, RaSelected from-C1-6Alkyl amino ,-C1-6Alkyl amino C1-6Alkyl ,-C1-6Alkyl amino (C1-6Alkane Base) (C1-6Alkyl) ,-C1-6Alkyl oxy C1-6Alkyl ,-C1-6Alkyl C3-8Heterocyclylalkyl, RbSelected from hydrogen, C1-6Alkyl, wherein working as Q When selected from O, RbIt is not present.
In some preferred embodiments, the compound of general formula Ia of the present invention or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, wherein X is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, amino.
In some preferred embodiments, the compound of general formula Ia of the present invention or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, wherein R1Selected from phenyl, naphthalene, pyridyl group, pyrimidine radicals, pyrrole radicals, pyrazolyl, furyl, thiophene Pheno base, thiazolyl, imidazole radicals, oxazolyl, isoxazolyl, indyl, isoindolyl, Pyrazolopyridine, quinolyl, isoquinolin Base, benzofuranyl, benzopyrene oxazolyl, benzothienyl and benzoxazolyl, the phenyl, naphthalene, pyridyl group, pyrimidine Base, pyrrole radicals, pyrazolyl, furyl, thienyl, thiazolyl, imidazole radicals, oxazolyl, isoxazolyl, indyl, isoindolyl, Pyrazolopyridine, quinolyl, isoquinolyl, benzofuranyl, benzopyrene oxazolyl, benzothienyl and benzoxazolyl optionally quilt One or more C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3Alkoxy, oxo, halogen, amino, C1-3Alkyl Amino, C1-3Alkylaminoacyl, aminoacyl, C1-3Alkyl acyl, C2-4Alkenylacyl, C1-3Alkyl acylamino, C2-4Alkenyl Acyl amino, nitro, cyano replace, wherein 2 adjacent substituent groups can atom in connection constitute cyclopropane together Base, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxolanes base, Isosorbide-5-Nitrae-dioxocyclohex alkyl, the cyclopropane Base, cyclobutane base, pentamethylene base, cyclohexyl, 1,3- dioxolanes base, 1,4- dioxocyclohex alkyl are optionally further chosen From C1-3Alkyl, halogenated C1-3Alkyl, C1-3Alkoxy, halogenated C1-3One or more groups substitution of alkoxy, oxo, halogen.
In some preferred embodiments, the compound of general formula Ia of the present invention or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, wherein each R2Independently selected from hydrogen, methyl, ethyl, trifluoromethyl, methoxyl group, ethyoxyl, fluorine, Chlorine, amino, methylamino, dimethylamino, ethylamino, lignocaine, methylethylamine, nitro, cyano, wherein n is selected from 1,2 and 3；
In some preferred embodiments, the compound of general formula Ia of the present invention or its pharmaceutically acceptable salt, isomers, Solvate, crystallization or prodrug, wherein Q is selected from N and O, RaSelected from-C1-3Alkyl amino ,-C1-3Alkyl amino C1-3Alkyl ,-C1-3 Alkyl amino (C1-3Alkyl) (C1-3Alkyl) ,-C1-3Alkyl oxy C1-3Alkyl ,-C1-3Alkyl C3-6Nitrogen-containing heterocycle alkyl, RbIt is selected from Hydrogen, C1-3Alkyl, wherein when Q is selected from O, RbIt is not present；
It is further preferred that Q is selected from N and O, RaSelected from-ethyleneimino ,-ethylidene-methylamino ,-ethylidene-diformazan Amino ,-ethylenemethoxy ,-ethylidene ethyoxyl ,-ethylidene nafoxidine base ,-ethylidene piperidyl ,-ethylidene piperazine Base ,-ethylidene methyl piperazine base, RbSelected from hydrogen, C1-3Alkyl, wherein when Q is selected from O, RbIt is not present.
In a specific embodiment, the present invention provides following compound or its pharmaceutically acceptable salt, isomery Body, solvate, crystallization or prodrug:
On the other hand, the present invention provides the preparation method of compounds of formula I of the invention.The system of compounds of formula I Preparation Method includes the following steps:
The intermediate that formula 3 is made in necleophilic reaction occurs for the raw material of A formula 1 and the raw material of formula 2；
The intermediate of B formula 3 reacts the intermediate that formula 5 is made with the raw material of formula 4；
The intermediate of C formula 5 is reacted with the raw material of formula 6 is made compounds of formula I.
Above-mentioned X, Y, R1、R2、Q、Ra、RbWith the definition in general formula I.
The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically acceptable salt, Isomers, solvate, crystallization or prodrug.
In some embodiments, the present invention provides pharmaceutical composition, and it includes the compound of the present invention, isomers, molten Object, crystallization or prodrug are closed in agent, also comprising one or more compounds selected from following composition: Gefitinib, Tarceva, La Pa Buddhist nun (dacomitinib), pelitinib are replaced for Buddhist nun, Afatinib, Vande Thani, Canertinib, Ah pa for Buddhist nun, Dacca (pelitinib), WZ4002, AG-490, AZD8931 etc..
Can by the compound of the present invention, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, Diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but unlimited In in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, example Such as by being transfused or injecting, the approach for passing through transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorption is applied.It gives Medicine can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including piece Agent, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be by methods known in the art system It is standby, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide the compound of the present invention, isomers, solvate, crystallization or prodrug or the present invention Medicine composite for curing and/or pre- preventing tumor method and preparation treatment and/or prevention tumour medicine in application, including Easily send out crowd to tumour or tumor patient apply the compound of the present invention, isomers, solvate, crystallization or prodrug or comprising The pharmaceutical composition of the compound of the present invention, isomers, solvate, crystallization or prodrug, Tumor incidence is effectively reduced, prolongs Bearing tumor patient vitals.
In some embodiments, the present invention provides compounds of formula I of the invention, isomers, solvate, crystallization Or prodrug or medicine composite for curing of the invention have the method for the tumour of drug resistance, including suffering to the tumour with drug resistance Person applies the compound of the present invention, isomers, solvate, crystallization or the prodrug of therapeutically effective amount or includes change of the invention Close the pharmaceutical composition of object, isomers, solvate, crystallization or prodrug.In other embodiments, the present invention provides this hair Bright compounds of formula I, isomers, solvate, crystallization or prodrug or pharmaceutical composition of the invention are in preparation treatment tool There is the application in the drug of the tumour of drug resistance.The tumour with drug resistance, which can be, has drug resistance to a variety of drugs Tumour preferably has the tumour of drug resistance to EGFR inhibitor, such as to the first, second, third generation EGFR inhibitor, such as right Gefitinib, Tarceva and Lapatinib have the tumour of drug resistance.The tumour includes but is not limited to solid tumor, preferably Lung cancer, head and neck neoplasm, colorectal cancer, bladder cancer, cancer of pancreas, breast cancer, prostate cancer, gastric cancer, carcinoma of mouth, liver cancer, ovary Cancer.It is highly preferred that the tumour is non-small cell lung cancer.In some embodiments, the present invention provides general formula I's of the invention The method that compound, isomers, solvate, crystallization or prodrug treatment have the tumour of drug resistance, wherein the tumour carries EGFR mutated gene.In one embodiment, the EGFR mutated gene that the tumour carries is that the 20th exon exists T790M mutation.In another embodiment, the EGFR mutated gene that the tumour carries is that the 21st exon exists L858R mutation and/or missing/insertion mutation.In another embodiment, the EGFR mutated gene of the tumour carrying is T790M and L858R double mutations.In other embodiments, the present invention is provided to treat the general formula I of the invention of tumour Compound, isomers, solvate, crystallization or prodrug or pharmaceutical composition of the invention, wherein treatment function of tumor performance In curative effect outstanding, the selectivity of height and/or less side effect.In some other embodiments, the present invention provides this hair The side of bright compounds of formula I, isomers, solvate, crystallization or prodrug or medicine composite for curing tumour of the invention Method, the method includes giving the compounds of formula I of the invention for needing its bacterium, isomers, solvent Object, crystallization or prodrug or pharmaceutical composition of the invention are closed, the effect in terms of generated treatment tumour shows treatment outstanding Effect, the selectivity of height and/or less side effect.
Term definition
Unless otherwise defined, all technical and scientific terms used herein has and common skill of the art The normally understood identical meaning of art personnel.
" isomers " of the invention includes compound along configuration structure body, conformer and enantiomter.Configuration isomery Body refers to the cis-trans-isomer of cis or trans configuration.Conformer refers to the stereoisomer generated due to singly-bound rotation.
It is pharmaceutically acceptable that " pharmaceutically acceptable salt " of the invention refers to that compound of the present invention is formed with acid Salt, the acid can be selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, Fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam etc..
" solvate " of the invention refer to solute (salt of reactive compound, the reactive compound such as of the invention) and The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the invention refers to that the various solid forms that compound of the present invention is formed, including crystal form, nothing are determined Shape.
" prodrug " of the invention refer under the physiological condition of organism, due to reacting and conversion cost with enzyme, gastric acid etc. The compound of the compound of invention is converted to the compound of the compound of the present invention by the oxidation of enzyme, reduction, hydrolysis etc. And/or the compound of the compound of the present invention is converted to by the hydrolysis etc. of gastric acid etc..
" pharmaceutical composition " of the invention refer to comprising any compound as described herein, including isomers, prodrug, Solvate, the protection form of pharmaceutically acceptable salt or its chemistry and one or more pharmaceutically acceptable carriers it is mixed Close object.
It is of the invention " preparation for treat and/or the drug of pre- preventing tumor in application " refer to and can inhibit tumour Growth, development and/or transfer, mainly given to required human or animal control give the compound of the present invention for the treatment of effective dose with Inhibit, slow down or reverse the growth, development or expanding of subject's tumour.
" alkyl " of the invention refers to straight chain, branch or cricoid saturated hydrocarbyl, preferably 12 carbon atom alkyl below, More preferable 6 carbon atoms alkyl below.The embodiment of alkyl includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, positive fourth Base, isobutyl group, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohesyl, 2,2 ,-methyl fourth Base and 2,3- dimethylbutyl." C of the invention1-6Alkyl " refers to the straight chain containing 1-6 carbon atom, branch or cricoid full And alkyl." C of the invention1-3Alkyl " refers to the straight chain containing 1-3 carbon atom, branch or cricoid saturated hydrocarbyl.
" alkenyl " of the invention refers to the linear chain or branched chain unsaturated alkyl containing one or more carbon-carbon double bonds (C=C). " C of the invention2-6Alkenyl " refers to the unsaturated alkyl containing 1 or 2 carbon-carbon double bonds and containing 2 to 6 carbon atoms.This hair Bright " C2-4Alkenyl " refers to the unsaturated alkyl containing 1 or 2 carbon-carbon double bonds and containing 2 to 4 carbon atoms.
" alkoxy " of the invention refers to-O- alkyl.
" halogen " of the invention refers to fluorine, chlorine, bromine, iodine.
" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen atom.
" halogenated alkoxy " of the invention refers to the alkoxy at least replaced by a halogen, preferably at least by a halogen The C that element replaces1-6Alkoxy, further preferably halogenated C1-3Alkoxy, suitable halogenated C1-3Alkoxy is chloromethane epoxide, fluorine Methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy；Two chloroethoxies, difluoroethoxy, trichlorine Ethyoxyl, trifluoro ethoxy.
" alkyl amino " of the invention refers to by alkyl-substituted amino, including alkyl monosubstituted amino, double alkyl aminos.
" aryl " of the invention includes mononuclear aromatics and polycyclic aromatic hydrocarbon.Contain a phenyl ring in monocyclic aromatic hydrocarbon group, specifically Such as benzene,toluene,xylene, halogeno-benzene, styrene；In polycyclic aromatic group contain more than two phenyl ring, as biphenyl, naphthalene, Anthracene etc..
" heteroaryl " of the invention, which refers to, at least contains 1 heteroatomic aryl.
" heterocycle " of the invention refers at least containing a heteroatomic saturation, fractional saturation and complete unsaturated ring Shape group, wherein hetero atom is N, O or S, including single heterocycle and condensed hetero ring base, total annular atom number of the preferably described heterocycle are 5-15.Suitable list heterocycle includes but is not limited to furans, thiophene, pyrroles, thiazole, imidazoles, 1,2,3- triazole, 1,2,4- tri- Nitrogen azoles, 1,2,3- thiadiazoles, oxazole, 1,2,4- oxadiazoles, 1,3,4- oxadiazoles, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydro furan It mutters, nafoxidine, piperidines, piperazine, morpholine, isoxazoline etc..Suitable condensed hetero ring base include but is not limited to quinoline, isoquinolin, Indoles, benzodioxole base, benzo dioxine base, benzofuran, benzothiophene, purine, acridine, carbazole, Fluorenes, chromene ketone, Fluorenone, quinoxaline, 3,4- dihydro naphthalenone, dibenzofurans, hydrogenated dibenzofurans, benzoxazolyl etc..
Specific embodiment
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below It encloses.
1 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1- methyl Yin Diindyl -4- base) -1,3,5- triazine -2- amino) phenyl) allyl amide
The synthesis of the chloro- N- of step a 4- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -1,3,5- triazine -2- amine
In 100ml reaction flask, the fluoro- 2- methoxyl group -5- nitroaniline (4.0g, 21.5mmol) of 4-, DIPEA are sequentially added (8.32g, 64.5mmol) and 60ml tetrahydrofuran, dissolution, is cooled to 0-2 DEG C, 2,4-, bis- chloro-1,3,5-triazines is added portionwise (3.14g, 21.08mmol), finishes, the reaction was continued 5h, stops reaction, and 60ml water is added, and stirs, and filtering, filter cake is washed with water, and does It is dry to obtain title compound, it is directly used in next step.
Step b N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- methyl indol -4- base) -1,3,5- triazine -2- The synthesis of amine
In 30ml microwave reaction bottle, 1- methyl indol -4- borate (800mg, 3.11mmol), step a are sequentially added The chloro- N- of gains 4- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -1,3,5-triazines -2- amine (965mg, 3.11mmol), [1, Bis- (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex (110mg, 0.04eq), x-phos (237mg, 0.16eq), cesium carbonate (3.0g, 9.33mmol) and Isosorbide-5-Nitrae-dioxane/H2O (15ml/2.5ml), dissolution, argon gas displacement, 105 DEG C microwave reaction 90min, concentration, column chromatographic purifying obtain title compound.
Step c N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenone) -4- The synthesis of (1- methyl indol -4- base) -1,3,5- triazine -2- amine
In 50ml single port bottle, step b gains N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- is sequentially added Methyl indol -4- base) -1,3,5-triazines -2- amine (52mg, 0.13mmol), N, N, N '-trimethyl ethylenediamine (20.0mg, 0.19mmol), DIPEA (50mg, 0.39mg) and 10ml dioxane, dissolution, 110 DEG C of back flow reaction 3h stop reaction, dense Contracting, column chromatographic purifying obtain title compound.
Step d N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- aminophenyl) -4- The synthesis of (1- methyl indol -4- base) -1,3,5- triazine -2- amine
In 50ml single port bottle, step c gains N- (4- ((2- (dimethylamino) ethyl) (methyl) ammonia is sequentially added Base) -2- methoxyl group -5- nitrobenzophenone) -4- (1- methyl indol -4- base) -1,3,5-triazines -2- amine (54mg, 0.11mmol), 10%Pd-C (5mg) and 10ml methanol are depressed, H in 1 normal atmosphere21h is restored, reaction is stopped, title compound is concentrated in filtering Object obtains title compound, is directly used in next step.
Step e N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1- methyl Yin Diindyl -4- base) -1,3,5 triazine -2- amino) phenyl) and allyl amide synthesis
In 50ml single port bottle, step d gains N- (4- ((2- (dimethylamino) ethyl) (methyl) amino)-is added 2- methoxyl group -5- aminophenyl) it is -4- (1- methyl indol -4- base) -1,3,5-triazines -2- amine (41mg, 0.09mmol), two different Propylethylamine (35.0mg, 0.27mmol), 15ml anhydrous methylene chloride, dissolution instill allyl acyl chlorides (10mg, 0.11mmol) Methylene chloride (1ml) solution, 10min fully reacting, concentration, column chromatographic purifying obtains title compound.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:501.4[M+H]。
2 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1- methyl Yin - 2 base of diindyl) -1,3,5- triazine -2- amino) phenyl) allyl amide
Step a N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- methyl indol -2- base) -1,3,5- triazine -2- The synthesis of amine
With embodiment 1 the chloro- N- of step a gains 4- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -1,3,5- triazine -2- amine It is raw material with 1- methyl indol -2- boric acid, title compound is made according to the method for 1 step b of embodiment.
Step b 2N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1- methyl Yin - 2 base of diindyl) -1,3,5- triazine -2- amino) phenyl) and allyl amide synthesis
With step a gains N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- methyl indol -2- base) -1,3,5- Triazine -2- amine, N, N, N '-trimethyl ethylenediamine and allyl acyl chlorides are raw material, according to 1 step c of embodiment, step d and step e Method be made title compound.
1H-NMR(300MHz,DMSO-d6)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-Ms m/z:501.3[M+H]。
3 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (3- (1- first Base Carbamoylphenyl)) -1,3,5- triazine -2- amino) phenyl) allyl amide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- (methyl-carbamoyl) phenyl boric acid Ester, N, N, N '-trimethyl ethylenediamine and allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:2.25(6H,d),2.37-2.41(m,2H),2.72(3H,s),2.80(3H, s),2.92(2H,m),3.81(3H,s),5.75-5.77(1H,d),6.24-6.(1H,d),6.42-6.48(1H,m),7.02 (1H,s),7.62(1H,s),8.02-8.03(1H,d),8.27(1H,s),8.59(2H,s),8.77(1H,s),8.83,(1H, s),9.27(1H,s),10.11(1H,s)。
ESI-Ms m/z:505.3[M+H]。
(((3,4- is (sub- by 4- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- by 4 N- of embodiment Two oxygroup of methyl) phenyl)) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4- (methylenedioxy) benzene boron Acid esters, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:2.25(6H,d),2.40(2H,s),2.70(4H,s),2.91(2H,m), 3.81(3H,s),5.74-5.76(1H,d),6.12(2H,s),6.27-6.30(1H,m),6.40-6.45(1H,m),7.02 (2H,s),7.90(1H,s),8.09-8.14(1H,d),8.66(1H,s),8.90-8.95(1H,s),10.02(1H,s)。
ESI-Ms m/z:492.3[M+H]。
5 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1- methyl Yin Diindyl -5- base) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1- methyl indol -5- borate, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:501.4[M+H]。
6 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (1H- indoles - 3- yl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1H- indoles -3- borate, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:487.3[M+H]。
7 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (4- methoxy Base phenyl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyphenylboronic acid ester, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:2.21(s,6H),2.36-2.39(t,2H),2.68(s,3H),2.88- 2.89(t,2H),3.80(s,3H),3.82(s,3H),5.73-5.77(d,1H),6.23-6.29(d,1H),6.39-6.48 (dd, 1H), 6.99-7.04 (m, 3H), 8.28 (s, 1H), 8.39-8.42 (m, 2H), 8.64 (s, 1H), 8.96 (brs, 1H), 10.10(s,1H)。
ESI-Ms m/z:478.3[M+H]。
8 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- amino Fonnylphenyl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- carbamoyl borate ester, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:2.28(s,6H),2.35-2.39(t,2H),2.73(s,3H),2.89- 2.91(t,2H),3.81(s,3H),5.75-5.79(d,1H),6.24-6.27(d,1H),6.39-6.44(dd,1H),7.03 (s,1H),7.42(s,1H),7.60(s,1H),8.06-8.17(m,3H),8.59(s,1H),8.76(s,1H),8.64(s, 1H),9.25(s,1H),10.10(s,1H)。
ESI-Ms m/z:491.4[M+H]。
9 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (2,3- bis- Hydrogen benzo [1,4] dioxin -6- base) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, phendioxin, 4- dioxane -6- boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:10.10(s,1H),8.65(s,2H),8.35(s,1H),7.96(s,1H), 7.86(s,1H),7.02(s,1H),6.96(s,1H),6.43-6.38(m,2H),5.77-5.75(d,1H),4.32-4.28(d, 4H),3.80(s,3H),2.88(s,2H),2.73(s,4H),2.34-2.32(s,2H),2.09(s,5H)。
ESI-Ms m/z:506.3[M+H]。
10 N- of embodiment (2- ((2- (4- methylpiperazine-1-yl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (4- methoxyphenyl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyphenylboronic acid, N- methyl - 2- (4- methylpiperazine-1-yl) ethamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.34(s,1H),8.66(s,1H),8.39(s,4H),7.04(s,2H), 6.96(s,1H),6.15-6.59(s,1H),6.28(s,1H),5.76-5.61(d,1H),3.84-3.82(s,6H),3.57- 3.48(m,3H),2.70(s,4H),2.50(s,4H),2.39-2.29(m,3H),2.13-2.08(s,4H)。
ESI-Ms m/z:533.4[M+H]。
11 N- of embodiment (2- ((2- (4- methylpiperazine-1-yl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1H- indol-3-yl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1H- indoles -3- boric acid, N- methyl - 2- (4- methylpiperazine-1-yl) ethamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:542.4[M+H]。
12 N- of embodiment (2- ((2- (piperidin-1-yl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (2,3- bis- Hydrogen benzo [1,4] dioxin -6- base) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, phendioxin, 4- dioxane -6- boron Acid, N- methyl -2- (piperidin-1-yl) ethamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.37(s,1H),9.01(bs,1H),8.64(s,1H),8.29(s,1H), 7.95-7.94(m,1H),7.84(s,1H),6.95(s,2H),6.62-6.56(m,1H),6.26-6.23(m,1H),5.75- 5.73(d,1H),4.31-4.27(m,4H),3.80(s,3H),2.98(m,2H),2.69(s,3H),2.35-2.32(m,6H), 1.47(m,4H),1.36(m,2H)。
ESI-Ms m/z:546.5[M+H]。
13 N- of embodiment (2- ((2- (piperidin-1-yl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (4- methoxy Base phenyl) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyphenylboronic acid, N- methyl - 2- (piperidin-1-yl) ethamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.1H-NMR (500MHz,DMSO-d6)δ:9.40(s,1H),9.01(bs,1H),8.66(s,1H),8.40(m,2H),8.17(s,1H), 7.04(m,2H),6.96(s,1H),6.64-6.58(m,1H),6.28-6.25(m,1H),5.77-5.75(d,1H),3.84- 3.82(s,6H),3.00-2.99(m,2H),2.70(s,3H),2.5(m,2H),2.40-2.36(m,4H),1.49(m,4H), 1.37(m,2H)。
ESI-Ms m/z:518.4[M+H]。
14 N- of embodiment (3- ((4- ((4- (4- Acetylpiperazine -1- base) -2- methoxyphenyl) amino) -1,3,5- three Piperazine -2- base) amino) phenyl) acrylamide
Step a N- (3- ((the chloro- 1,3,5- triazine -2- base of 4-) amino) phenyl) acrylamide
0.165g 2 is weighed, bis- chloro-1,3,5-triazines of 4- are dissolved in reaction flask with 5mL THF, are slowly added dropwise at 0 DEG C Enter 0.155g DIPEA, after stirring 10min, the THF into 5ml dissolved with 0.216g N- (3- aminobenzene) acrylamide is slowly added dropwise Solution stirs 30min, stops reaction, and 30mL ice water is added, and ethyl acetate extracts (3 × 15mL), merges organic layer, saturation food Salt water washed once, and anhydrous sodium sulfate dries, filters, and be spin-dried for, and obtain title compound.
ESI-MS m/z:276[M+H]。
Step b N- (3- ((4- ((4- (4- Acetylpiperazine -1- base) -2- methoxyphenyl) amino) -1,3,5- triazine - 2- yl) amino) phenyl) acrylamide
Weigh 0.26g step a gains N- (3- ((the chloro- 1,3,5- triazine -2- base of 4-) amino) benzene) acrylamide and Ethyl ketone is in reaction flask by 0.5g 1- (4- (4- amino -3- methoxyphenyl) piperazine -1- base), after being dissolved with 10mLTHF, is added dropwise Enter 5 drop trifluoroacetic acids, after 50 DEG C of stirring 20min, stop reaction, 30mL ice water is added, ethyl acetate extracts (3 × 15mL), closes And organic layer, saturated salt solution washed once, anhydrous sodium sulfate dries, filters, and concentration, column chromatographic purifying obtains title compound.
1H NMR(300M Hz,DMSO-d6):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-MS m/z:489[M+H]。
15 N- of embodiment (3- ((4- ((4- (4- methylpiperazine-1-yl) -3- trifluoromethyl) amino) -1,3,5- three Piperazine -2- base) amino) phenyl) acrylamide
With N- (3- aminobenzene) acrylamide, the chloro- 1,3,5- triazine of 2,4- bis- and 3- trifluoromethyl -4- (4- methyl piperazine - 1- ylmethyl) aniline be raw material, with embodiment 14 method be made title compound.
1H NMR(300M Hz,DMSO-d6):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-MS m/z:513.3[M+H]。
16 N- of embodiment (3- ((4- ((4- (4- ethyl piperazidine -1- base) -2- methoxyphenyl) amino) -1,3,5- three Piperazine -2- base) amino) phenyl) acrylamide
With N- (3- aminobenzene) acrylamide, the chloro- 1,3,5- triazine of 2,4- bis- and 2- methoxyl group -4- (4- ethyl piperazidine -1- Base) aniline be raw material, with embodiment 14 method be made title compound.
1H NMR(300M Hz,DMSO-d6):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-MS m/z:475.3[M+H]。
17 N- of embodiment (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) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 6- amino -1,3,5- triazine of 2,4- bis-, 1- Methyl-1H-indole - 3- boric acid, N- methyl -2- (4- methylpiperazine-1-yl) ethamine, allyl acyl chlorides are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:571.3[M+H]。
18 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (fluoro- 3- of 4- Aminomethyl phenyl) -1,3,5- triazine -2- base amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- methyl -4- fluorobenzoic boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:2.33(9H,m),2.54-2.56(2H,t),2.67-2.70(3H,s), 2.98(2H,t),3.84(3H,s),5.76-5.78(1H,d),6.26-6.30(1H,d),6.52-6.57(1H,m),7.03 (1H,s),7.27-7.28(1H,m),8.16(1H,d),8.31-8.32(1H,s),8.43-8.47(1H,s),8.73(1H,s), 8.86-9.39(1H,s),10.00(1H,s)。
ESI-Ms m/z:480.4[M+H]。
19 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (4- (pyridine -3- Base) -1,3,5- triazine -2- base amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, pyridine -3- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:449.3[M+H]。
20 N- of embodiment (2- ((2- (piperidin-1-yl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (2,3- bis- Hydrogen -1- indone -5- base) -1,3,5- triazine -2- amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the bromo- 1- indone of 5-, N- methyl -2- (piperidin-1-yl) ethamine, allyl acyl chlorides are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.39(s,1H),8.79(s,1H),8.46-7.43(d,1H),8.30(m, 3H),7.75(m,1H),6.98(m,1H),6.67-6.57(m,1H),6.3.-6.25(m,1H),5.79-5.75(m,1H), 3.83(s,3H),2.99(m,4H),2.71(s,3H),2.35-2.27(m,8H),1.47(m,4H),1.37(m,2H)。
ESI-Ms m/z:541.64[M+H]。
21 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, benzofuran -5- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.12(s,1H),8.91(d,2H),8.74(s,1H),8.45(s,2H), 8.25(s,1H),8.09(s,1H),7.70(s,1H),7.05(s,1H),6.43–6.45(m,1H),6.32(d,1H),5.78- 5.80(d,1H),3.84(s,3H),3.36(t,2H),3.13(s,3H),2.35(t,2H),2.23(s,6H)。
ESI-Ms m/z:488.3[M+H]。
22 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- first Base-benzo [d] pyrazoles -6- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1- methylindazole -6- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.13(s,1H),9.06(s,1H),8.78(s,1H),8.70(s,1H), 8.23(s,2H),8.13(s,1H),7.86(s,1H),7.05(s,1H),6.42–6.47(m,1H),6.23-6.26(d,1H), 5.76-5.78(d,1H),4.11(s,3H),3.84(s,3H),2.91(t,2H),2.73(s,3H),2.37(t,2H),2.24 (s,6H)。
ESI-Ms m/z:502.2[M+H]。
23 N- of embodiment (2- ((2- (methoxyl group) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-benzene And [d] pyrazoles -6- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1- methylindazole -6- boric acid, N- first Base -2- methoxyethyl amine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:9.29(s,2H),9.05(s,1H),8.77(s,1H),8.69(s,1H), 8.21-8.23(s,1H),8.14(s,1H),7.86(s,1H),7.00(s,1H),6.44–6.49(m,1H),6.23-6.26(d, 1H),5.76-5.78(d,1H),4.12(s,3H),3.83(s,3H),3.51(t,2H),3.35(s,3H),2.97(t,2H), 2.76(s,3H)。
ESI-Ms m/z:489.2[M+H]。
24 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup) -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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1- methylindazole -6- boric acid, N, N- Dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.71(s,1H),8.77(s,1H),8.67(s,1H),8.47(s,2H), 8.18-8.20(s,1H),8.13(s,1H),7.85(s,1H),6.97(s,1H),6.48-6.53(m,1H),6.21-6.25(d, 1H),5.74-5.76(d,1H),4.22(t,2H),4.20(s,3H),3.84(s,3H),2.63(t,2H),2.28(s,6H)。
ESI-Ms m/z:489.2[M+H]。
((((5- is fluoro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 25 N- of embodiment 1H- indoles -2- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- indoles -2- boric acid of 5-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(300MHz,DMSO-d6)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-Ms m/z:505.2[M+H]。
26 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- first Base -5- tert-butyl-phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- tert-butyl -5- methyl-benzene boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(300MHz,DMSO-d6)δ:9.90(s,1H),9.13(s,1H),8.72(s,1H),8.19(s,1H), 8.09(s,1H),8.05(s,1H),7.44(s,1H),7.02(s,1H),6.66(s,1H),6.22-6.66(d,1H),5.73- 5.76(d,1H),3.83(s,3H),3.30(s,3H),2.50(s,3H),2.67(t,2H),2.48(t,2H),2.22(s,6H), 1.29(s,9H)。
ESI-Ms m/z:518.3[M+H]。
27 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (9,9- bis- Methyl fluorenes -2- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 9,9- dimethyl fluorene -2- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(300MHz,DMSO-d6)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-Ms m/z:564.2[M+H]。
28 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (isoquinoline Quinoline -4- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- isoquinolin boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)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-Ms m/z:499.4[M+H]。
29 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (isoquinoline Quinoline -6- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 6- isoquinolin boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:10.10(s,1H),9.42(s,1H),9.39(s,1H),9.29(s,1H), 9.16(s,1H),8.86(s,1H),8.60(s,1H),8.21(s,1H),8.17(s,1H),8.10(s,1H),7.05(s,1H), 6.58(s,1H),6.35(s,1H),5.82(d,1H),3.86(s,3H),2.98(t,2H),2.72(s,3H),2.36(t,2H), 2.32(s,6H)。
ESI-Ms m/z:499.4[M+H]。
30 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, benzofuran -3- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(300MHz,DMSO-d6)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-Ms m/z:488.4[M+H]。
31 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) the chloro- 5- of -4- ((4- (benzo [b] thiophene Pheno -3- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the chloro- 5- nitroaniline of the fluoro- 2- of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, benzothiophene -3- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,CDCl3-d6)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-Ms m/z:509.0[M+H]。
32 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (2,2- bis- Fluoro- 1,3- benzo two dislikes cyclopentadienyl -5- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- 1,3- benzo of the bromo- 2,2- bis- of 5- Two dislike cyclopentadienyl, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, make according to the method for embodiment 1 Obtain title compound.
1H-NMR(300MHz,CDCl3-d6)δ:10.20(s,1H),9.69(s,1H),9.02(s,1H),8.76(s,1H), 8.52(s,1H),8.37-8.39(d,1H),7.54-7.57(d,1H),6.99-7.08(d,2H),6.35-6.38(d,1H), 5.74-5.77(d,1H),3.86(s,3H),3.31(t,2H),2.75(t,2H),2.62(s,3H),2.41(s,6H)。
ESI-Ms m/z:528.0[M+H]。
((((3- is fluoro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 33 N- of embodiment 4,5- Dimethoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- 4,5- dimethoxy benzene boron of 3- Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(300MHz,CDCl3-d6)δ:10.07(s,1H),9.12(s,1H),8.73(s,1H),8.28(s,1H), 7.84-7.88(d,2H),7.03(s,1H),6.39-6.44(m,1H),6.23-6.27(m,1H),5.74-5.76(m,1H), 3.89(s,6H),3.82(s,3H),2.90(t,2H),2.71(s,3H),2.36(t,2H),2.22(s,6H)。
ESI-Ms m/z:526.1[M+H]。
34 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3,5- bis- Fluoro- 4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the bromo- 2,6- difluoroanisole of 4-, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(300MHz,CDCl3-d6)δ:9.89(s,1H),9.00(s,1H),8.76(s,1H),8.13(s,3H), 7.02(s,1H),6.58(s,1H),6.29-6.32(d,1H),5.75-5.77(d,1H),4.04(s,3H),3.84(s,3H), 3.27(s,3H),3.04(s,2H),2.68(s,2H),2.42(s,6H)。
ESI-Ms m/z:514.3[M+H]。
((((3- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 35 N- of embodiment 4- aminomethyl phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4- methylphenylboronic acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.10(s,1H),9.20(s,1H),8.73(s,1H),8.36(s,1H), 8.30(s,2H),7.52–7.50(d,1H),7.03(s,1H),6.45–6.24(m,2H),5.78–5.74(d,1H),3.81(s, 3H),2.90–2.87(t,2H),2.73(s,3H),2.42(s,3H),2.35–2.31(m,2H),2.21(s,6H).
ESI-Ms m/z:496.4[M+H]。
((((3- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 36 N- of embodiment 4-fluorophenyls)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4- fluorobenzoic boric acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.10(s,1H),9.14–8.99(m,1H),8.75(s,1H),8.54 (s,1H),8.47(s,1H),8.21(s,1H),7.56(s,1H),7.04(s,1H),6.45–6.39(m,1H),6.30–6.27 (m,1H),5.77–5.75(d,1H),3.82(s,3H),2.90(s,2H),2.73(s,3H),2.36(s,2H),2.23(s, 6H).
ESI-Ms m/z:500.2[M+H]。
37 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 3- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -3- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 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-Ms m/z:499.2[M+H]。
38 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3,4-two Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4- dimethoxyphenylboronic, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:10.11(s,1H),9.04(s,1H),8.67(s,1H),8.27(s,1H), 8.10-8.07(d,1H),7.89(s,1H),7.09-7.00(m,2H),6.46-6.37(m,1H),6.27-6.21(d,1H), 5.77-5.74(d,1H),3.84(s,6H),3.12(s,2H),2.90(s,3H),2.72(s,3H),2.37–2.24(m,2H), 2.22(s,6H).
ESI-Ms m/z:508.2[M+H]。
39 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (4-biphenyl Base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- biphenylboronic acid, N, N, N '-front three Base ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 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-Ms m/z:524.2[M+H]。
40 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, benzothiophene -3- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:9.94(s,1H),9.36(s,1H),9.03(s,1H),8.73(s,2H), 8.48(s,1H),8.07-8.05(m,1H),7.42(s,2H),7.04(s,1H),6.70-6.66(d,1H),6.27-6.21(d, 1H),5.76-5.72(d,1H),3.81(s,3H),3.12(s,2H),2.80(s,2H),2.71(s,3H),2.25(s,6H).
ESI-Ms m/z:504.1[M+H]。
41 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3,4-two Aminomethyl phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4- dimethylphenyl boronic acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.13(s,1H),9.14(s,1H),8.90(s,1H),8.71(s,1H), 8.27(s,1H),8.19-8.16(d,1H),7.29-7.27(d,1H),7.04(s,1H),6.47-6.40(m,1H),6.29- 6.25(d,1H),5.79-5.76(d,1H),3.83(s,3H),2.91(s,2H),2.73(s,3H),2.36-2.34(s,2H), 2.30(s,6H),2.23(s,6H).
ESI-Ms m/z:476.2[M+H]。
42 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (1-methyl Pyrazolyl -4- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 1- methyl-1 H- pyrazoles -4- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
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-Ms m/z:452.2[M+H]。
43 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 4- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -4- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:499.0[M+H]。
44 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 5- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -5- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:498.9.[M+H]。
45 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3,4,5- Trimethoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4,5- trimethoxy phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(300MHz,DMSO-d6)δ:9.99(s,1H),9.73(s,1H),9.23(s,1H),8.72(s,1H), 7.68(s,2H),6.98(s,2H),6.28-6.23(s,1H),5.76-5.73(d,1H),3.84(s,9H),3.74(s,3H), 2.90-2.86(m,2H),2.75(s,6H),2.34-2.31(m,2H),2.21(s,3H).
ESI-Ms m/z:538.0[M+H]。
46 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methyl -5- ((4- (quinoline -5- Base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -5- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:10.14(s,1H),9.78(s,1H),9.26(s,1H),8.96–8.75(t, 2H),8.47–8.38(m,2H),8.20(s,2H),7.23(s,1H),7.21(s,1H),6.49–6.44(m,1H),6.28– 6.24(d,1H),5.79–5.78(d,1H),2.85(s,2H),2.68(s,3H),2.50(s,2H),2.39(s,6H),2.19 (s,3H).
ESI-Ms m/z:483.3[M+H]。
47 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, benzothiophene -3- boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:488.0[M+H]。
48 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (5- phenyl Thiophene -2- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 5- phenyl -2- thiophene phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:530.3[M+H]。
((((3- is fluoro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 49 N- of embodiment 4-aminomethyl phenyls)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- 4- methylphenylboronic acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.08(s,1H),9.00(s,1H),8.73(s,1H),8.27–8.11(m, 3H),7.44(s,1H),7.03(s,1H),6.45–6.26(m,2H),5.78–5.75(d,1H),3.81(s,3H),2.90– 2.88(t,2H),2.73(s,3H),2.35–2.32(m,5H),2.21(s,6H).
ESI-Ms m/z:480.0[M+H]。
((((2- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 50 N- of embodiment 3,4,5-trimethoxyphenyls)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 3,4,5- trimethoxy-benzene of 2- Boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(300MHz,DMSO-d6)δ:9.94(s,1H),9.39(s,1H),8.71(s,1H),8.14(s,1H), 7.17(s,1H),6.94(s,1H),6.54-6.49(m,1H),6.22-6.19(s,1H),5.74-5.72(d,1H),3.83(s, 9H),2.68(s,3H),2.55(s,2H),2.50(s,5H),2.33(s,6H)。
ESI-Ms m/z:571.9[M+H]。
((((5- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 51 N- of embodiment Benzo [b] furans -3- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- benzofuran -3- boric acid of 5-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(500MHz,DMSO-d6)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-Ms m/z:522.2[M+H]。
52 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-methoxies Base phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- methoxyphenylboronic acid, N, N, N ' - Trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:10.08(s,1H),9.21(s,1H),8.75(s,1H),8.48(m,1H), 8.38(s,1H),8.20(m,1H),7.61-7.58(m,2H),7.03(s,1H),6.47–6.38(m,1H),6.28–6.22(d, 1H),5.77-5.74(m,1H),3.81(s,3H),2.99-2.90(m,5H),2.72(s,3H),2.37(t,2H),2.23(s, 6H)。
ESI-Ms m/z:478.3[M+H]。
53 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (4-methoxybenzenes Base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyphenylboronic acid, N, N,-two Methylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.71(s,1H),9.03(brs,1H),8.64(s,1H),8.37–8.32 (m,3H),7.05–7.03(m,2H),6.93(s,1H),6.52–6.47(m,1H),6.26-6.23(d,1H),5.74-5.72 (d,1H),4.12(m,2H),3.82(m,6H),2.64-2.62(m,2H),2.28(s,6H).
ESI-Ms m/z:465.2[M+H]。
54 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-first The chloro- phenyl of base -5-) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 5- methylphenylboronic acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.11(s,1H),9.06(s,1H),8.76(s,1H),8.22–8.17(m, 3H),7.50(s,1H),7.04(s,1H),6.45–6.40(m,1H),6.27–6.24(d,1H),5.77-5.75(d,1H), 3.82(s,3H),2.89(t,2H),2.72(s,3H),2.40(s,3H),2.36(t,2H),2.23(s,6H).ESI-Ms m/z: 496.2[M+H]。
((((3-is fluoro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 55 N- of embodiment The chloro- phenyl of 5-) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 5- fluorobenzoic boric acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:10.13(s,1H),9.20(s,1H),8.80(s,1H),8.35(s,1H), 8.22–8.17(m,2H),7.70(s,1H),7.04(s,1H),6.43–6.38(m,1H),6.30–6.26(m,1H),5.77- 5.75(d,1H),3.82(s,3H),2.88(t,2H),2.73(s,3H),2.33(t,2H),2.21(s,6H).
ESI-Ms m/z:500.2[M+H]。
56 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (3-fluoro- chloro- benzene of 5- Base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 5- fluorobenzoic boric acid of 3-, N, N, - Dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:9.68(s,1H),9.27(s,1H),8.80(s,1H),8.78-8.70(m, 1H),8.25–8.11(m,2H),7.68(s,1H),6.95(s,1H),6.49–6.48(m,1H),6.27–6.263(m,1H), 5.74-5.72(d,1H),4.21(t,2H),3.81(s,3H),2.63(t,2H),2.28(s,6H).ESI-Ms m/z:487.2 [M+H]。
57 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-trifluoros Methyl-5-chloro-phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 5- trifluoromethylbenzene boronic acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(300MHz,DMSO-d6)δ:10.10(s,1H),9.41(s,1H),8.78-8.70(m,4H),7.90(s, 1H),7.04(s,1H),6.45–6.36(m,1H),6.26–6.20(m,1H),5.77-5.73(d,1H),3.80(s,3H), 2.88(t,2H),2.73(s,3H),2.34(t,2H),2.22(s,6H).
ESI-Ms m/z:550.2[M+H]。
58 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methyl Phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- methylphenylboronic acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:10.10(s,1H),9.18(s,1H),8.75(s,1H),8.48(m,1H), 8.36(s,1H),8.10(m,1H),7.65-7.63(m,2H),7.03(s,1H),6.60–6.58(m,1H),6.33–6.30(d, 1H),5.81-5.79(m,1H),3.81(s,3H),3.10(m,2H),2.73(s,3H),2.38(t,2H),2.30(s,3H), 2.26(s,6H).
ESI-Ms m/z:462.3[M+H]。
59 N- of embodiment (2- ((2- (1- pyrrolidinyl) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- (N, N- dimethylamino formoxyl) Phenyl boric acid, N- methyl-(2- pyrrolidin-1-yl-ethyl)-amine, allyl acyl chlorides and diisopropylethylamine are raw material, according to implementation Title compound is made in the method for example 1.
1H-NMR(300MHz,DMSO-d6)δ:9.76(s,1H),9.22(brs,1H),8.75(s,1H),8.48(m,1H), 8.38(s,1H),8.23(s,1H),7.61-7.58(m,2H),7.02(s,1H),6.53–6.44(m,1H),6.27–6.21(d, 1H),5.77-5.73(m,1H),3.85(s,3H),2.98(s,6H),2.94-2.91(m,4H),2.71(s,3H),2.55- 2.53(m,4H),1.73(m,4H).
ESI-Ms m/z:545.4[M+H]。
60 N- of embodiment (2- ((2- (1- pyrrolidinyl) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (4-methoxies Base phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyphenylboronic acid, N- methyl - (2- pyrrolidin-1-yl-ethyl)-amine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(300MHz,DMSO-d6)δ:9.75(s,1H),9.64(brs,1H),8.67(s,1H),8.43-8.40 (m,2H),8.19(s,1H),7.06-7.00(m,3H),6.58–6.49(m,1H),6.30–6.25(d,1H),5.78-5.75 (m,1H),3.85(s,3H),3.83(s,3H),3.06–3.02(m,2H),2.70–2.67(m,9H),1.77(m,4H).
ESI-Ms m/z:504.3[M+H]。
61 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (2-naphthalenes Base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 2- naphthalene boronic acids, N, N, N '-trimethyl Ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:10.13(s,1H),9.20(brs,2H),8.80(s,1H),8.52-8.49 (m, 1H), 8.22-8.16 (m, 2H), 8.05-7.99 (m, 2H), 7.66-7.56 (m, 2H), 7.06 (s, 1H), 6.54-6.31 (m,2H),5.83-5.80(d,1H),3.86(s,3H),2.93(t,2H),2.73(s,3H),2.41(t,2H),2.26(s, 6H).
ESI-Ms m/z:498.4[M+H]。
62 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) 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 -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- (N, N- dimethylamino formoxyl) Phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are made according to the method for embodiment 1 Obtain title compound.
1H-NMR(300MHz,DMSO-d6)δ:10.07(s,1H),9.22(brs,1H),8.75(s,1H),8.50-8.49 (m,1H),8.37(s,1H),8.20-8.16(m,1H),7.61–7.58(m,2H),7.03(s,1H),6.46–6.37(m,1H), 6.28–6.22(d,1H),5.77-5.74(d,1H),3.80(s,3H),2.98-2.90(m,8H),2.72(s,3H),2.36(t, 2H),2.23(s,6H).
ESI-Ms m/z:519.4[M+H]。
63 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (2-naphthalene)-1,3, 5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 2- naphthalene boronic acids, N, N, N '-trimethyl Ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:9.75(s,1H),9.13(brs,2H),8.77(s,1H),8.48-8.45 (m, 1H), 8.25-8.15 (m, 2H), 8.01-7.99 (m, 2H), 7.66-7.58 (m, 2H), 6.97 (s, 1H), 6.54-6.31 (m,2H),5.81-5.79(m,1H),3.90-3.85(m,5H),2.73-2.63(m,2H),2.30(s,6H).
ESI-Ms m/z:485.3[M+H]。
64 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-(N, N- dimethylamino) phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- (N, TMSDMA N dimethylamine base) benzene boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(300MHz,DMSO-d6)δ:10.07(s,1H),9.20(brs,1H),8.76(s,1H),8.50-8.48 (m,1H),8.37(s,1H),8.22-8.18(m,1H),7.63–7.59(m,2H),7.03(s,1H),6.46–6.40(m,1H), 6.28–6.23(d,1H),5.78-5.75(d,1H),3.83(s,3H),3.00-2.95(m,8H),2.73(s,3H),2.35(t, 2H),2.22(s,6H).
ESI-Ms m/z:491.2[M+H]。
65 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (7- methoxy Base-2-naphthalene)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 7- methoxyl group -2- naphthalene boronic acids, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(300MHz,DMSO-d6)δ:10.15(s,1H),9.14-9.11(brs,2H),8.77(s,1H),8.48- 8.45 (m, 1H), 8.30 (s, 1H), 8.14-8.12 (m, 1H), 7.92-7.90 (m, 1H), 7.41 (s, 1H), 7.23-7.21 (m, 1H),7.06(s,1H),6.52–6.30(m,2H),5.83-5.80(m,1H),3.92(s,3H),3.85(s,3H),2.91(t, 2H),2.74(s,3H),2.34(t,2H),2.22(s,6H).
ESI-Ms m/z:528.2[M+H]。
66 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 6- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -6- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(300MHz,DMSO-d6)δ:9.78(s,1H),9.13(brs,1H),8.83(s,1H),8.77(s,1H), 8.47-8.44 (m, 1H), 8.26-8.15 (m, 2H), 8.01-7.99 (m, 1H), 7.66-7.58 (m, 2H), 6.87 (s, 1H), 6.54–6.34(m,2H),5.81-5.78(m,1H),3.92-3.87(m,5H),2.75-2.65(s,3H),2.41(t,2H), 2.30(s,6H).
ESI-Ms m/z:499.3[M+H]。
67 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methyl -5- ((4- (3,4- diformazan Phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methyl-5-nitro aniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4- dimethoxyphenylboronic, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:9.58(s,1H),8.67(s,1H),8.17(s,1H),7.98(s,1H), 7.86(s,1H),7.19(s,1H),7.08–7.06(s,1H),6.45–6.37(m,1H),6.25–6.19(d,1H),5.78- 5.74(d,1H),3.83(s,4H),3.75(s,3H),2.84(s,2H),2.68(s,3H),2.38(m,2H),2.24(s,6H), 2.18(s,3H)。
ESI-Ms m/z:492.3[M+H]。
68 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methyl-5- ((4- (3,4,5-three Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methyl-5-nitro aniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,4,5- trimethoxy phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:9.68(s,1H),8.69(s,1H),8.18(s,1H),7.64(s,2H), 7.19(s,1H),6.47–6.37(m,1H),6.24–6.18(d,1H),5.77-5.74(d,1H),3.78(s,5H),3.73(s, 5H),2.85(s,2H),2.67(s,3H),2.39(m,2H),2.24(s,6H),2.19(s,3H)。ESI-Ms m/z:522.0[M +H]。
69 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- first Base -1H- indol-3-yl) -6- amino -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 6- amino -1,3,5- triazine of 2,4- bis-, N- methyl indol -2- boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
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-Ms m/z:515.6[M+H]。
70 N- of embodiment (2- ((2- (1- piperidyl) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl - 1H- indol-3-yl) -6- amino -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 6- amino -1,3,5- triazine of 2,4- bis-, N- methyl indol -2- boron Acid, N- methyl -2- (piperidin-1-yl) ethamine, allyl acyl chlorides and diisopropylethylamine are raw material, according to the method for embodiment 1 Title compound is made.
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-Ms m/z:556.6[M+H]。
71 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- (phenyl -1 4-, 3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, phenyl boric acid, N, N, N '-trimethyl second Diamines, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 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-Ms m/z:447.5[M+H]。
72 N- of embodiment (2- ((2- (1- pyrrolidinyl) ethyl) (methyl) amino) -4- methoxyl group -5- (phenyl -1 4-, 3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, phenyl boric acid, N- methyl -2- (pyrroles Alkane -1- base) ethamine, allyl acyl chlorides and diisopropylethylamine be raw material, title compound is prepared Following the procedure of Example 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-Ms m/z:474[M+H]。
73 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-trifluoros Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- trifluoromethoxy phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:2.25(6H,s),2.39-2.35(2H,m),2.71(3H,s),2.92- 2.89(2H,m),3.80(3H,s),5.75-5.73(1H,dd),6.27-6.24(1H,m),6.48-6.42(1H,m),7.03 (1H,m),7.66-7.60(1H,m),8.27-8.24(2H,m),8.46(1H,s),8.77(1H,s),8.89-8.88(1H,s), 9.36(1H,bs),10.07(1H,s)。
ESI-Ms m/z:532.3[M+H]。
74 N- of embodiment (2- ((2- (1- pyrrolidinyl) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-trifluoros Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- trifluoromethoxy phenyl boric acid, N- Methyl -2- (pyrrolidin-1-yl) ethamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(500MHz,DMSO-d6)δ:1.73(4H,m),2.39-2.35(6H,m),2.71(3H,s),2.98 (2H,m),3.81(3H,s),5.75-5.73(1H,dd),6.27-6.24(1H,m),6.50-6.44(1H,m),7.03(1H, m),7.66-7.61(2H,m),8.20(1H,m),8.27(1H,m),8.46(1H,s),8.77(1H,s),9.22(1H,bs), 9.77(1H,s)。
ESI-Ms m/z:558.3[M+H]。
75 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methyl -5- ((4- (1- methyl - 1H- indol-3-yl) -6- amino -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methyl-5-nitro aniline of 4-, the chloro- 6- amino -1,3,5- triazine of 2,4- bis-, N- methyl indol -3- boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
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-Ms m/z:500.5[M+H]。
76 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3-first Base -4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyl group -3- methylphenylboronic acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(500MHz,DMSO-d6)δ:2.21(9H,s),2.34-2.31(2H,m),2.72(3H,s),2.90- 2.86(2H,m),3.82(3H,s),3.87(3H,s),5.78-5.74(1H,dd),6.28-6.23(1H,m),6.46-6.41 (1H,m),7.06-7.03(2H,m),8.32-8.26(2H,m),8.66(1H,s),8.85(2H,m),10.11(1H,s)。
ESI-Ms m/z:492.5[M+H]。
((((3-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 77 N- of embodiment 4- trifluoromethyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4- trifluoromethyl boron of 3- Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,DMSO-d6)δ:2.27(6H,s),2.50-2.39(2H,m),2.72(3H,s),2.93 (2H,m),3.81(3H,s),5.78-5.74(1H,dd),6.29-6.23(1H,m),6.48-6.39(1H,m),7.04(1H, s),8.02(1H,br),8.14(1H,s),8.45(1H,m),8.57(1H,s),8.81(1H,s),9.34(1H,m),10.04 (1H,m)。
ESI-Ms m/z:550.2[M+H]。
((((2-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 78 N- of embodiment 5- trifluoromethyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 5- trifluoromethylbenzene boronic acid of 2-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(500MHz,DMSO-d6)δ:2.27(6H,s),2.50-2.39(2H,m),2.72(3H,s),2.93 (2H,m),3.81(3H,s),5.74-5.69(1H,dd),6.23-6.17(1H,m),6.41-6.35(1H,m),6.99(1H, s),7.86(2H,m),8.16-8.10(1H,m),8.30(1H,s),8.77-8.74(1H,m),9.64(1H,s),10.04(1H, m)。
ESI-Ms m/z:550.2[M+H]。
79 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (3-chloro- 4- trifluoros Aminomethyl phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4- trifluoromethyl boron of 3- Acid, N, N- dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(500MHz,DMSO-d6)δ:2.27(6H,s),2.60(2H,m),3.81(3H,s),4.20(2H,m), 5.74-5.72(1H,dd),6.24(1H,m),6.49(1H,m),6.95(1H,s),8.09-7.98(1H,m),8.54-8.41 (3H,m),8.81(1H,m),9.39(1H,s),9.66(1H,s)。
ESI-Ms m/z:537.2[M+H]。
80 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1H- Yin Diindyl -7- base) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, indoles -7- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 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-Ms m/z:487.2[M+H]。
81 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (3-methyl-4- first Phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 4- methoxyl group -3- methylphenylboronic acid, N, N- dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:2.21(6H,s),2.27(3H,s),3.79(2H,m),3.86(6H,s), 4.54(2H,m),5.67-5.65(1H,dd),6.22-6.19(1H,m),6.76(1H,m),6.94(1H,s),7.04(1H,m), 8.25-8.20(2H,m),8.35(1H,s),8.63(1H,s),9.05(1H,br),10.31(1H,s)。
ESI-Ms m/z:479.2[M+H]。
82 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (2,5-two Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 2,5- dimethoxyphenylboronic, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:2.22(6H,s),2.39-2.37(2H,m),2.70(3H,s),2.90- 2.86(2H,m),3.72(6H,s),3.78(3H,s),5.75-5.72(1H,dd),6.23-6.17(1H,m),6.41-6.35 (1H,m),7.08-7.04(2H,m),7.18-7.17(1H,m),8.17(1H,m),8.38(1H,s),8.65(1H,s),9.24 (1H,s),10.03(1H,m)。
ESI-Ms m/z:508.2[M+H]。
83 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (2,5-dimethoxys Phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 2,5- dimethoxyphenylboronic, N, N- dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:2.29(6H,s),2.72-2.67(2H,m),3.72(6H,s),3.78 (3H,s),4.19(2H,m),5.75-5.72(1H,dd),6.23-6.17(1H,m),6.41-6.35(1H,m),7.08-7.04 (2H,m),7.18-7.17(1H,m),8.17(1H,m),8.38(1H,s),8.65(1H,s),9.24(1H,s),10.03(1H, m)。
ESI-Ms m/z:495.2[M+H]。
84 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3,5-two Methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,5- dimethoxyphenylboronic, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:2.33(6H,s),2.54(2H,m),2.70(3H,s),2.98(2H,m), 3.81(9H,s),5.76-5.72(1H,dd),6.04(1H,s),6.26-6.20(1H,m),6.57-6.48(1H,m),6.70 (1H,s),7.01(1H,s),7.52(2H,s),8.72(1H,s),9.26(1H,s),10.01(1H,s)。ESI-Ms m/z: 508.2[M+H]。
85 N- of embodiment (2- ((2- (dimethylamino) ethyl) oxygroup)-4- methoxyl group-5- ((4- (3,5-dimethoxys Phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3,5- dimethoxyphenylboronic, N, N- dimethylethanolamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1 Object.
1H-NMR(500MHz,DMSO-d6)δ:2.33(6H,s),2.72(2H,m),3.80-3.76(9H,s),4.23- 4.21(2H,m),5.73-5.71(1H,dd),6.22-6.19(1H,m),6.55-6.50(1H,m),6.70(1H,br),6.93 (1H,s),7.48(2H,m),8.21(1H,s),8.70(1H,bs),9.26(1H,s),9.70(1H,m)。
ESI-Ms m/z:495.2[M+H]。
86 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 8- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -8- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 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-Ms m/z:499.2[M+H]。
87 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (quinoline - 7- yl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, quinoline -7- boric acid, N, N, N '-three Methyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title compound is prepared Following the procedure of Example 1.
1H-NMR(500MHz,DMSO-d6)δ:2.20(6H,s),2.35(2H,m),2.69(3H,s),2.87(2H,m), 3.80(3H,s),5.79-5.71(1H,dd),6.25-6.22(1H,m),6.43-6.37(1H,m),7.02(1H,s),7.57 (1H,s),7.70(1H,s),7.91-7.90(1H,m),8.11-8.09(1H,m),8.49-8.40(2H,m),8.73(1H,s), 8.95(1H,s),9.32(1H,s),9.95(1H,s)。
ESI-Ms m/z:499.2[M+H]。
88 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- methoxy Base-4-fluorophenyl)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- 3- methoxyphenylboronic acid of 4-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,DMSO-d6)δ:2.21(6H,s),2.32-2.26(2H,m),2.72(3H,s),2.88 (2H,m),3.81(3H,s),3.87(3H,s),5.77-5.74(1H,dd),6.29-6.21(1H,m),6.39-6.35(1H, m),6.90(1H,s),7.37-7.35(1H,m),8.06(2H,m),8.73-8.67(2H,m),9.21-9.12(1H,br), 10.08(1H,s)。
ESI-Ms m/z:496.0[M+H]。
89 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- isopropyl Base-4-methoxyphenyl)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- isopropyl -4- methoxybenzene boron Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,DMSO-d6)δ:1.16-1.14(6H,s),2.23(6H,s),2.39-2.37(2H,m), 2.72(3H,s),2.92-2.90(2H,m),3.28-3.23(1H,s),3.81(3H,s),3.87(3H,s),5.76-5.73 (1H,dd),6.26-6.20(1H,m),6.46-6.37(1H,m),7.07-7.03(2H,m),8.30-8.22(3H,m),8.66 (1H,s),9.01(1H,s),10.09(1H,s)。
ESI-Ms m/z:520.1[M+H]。
((((3- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 90 N- of embodiment 4-methoxyl group-5- aminomethyl phenyls)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- chlorine 4- methoxyl group -5- methylbenzene Boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(500MHz,DMSO-d6)δ:2.36(3H,s),2.50(6H,s),2.39-2.37(2H,m),2.72 (3H,s),2.92-2.90(2H,m),3.821(3H,s),3.85(3H,s),5.73-5.69(1H,dd),6.29-6.23(1H, m),6.97(1H,s),7.18-7.17(1H,br),8.26(2H,m),8.72(1H,s),9.07-9.04(1H,br),9.80 (1H,s),10.60(1H,s)。
ESI-Ms m/z:526.3[M+H]。
((((3- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 91 N- of embodiment 5-methoxyphenyls)-1,3,5- triazine-2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- chloro-5-methoxyl phenylboric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and title is prepared Following the procedure of Example 1 Compound.
1H-NMR(500MHz,DMSO-d6)δ:2.34(6H,s),2.56(2H,m),2.69(3H,s),2.98(2H,m), 3.82-3.81(6H,s),5.75-5.73(1H,dd),6.27-6.23(1H,m),6.55-6.50(1H,m),7.02(1H,s), 7.25(1H,s),7.83(1H,s),7.96(1H,s),8.15(1H,s),8.74(1H,s),9.32-9.28(1H,br),9.97 (1H,s)。
ESI-Ms m/z:512.2[M+H]。
((((3-is fluoro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 92 N- of embodiment 4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the fluoro- 4- methoxyphenylboronic acid of 3-, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(300MHz,DMSO-d6)δ:10.26(s,1H),9.72(s,1H),8.99(s,1H),8.70(m,1H), 8.82-8.19(m,2H),7.29(m,1H),6.98-6.95(m,2H),6.32–6.29(m,1H),5.75–5.72(m,1H), 3.93(s,3H),3.85(s,3H),3.28-3.18(m,4H),2.71(s,6H),2.63(s,3H)。
ESI-Ms m/z:496.2[M+H]。
((((2-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 93 N- of embodiment 4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 2- chloro-4-methoxy phenyl boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(300MHz,DMSO-d6)δ:9.45(s,1H),9.25(s,1H),8.71(s,1H),8.13(m,1H), 7.88-7.86(m,1H),7.10(s,1H),7.03-7.01(m,1H),6.91(s,1H),6.64–6.58(m,1H),6.32– 6.28(m,1H),5.80-5.78(d,1H),3.84(s,6H),3.31-3.25(m,4H),2.81(s,6H),2.62(s,3H)。
ESI-Ms m/z:512.2[M+H]。
((((4-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 94 N- of embodiment 3,5- Dimethoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 3,5- dimethoxy benzene boron of 4- Acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(300MHz,DMSO-d6)δ:9.50(s,1H),9.31(s,1H),9.22(s,1H),8.77(s,1H), 7.73(m,2H),7.02(s,1H),6.65–6.59(m,1H),6.31–6.21(d,1H),5.81-5.79(d,1H),3.90(s, 6H),3.85(s,3H),3.31-3.30(t,2H),3.27-3.26(t,2H),2.81(s,6H),2.62(s,3H)。
ESI-Ms m/z:543.2[M+H]。
((((3-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 95 N- of embodiment 4- methyl -5- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, chloro- -5 methoxybenzene of 4- methyl of 3- Boric acid, N, N, N '-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(300MHz,CDCl3-d6)δ:10.07(s,1H),9.23(s,1H),8.73(s,2H),8.02(s, 1H),7.85(s,1H),7.04(s,1H),6.44-6.37(m,1H),6.25-6.22(m,1H),5.76-5.74(m,1H), 3.85(s,3H),3.81(s,3H),2.988(s,2H),2.72(s,3H),2.33(t,2H),2.27(s,3H),2.22(s, 6H)。
ESI-Ms m/z:527.2[M+H]。
((((3-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 96 N- of embodiment 4,5- Dimethoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4,5- dimethoxy benzene boron of 3- Acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,CDCl3-d6)δ:10.03(s,1H),9.34(s,1H),8.71(s,1H),8.20(s, 1H),7.42(s,1H),7.07(s,1H),6.99(s,1H),6.39-6.44(m,1H),6.19-6.23(m,1H),5.73- 5.75(m,1H),3.83(s,3H),3.79-3.81(d,6H),2.89-2.90(t,2H),2.70(s,3H),2.39(t,2H), 2.24(s,6H)。
ESI-Ms m/z:542.3[M+H]。
((((3-is chloro- by 4- by-4- methoxyl group-5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 97 N- of embodiment 4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- chloro-4-methoxy phenyl boric acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 titled Close object.
1H-NMR(500MHz,CDCl3-d6)δ:10.02(s,1H),9.10(s,1H),8.69(s,1H),8.40(s, 2H),8.16(s,1H),7.27-7.29(d,1H),7.03(s,1H),6.46-6.52(m,1H),6.25-6.30(m,1H), 5.74-5.77(m,1H),3.95(s,3H),3.82(s,3H),2.95(t,2H),2.71(s,3H),2.48(t,2H),2.30 (s,6H)。
ESI-Ms m/z:512.3[M+H]。
((((3- is chloro- by 4- by -4- methoxyl group -5- by 2- ((2- (dimethylamino) ethyl) (methyl) amino) by 98 N- of embodiment Thieno [2,3-B] pyridyl group) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, thieno [2,3-B] pyridine -3- boron Acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,CDCl3-d6)δ:10.11(s,1H),9.40(s,1H),9.11-9.16(d,1H),8.75 (s,1H),8.62(s,2H),8.27(s,1H),7.34(s,1H),7.07(s,1H),6.44-6.49(m,1H),6.21-6.24 (m,1H),5.74-5.76(m,1H),3.79(s,3H),2.95(t,2H),2.76(s,3H),2.43(t,2H),2.26(s, 6H)。
ESI-Ms m/z:505.3[M+H]。
99 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino)-4- methoxyl group-5- ((4- (3,5-two Chloro-4-methoxy phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, the chloro- 4- methoxybenzene boron of 3,5- bis- Acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,CDCl3-d6)δ:10.07(s,1H),9.69(s,1H),9.42(s,1H),8.76(s, 1H),8.40(s,2H),6.70(s,2H),6.27-6.33(m,1H),5.73-5.76(m,1H),3.92(s,3H),3.84(s, 3H),3.16(t,2H),2.71(s,3H),2.40(t,2H),2.26(s,6H)。
ESI-Ms m/z:546.0[M+H]。
100 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- first Oxygroup -4- cyclopropyl phenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- methoxyl group -4- cyclopropyl-phenyl boron Acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, and mark is prepared Following the procedure of Example 1 Inscribe compound.
1H-NMR(500MHz,CDCl3-d6)δ:9.52(s,1H),9.32(s,1H),9.10(s,1H),8.71(s,1H), 7.93-7.95(d,1H),7.87(s,1H),7.09(m,1H),6.92-6.94(m,1H),6.65-6.70(m,1H),6.29- 6.32(m,1H),5.79-5.81(m,1H),3.68(s,6H),3.27(s,2H),2.81(s,6H),2.63(s,3H),2.51 (t,2H),2.19(m,1H),0.96-1.00(m,2H),0.71-0.72(m,2H)。
ESI-Ms m/z:518.2[M+H]。
101 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (3- tri- Methyl fluoride -4- methoxyphenyl) -1,3,5- triazine -2- base) amino) phenyl) acrylamide
With the fluoro- 2- methoxyl group -5- nitroaniline of 4-, the chloro- 1,3,5- triazine of 2,4- bis-, 3- trifluoromethyl -4- methoxybenzene Boric acid, N, N, N ,-trimethyl ethylenediamine, allyl acyl chlorides and diisopropylethylamine are raw material, are prepared Following the procedure of Example 1 Title compound.
1H-NMR(500MHz,CDCl3-d6)δ:10.07(s,1H),9.24(s,1H),8.70(s,2H),8.56(s, 2H),7.42(d,1H),7.03(s,1H),6.41-6.47(m,1H),6.21-6.27(m,1H),5.73-5.77(m,1H), 3.99(s,3H),3.80(s,3H),2.89-2.92(t,2H),2.72(s,3H),2.38-2.40(t,2H),2.41(s,6H)。
ESI-Ms m/z:546.2[M+H]。
The evaluation of 1 vitro kinase activity of experimental example
1 experimental material
1.1 enzyme
EGFRWTKinases is purchased from Carna company；
EGFRT790M/L858RKinases is purchased from Invitrogen company.
1.2 reagent
Atriphos (ATP), is purchased from Sigma company；
Dimethyl sulfoxide (Dimethyl sulfoxide, DMSO), is purchased from Sigma company；
Peptide (Peptide FAM-P22), is purchased from GL Biochem company；
Ethylenediamine tetra-acetic acid (EDTA), is purchased from Sigma company
1.3 instrument
Caliper EZ reader micro-fluidic chip instrument, is purchased from Caliper Life Sciences, Inc.
2 experimental methods
1) prepare 1 × kinases basis buffer and stop buffer
A.1 × kinases basis buffer is (for EGFRWT)
50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2, 10mM MnCl2, 2mM DTT.
B.1 × kinases basis buffer is (for EGFRT790M/L858R)
50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2, 2mM DTT.
C. stop buffer
100mM HEPES, pH7.5,0.0015%Brij-35,0.2%Coating Reagent#3,50mM EDTA.
2) prepare compound
A. the compound of the present invention:
The compound prepared according to above embodiments is dissolved to 10mM respectively with 100%DMSO.It is dilute with complete medium Release to 50 μM, after being then diluted to 5 μM with the complete medium containing 0.1%DMSO, successively 3 times of dilutions, totally 10 concentration (for EGFRWT)；
The compound prepared according to above embodiments is dissolved to 10mM respectively with 100%DMSO.It is dilute with complete medium Release to 50 μM, after being then diluted to 1 μM with the complete medium containing 0.1%DMSO, successively 3 times of dilutions, totally 10 concentration (for EGFRT790M/L858R)；
B. be added in empty hole 100 μ l 100%DMSO for prepare without kinases without compound control group and have kinases Without compound control group；
Marking 96 orifice plates used is to carry out source plate.
C. prepare medium plate
10 μ l compounds are always shifted in source plate into 96 new orifice plates, as medium plate.
90 μ 1 × kinase buffer liquids of l are added in the every hole of medium plate.
Oscillation mixes 10min.
3) preparing experiment plate
A. from 96 hole medium plates, 5 μ l are shifted into 384 orifice plates in every hole.
4) kinase reaction
A. prepare 2.5 × kinase solution
By EGFRWTKinases and EGFRT790M/L858RKinases stoste is separately added into 1 × basis buffer, it is configured to 2.5 × Kinase solution.
B. prepare 2.5 × peptide solution
The peptide of FAM label and ATP are added in 1 × basis buffer, 2.5 × peptide solution is configured to.
C. 10 2.5 × kinase solutions of μ l are shifted into 384 hole experimental plates.
D. it is incubated at room temperature 10min.
E. 10 μ 2.5 × peptide of l solution are shifted into 384 hole experimental plates.
Setting simultaneously is (molten comprising 2%DMSO, 1 × basis buffer and 2.5 × peptide without compound control group without kinases Liquid and there is kinases without compound control group (including 2%DMSO, 2.5 × kinase solution and 2.5 × peptide solution).
F. kinase reaction and termination
A period of time is incubated under the conditions of 28 DEG C.
25 μ l stop buffers are added and terminate reaction.
5) Caliper instrument readings
Data are read on Caliper instrument.
6) matched curve
A. each group conversion data are obtained from Caliper program.
B. inhibiting rate is calculated
Inhibiting rate %=(max-com)/(max-min) × 100, wherein " max " representative has kinases without compound control, " min " is represented without kinases without compound control, and " com " represents test-compound group.
C. IC is calculated using 5.0 data processing software of Graphpad50Value.It the results are shown in Table 1.
Table 1
Note: "-" expression does not detect
The experimental results showed that, the compound of the present invention is to mutant egf R kinases, such as mutant egf R aboveT790M/L858R Kinases has good inhibitory activity, shows excellent selectivity, is expected to become confrontation pharmacological property tumour, especially prominent to EGFR Become the drug for causing drug resistant tumour that there is special curative effect.
2 cell in vitro activity rating of experimental example
1 experimental material
1.1 cell
Experiment cell strain NCI-H1975 (there is the bis- mutant cells of EGFR L858R and T790M to be mutated) and A431 (EGFR Wild-type cell), it is purchased from ATCC；
1.2 reagent
Cell Titer-Glo luminescent cell viability assay is purchased from Promega company；
RPMI1640medium is purchased from Invitrogen company；
DMEM medium is purchased from Invitrogen company；
Fetal calf serum is purchased from Invitrogen company；
NCI-H1975 cell culture is in the RPMI1640 culture medium of the fetal calf serum (GIBCO) containing 10% inactivation, containing blueness 100 μ g/mL of mycin 100IU/mL and streptomysin；
A431 cell culture contains penicillin in the DMEM culture medium of the fetal calf serum (GIBCO) containing 10% inactivation 100 μ g/mL of 100IU/mL and streptomysin.
2 experimental methods
1) CTG measuring method
A. it after NCI-H1975 the and A431 cell of logarithmic growth phase being digested respectively, blows and beats into single cell suspension, is inoculated in 96 well culture plates, every 100 μ L of hole culture medium, each various 3 piece of 96 orifice plate of cell strain, wherein NCI-H1975 cell per well is inoculated with 3X 103A cell, A431 cell per well are inoculated with 4X 103A cell；B. by 96 orifice plates in 37 degree, 5%CO2It is cultivated in incubator 16-24 hours, after cell is adherent, test-compound is added by following concentration requirement, and (compound was on NCI-H1975 cell Highest test concentrations are 4 μM, 3 times of dilutions, totally 9 concentration；Highest test concentrations on A431 cell are 10 μM, 3 times of dilutions, Totally 9 concentration),
C. it is further cultured in the incubator 72 hours；
D. the CTG solution of 100 μ L is added, is protected from light oscillation 2min, is incubated for 10min；
E. culture plate is put intoMulti-mode micropore board detector read plate；
F. record fluorescence (luminescence) readings is as a result, be calculated according to the following formula inhibiting rate:
Inhibiting rate (%)=(1- (RLUcom-RLUblank)/(RLUDMSO–RLUblank)) × 100%,
Wherein RLUcom is the fluorescent value of compound group, RLUDMSOFor the fluorescent value of DMSO control group, RLUblankFor nothing The fluorescent value of DMSO control group.
Drug effect inhibiting rate curve is drawn using XLFit curve fitting software and calculates IC50Value.It the results are shown in Table 2.
Table 2
The experimental results showed that, the compound of the present invention is good to the inhibiting effect of EGFR mutant cell above, relative to EGFR wild-type cell has preferable selectivity to mutant cell.
The external IGF1R kinases of experimental example 3 and the evaluation of INSR kinase activity
1 experimental material
1.1 enzyme
IGF1R kinases (type-1 insulin like growth factor receptor), is purchased from Invitrogen company；
INSR kinases (insulin receptor), is purchased from Carna company
1.2 reagent
Atriphos (ATP), is purchased from Sigma company；
Dimethyl sulfoxide (Dimethyl sulfoxide, DMSO), is purchased from Sigma company；
Peptide (Peptide FAM-P22), is purchased from GL Biochem company；
Peptide (Peptide FAM-P13), is purchased from GL Biochem company；
Ethylenediamine tetra-acetic acid (EDTA), is purchased from Sigma company
2 experimental methods
1) prepare 1 × kinases basis buffer and stop buffer
A.1 × kinases basis buffer (for INSR)
50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2, 10mM MnCl2, 2mM DTT.
B.1 × kinases basis buffer (for IGF1R)
50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2, 2mM DTT.
C. stop buffer
100mM HEPES, pH7.5,0.0015%Brij-35,0.2%Coating Reagent#3,50mM EDTA.
2) prepare compound
A. the compound of the present invention:
For IGF1R kinases and INSR kinase assays, the change for being prepared above embodiments according to the present invention with 100%DMSO It closes object and is dissolved to 10mM respectively.500 μM are diluted to complete medium, is then diluted with the complete medium containing 0.1%DMSO To after 10 μM, successively dilute for 3 times, totally 10 concentration；
B. be added in empty hole 100 μ l 100%DMSO for prepare without kinases without compound control group and have kinases Without compound control group；
Marking 96 orifice plates used is to carry out source plate.
C. prepare medium plate
10 μ l compounds are always shifted in source plate into 96 new orifice plates, as medium plate.
90 μ 1 × kinase buffer liquids of l are added in the every hole of medium plate.
Oscillation mixes 10min.
3) preparing experiment plate
A. from 96 hole medium plates, 5 μ l are shifted into 384 orifice plates in every hole.
4) kinase reaction
A. prepare 2.5 × kinase solution
IGF1R kinases and INSR kinases stoste are separately added into 1 × basis buffer, 2.5 × kinase solution is configured to.
B. prepare 2.5 × peptide solution
The peptide (Peptide FAM-P22) of FAM label and ATP are added in 1 × basis buffer, are configured to 2.5 × peptide solution (for INSR)；
The peptide (Peptide FAM-P13) of FAM label and ATP are added in 1 × basis buffer, are configured to 2.5 × peptide solution (for IGF1R).
C. 10 2.5 × kinase solutions of μ l are shifted into 384 hole experimental plates.
D. it is incubated at room temperature 10min.
E. 10 μ 2.5 × peptide of l solution are shifted into 384 hole experimental plates.
Setting simultaneously is (molten comprising 2%DMSO, 1 × basis buffer and 2.5 × peptide without compound control group without kinases Liquid and there is kinases without compound control group (including 2%DMSO, 2.5 × kinase solution and 2.5 × peptide solution).
F. kinase reaction and termination
A period of time is incubated under the conditions of 28 DEG C.
25 μ l stop buffers are added and terminate reaction.
5) Caliper instrument readings
Data are read on Caliper instrument.
6) matched curve
A. conversion data are obtained from Caliper program.
B. inhibiting rate is calculated
Inhibiting rate %=(max-com)/(max-min) × 100, wherein " max " representative has kinases without compound control, " min " is represented without kinases without compound control, and " com " represents test-compound group.
C. IC is calculated using Xlfit add4.3.1 data processing software50Value.It the results are shown in Table 3.
Table 3
Known EGFR inhibitor is strong to the inhibiting effect of IGF1R and INSR, may result in body hyperglycemia and is damaged The side effects such as insulin signal transduction.According to Experimental report, the irreversibility EGFR inhibitor AZD9291 of Astrazeneca AB To the IC of IGF1R kinases50About 2900nM is (referring to Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor,M.Raymond V.Finlay,et al.J Med Chem.2014 Oct 23；57(20):8249-67).It is of the invention above the experimental results showed that, the compound of the present invention is to swashing The inhibiting effect of enzyme IGF1R and INSR are weaker, IC50It is much in 5000nM, predict that it is weaker to blood sugar influence, safety is higher. In addition, experiments in vivo also indicates that, the compound of the present invention is on mouse blood sugar level without influence.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to Detailed description made by above, and claims should be belonged to.

Claims (5)

1. a kind of compound or its pharmaceutically acceptable salt, the compound is following compound:
2. a kind of pharmaceutical composition, it includes the compound of claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier.
3. the compound of claim 1 or its pharmaceutically acceptable salt or the composition of claim 2 preparation for treat and/ Or the application in the drug of pre- preventing tumor.
4. application according to claim 3, wherein the tumour is the tumour with drug resistance.
5. application according to claim 3, wherein the tumour is the tumour for having drug resistance to EGFR inhibitor.
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