CN105461695A - Pyrimidine or triazine derivative, and preparation method and use thereof - Google Patents

Pyrimidine or triazine derivative, and preparation method and use thereof Download PDF

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Publication number
CN105461695A
CN105461695A CN201510444329.1A CN201510444329A CN105461695A CN 105461695 A CN105461695 A CN 105461695A CN 201510444329 A CN201510444329 A CN 201510444329A CN 105461695 A CN105461695 A CN 105461695A
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methyl
base
amido
ethyl
pyrimidine
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CN105461695B (en
Inventor
张龙
赵树雍
范传文
周豪杰
杨莹莹
陈栋
郑庆梅
李玉浩
郑善松
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SHENZHEN FORWARD PHARMACEUTICALS Co.,Ltd.
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Qilu Pharmaceutical Co Ltd
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    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings

Abstract

The invention relates to an arylaminopyrimidine or triazine derivative, and a preparation method, a medicinal composition and a use thereof, and concretely relates to a compound represented by formula I, or a pharmaceutically acceptable salt or a solvate thereof. In the formula I, R1 to R7, X and Y are defined in the description and claims. The invention also relates to a preparation method of the compound of formula I, the medicinal composition containing the compound, and the pharmacy use of the compound and the medicinal composition. The compound of formula I is an effective tyrosine kinase irreversible inhibitor, and especially has a strong inhibition effect on EGFR-T790M drug-resistant tumors.

Description

Pyrimidine or pyrrolotriazine derivatives and its production and use
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the arylamine pyrimidine or triazine derivative and preparation method thereof with anti-tumor activity that a class is new, described arylamine pyrimidine or pyrrolotriazine derivatives have effective tyrosine kinase inhibitory activity, have the purposes of the propagation of tumour cell and the medicine aspect of migration driven for the preparation for the treatment of or the tumour mediated by receptor tyrosine kinase of assisting therapy Mammals (comprising people) or receptor tyrosine kinase.
Background technology
Point out in global cancer report (2014) that WHO issues, within 2012, the global number dying from cancer reaches 8,200,000.Due to the change of living environment and life habit, under the effect of poor environment and some unfavorable factors, the M & M of tumour is in rising trend.According to the address prediction of WHO, global cancer new cases was by by 1,400 ten thousand people of 2012, and 1,900 ten thousand people of cumulative year after year to 2025 year, will reach 2,400 ten thousand people by 2035.
The treatment of tumour was realized by finding tumour and destroying in the past, now along with deepening continuously of studying cell signaling pathway, people to the effect of the oncogene of inside tumor cells and antioncogene understand more and more deep, the antitumor drug new for the specific molecular shot design of tumour more and more receives publicity, become the hot fields of research, and anti-tumor drugs targeting has also been applied to clinical as a kind of new methods for the treatment of, and obtain significant progress in recent years.Now known, the propagation of protein tyrosine kinase (Proteintyrosinekinases, PTK) signal path and tumour cell, differentiation, migration and apoptosis have substantial connection (LiSun, etal., DrugDiscovToday, 2000,5,344-353), protein tyrosine kinase inhibitor interference or blocks protein Tyrosylprotein kinase path is utilized to may be used for oncotherapy (FabbroD., etal., CurrOpinPharmacol, 2002,2,374-381); Also can be used for treatment leukemia, multiple myeloma or lymphoma etc.
In recent years, people are devoted to T suppression cell signal transduction pathway with development of new target spot antitumor drug.Signal transduction inhibitor lowers existence and the proliferation signal of tumour, promotes apoptosis, instead of by cytotoxicity, therefore selectivity is higher, toxic side effect is less.Existing tens kinds of signal transduction inhibitors are applied to the clinical treatment of tumour at present, be mainly protein tyrosine kinase inhibitor series antineoplastic medicament, the wherein comparative maturity of the compound exploitation of 4-(substituted benzene amino) quinazoline structure type, as the micromolecular inhibitor Gefitinib of EGFR Tyrosylprotein kinase target spot, erlotinib and lapatinibditosylate etc.In addition, patent application WO96/33977, WO97/30035, WO98/13354, WO00/55141, WO02/41882, WO03/82290 and EP837063 etc. disclose and on 4-position, to carry phenylamino replace and on 6-and/or 7-position, carry some quinazoline derivant substituent, and they have receptor tyrosine kinase activity.
But along with kinases variation and the appearance of drug resistance of tumor, the s-generation is arisen at the historic moment for the irreversible inhibitor of EGFR family target spot.Irreversible inhibitor has many advantages, as with ATP-binding site covalent bonds, therefore combine firmly, do not need to maintain higher drug concentration, can dosage be reduced, extend administration time, reduce resistance etc.Being in the irreversible inhibitor of clinical III phase has HKI-272, Dacomitinib and afatinib at present.As the s-generation for the improved seeds in the irreversible inhibitor of EGFR target spot, afatinib goes on the market at present.Although but s-generation irreversible inhibitor preclinical study shows good overriding resistance tumor effect, clinical obvious curative effects is not shown to drug-resistant tumor.Trace it to its cause and be that the toxic reaction that high inhibition causes excessively to Wild type EGFR limits its clinical medicine dose, do not reach the effective exposed amount to drug-resistant tumor in body.Third generation selectivity irreversible inhibitor activates EGFR and EGFR-T790M as CO-1686, AZD-9291 etc. have to sudden change and has higher inhibit activities, and the feature more weak to Wild type EGFR, have outstanding performance in clinical studies with good security, for drug resistant non-small cell lung at present in later phase clinical research.
Small molecule tyrosine kinase inhibitors is as new anti-tumor drugs targeting, and for the treatment of tumour and prevention open a fan new window, and its side effect is slight, has good tolerance.Although existing more than 10 small molecule tyrosine kinase inhibitors is that clinical cancer therapy has made very large contribution at present, but still need to find that some have the other compound of the pharmacological characteristics of better activity in vivo and/or improvement than existing tyrosine kinase inhibitor, or find some powerful or for variation kinases still effective inhibitor as irreversible inhibitor etc.Therefore develop new improvement or more efficient tyrosine kinase inhibitor, more in depth understand relation between such medicine and known target protein and its mechanism playing antitumor action has great importance to clinical therapy of tumor.
Summary of the invention
The present inventor is surprised to find that by further investigation, arylamine pyrimidine or the pyrrolotriazine derivatives with formula I structure have effective tyrosine kinase irreversible restraining effect and/or have good interior medicine dynamics behavior, and in vitro study display, the compounds of this invention has significant restraining effect to H1975 tumour cell (EGFR-T-790 mutant drug-resistant tumour), and more weak to EGFR-wt restraining effect, demonstrate good selectivity.Consider that this compounds can reduce the toxic side effect (as skin acne, diarrhoea etc.) caused because of EGFR-wt target spot extra-inhibitory, can be more suitable for for oncotherapy.The present invention is based on this find and be accomplished.
First aspect present invention provides compound shown in formula I and pharmacy acceptable salt, solvate:
Wherein, R 1be selected from hydrogen, C 1-4the C of alkyl, halo 1-4alkyl, C 1-4heterocyclylalkyl, halogen, preferred hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-2-base, fluorine, chlorine, bromine, more preferably methyl, ethyl, difluoromethyl, trifluoromethyl, most preferable, ethyl, difluoromethyl;
R 2be selected from hydrogen, C 1-3the C of alkyl, halo 1-3alkyl, halogen, preferred hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, trichloromethyl, dichloromethyl, fluorine, chlorine, bromine, more preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine;
R 3be selected from tetrahydrofuran (THF)-3-base oxygen base, tetrahydrofuran (THF)-2-base oxygen base ,-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2,-N (CH 3) CH 2cH 2n (Boc) CH 3, 4-methylpiperazine-1-yl, 4-(dimethylin) piperidin-1-yl, 2-(cyclopropyl (2-(dimethylin) ethyl) amido, 2-((2-(nitrogen heterocyclic ethyl-1-base) ethyl) (methyl) amido, preferably-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2,-N (CH 3) CH 2cH 2n (Boc) CH 3, 4-methylpiperazine-1-yl, more preferably-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is selected from CH, C-CH 3, N, preferred CH, N, more preferably CH;
Y is selected from N, CH, C-Cl, C-F, C-CF 3, C-CHF 2, C-CH 3, C-CCl 3, preferred N, CH, C-Cl, C-CF 3, more preferably CH, C-Cl, C-CF 3;
R 7be selected from methyl, ethyl, methoxyethyl, preferable methyl, ethyl, more preferably methyl;
And work as R 1during for methyl, X is not CH, or Y is not CH, C-Cl, C-CH 3, or R 2be not hydrogen; Preferably, R is worked as 1during for methyl, X is selected from C-CH 3, N, or Y is selected from N, C-F, C-CF 3, C-CHF 2, C-CCl 3, or R 2for fluorine.
In a technical scheme of the present invention, R 1be selected from hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-2-base, fluorine, chlorine, bromine, more preferably methyl, ethyl, difluoromethyl, trifluoromethyl, most preferable, ethyl, difluoromethyl;
R 2be selected from hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, trichloromethyl, dichloromethyl, fluorine, chlorine, bromine, more preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2,-N (CH 3) CH 2cH 2n (Boc) CH 3, 4-methylpiperazine-1-yl, more preferably-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is selected from CH, C-CH 3, N, preferred CH, N, more preferably CH;
Y is selected from N, CH, C-Cl, C-F, C-CF 3, C-CHF 2, C-CH 3, C-CCl 3, preferred N, CH, C-Cl, C-CF 3, more preferably CH, C-Cl, C-CF 3;
R 7be selected from methyl, ethyl, methoxyethyl, preferable methyl, ethyl, more preferably methyl;
And work as R 1during for methyl, X is not CH, or Y is not CH, C-Cl, C-CH 3, or R 2be not hydrogen; Preferably, R is worked as 1during for methyl, X is selected from C-CH 3, N, or Y is selected from N, C-F, C-CF 3, C-CHF 2, C-CCl 3, or R 2for fluorine.
In another technical scheme of the present invention, R 1be selected from methyl, ethyl, difluoromethyl, trifluoromethyl, preferable methyl, ethyl, difluoromethyl;
R 2be selected from hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2, 4-methylpiperazine-1-yl;
X is selected from CH, N, preferred CH;
Y is selected from N, CH, C-Cl, C-CF 3, preferred CH, C-Cl, C-CF 3;
R 7be selected from methyl, ethyl, preferable methyl;
And work as R 1during for methyl, X is not CH, or Y is not CH, C-Cl, or R 2be not hydrogen; Preferably, R is worked as 1during for methyl, X is N, or Y is selected from N, C-CF 3, or R 2for fluorine.
In a preferred technical scheme of the present invention, R 1be selected from methyl, ethyl, difluoromethyl;
R 2be selected from hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is selected from CH, N, preferred CH;
Y is selected from N, CH, C-Cl, C-CF 3, preferred CH, C-Cl, C-CF 3;
R 7be selected from methyl;
And work as R 1during for methyl, X is N, or Y is selected from N, C-CF 3, or R 2for fluorine.
In a most preferred technical scheme of the present invention, R 1be selected from methyl, ethyl, difluoromethyl;
R 2be selected from hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is CH;
Y is selected from CH, C-Cl, C-CF 3;
R 7be selected from methyl;
And work as R 1during for methyl, Y is C-CF 3, or R 2for fluorine.
In first aspect present invention, described halogen or halogen atom are selected from fluorine, chlorine or bromine, in one embodiment preferred fluorine; Described alkyl to refer between carbon atom and between carbon atom with hydrogen atom all with the alkyl that singly-bound is connected, it comprises straight chained alkyl, branched-chain alkyl, cycloalkyl; Preferred C 1-6or C 1-4alkyl, particularly, described straight or branched alkyl is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl; Described halogenated alkane refers to the alkyl be optionally substituted with one or more halogen atoms, and the example of haloalkyl comprises trifluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl; Described cycloalkyl refers to the alkyl with ring texture, preferred C 3-7, C 4-6or C 3-5cycloalkyl, the example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Described Heterocyclylalkyl refers to that carbon atom in ring-type carbon skeleton structure is by the cycloalkyl of 1-2 hybrid atom MCM-41, its heteroatoms can be selected from N, O, S, and the example of Heterocyclylalkyl comprises nitrogen heterocyclic ethyl, tetrahydro-thienyl, tetrahydrofuran base, Pyrrolidine base, hexahydropyridine base, piperidyl; Described tetrahydrofuran (THF)-3-base comprises (S)-tetrahydrofuran (THF)-3-base, (R)-tetrahydrofuran (THF)-3-base; Described tetrahydrofuran (THF)-3-base oxygen base comprises (S)-tetrahydrofuran (THF)-3-base oxygen base, (R)-tetrahydrofuran (THF)-3-base oxygen base; Described " Boc " refers to tert-butoxycarbonyl (English full name is: t-Butyloxycarbonyl).
Formula I described according to a first aspect of the present invention or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is selected from hydrochloride, vitriol, mesylate, tosylate, fumarate, maleate and malate, or the solvate of these salt (such as hydrate).
Formula I described according to a first aspect of the present invention, it is selected from following compound:
2-((2-acrylamido-5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-methoxyl group-4-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-methoxyl group) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-oxyethyl group) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-(difluoro-methoxy) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-(difluoro-methoxy)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-p-methoxy-phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-isopropoxy-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl isophthalic acid H-indazole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(5-fluoro-1-methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-ethoxyl phenenyl)-acrylamide;
N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-p-methoxy-phenyl)-acrylamide;
N-(4-methoxyl group)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-2-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-(4-(dimethylin) piperidin-1-yl)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base aminocarbonyl phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-ethoxyl phenenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-methoxyethoxy phenyl) acrylamide;
N-(2-(cyclopropyl (2-(dimethylin) ethyl) amido)-4-methoxyl group-5-(4-(1-(2-methoxyethyl)-1H-indoles-3-yl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(nitrogen heterocyclic ethyl-1-base) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-p-methoxy-phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-methyl-pvrimidine-2-base amido) phenyl) acrylamide;
(S)-N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(5-fluoro-1-methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-chloropyrimide-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
Or its pharmacy acceptable salt, solvate.
Second aspect present invention provides the preparation method of formula I or its pharmacy acceptable salt described in first aspect present invention, and it comprises the following steps:
(1) in the presence of a lewis acid, in high boiling point anhydrous solvent, intermediate compound IV is obtained by reacting by compound shown in compound and formula III shown in formula II:
Or, by compound shown in formula II and formula III ' shown in compound react under catalyst action and prepare intermediate compound IV:
(2) intermediate compound IV obtains intermediate VI with compound V under suitable acid exists, and intermediate VI reacts under suitable alkali effect, then reduces to obtain intermediate VII through reductive agent:
(3) intermediate VII and acrylate chloride or acrylic anhydride are obtained by reacting formula I:
Or intermediate VII and 3-chlorpromazine chloride react, then through eliminating to obtain formula I:
And optionally,
(4) formula I and corresponding acid-respons obtain the pharmacy acceptable salt of formula I, or obtain the base of corresponding formula I through alkali tune;
Wherein, R 1-R 3and R 7, X, Y have the identical implication of first aspect present invention, Z is boric acid base group, borate group or tin trimethyl group.
In step (1), described high boiling point anhydrous solvent is selected from glycol dimethyl ether, dimethylbenzene; Described Lewis acid is selected from anhydrous AlCl 3, FeCl 3; Described catalyzer is palladium catalyst, preferred Pd/C, tetrakis triphenylphosphine palladium (Pd (PPh 3) 4), [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride (Pd (dppf) Cl 2);
In step (2), described suitable acid is selected from tosic acid, hydrochloric acid, Hydrogen bromide, preferred tosic acid; Described suitable alkali is selected from organic bases or mineral alkali, preferred triethylamine, diisopropyl ethyl amine, sodium hydride, potassium hydride KH and hydrolith; Described reductive agent is selected from SnCl 2concentrated hydrochloric acid, Zn powder acetic acid, Fe powder acetic acid, iron powder ammonium chloride, Pd/C shortening; Preferred Pd/C shortening, Fe powder ammonium chloride.
For the preparation method described in second aspect present invention, where necessary, for preventing some group (as amino, hydroxyl etc.) from undesirable reaction occurring, needing to be protected corresponding group, meanwhile, being removed protecting group in due course.These examples are too numerous to enumerate, and the use of the protecting group specifically do not mentioned and the method for deprotection also belong within scope of the present invention.
In the preparation method described in second aspect present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also preparation in accordance with the present invention method can synthesize other not specifically enumerated formula I of the present invention.
In the present invention, starting raw material 2 shown in formula II, 4-dichloro pyrimidine or triazine and the indoles described in formula III or indazole can win auspicious chemical Science and Technology Ltd. from Shanghai, Tianjin Heowns Biochemical Technology Co., Ltd. buys or method as be shown in the examples preparation, as 5-(trifluoromethyl) pyrimidine-2,2-(1H, 3H)-diketone, purchased from Tianjin Heowns Biochemical Technology Co., Ltd., obtains 5-(trifluoromethyl)-2,4-dichloro pyrimidine through reacting further.Starting raw material (S)-3-hydroxyl tetrahydrofuran can be bought from Shanghai Hanhong Chemical Industry Co., Ltd. and obtain, and hexa methyl ditin is purchased from the smooth Science and Technology Co., Ltd. of upper Haitai.
In the present invention, starting raw material substituted aromatic amines shown in formula V can prepare according to conventional methods, or market purchase obtains 2-nitrophenols as fluoro-in 5-purchase from Tianjin Heowns Biochemical Technology Co., Ltd., in scripture, preparation method obtains corresponding substituted aromatic amines, and the fluoro-5-N-methyl-p-nitroaniline of 2-methoxyl group-4-is purchased from Shanghai Hanhong Chemical Industry Co., Ltd..Other common agents or solvent if not otherwise indicated, are all directly bought, unprocessed direct use.As N, N, N ' N that-trimethylammonium ethylenediamine-hydrochloride or single Boc protect, N '-dimethyl quadrol is purchased from nine ancient cooking vessel chemistry (Shanghai) Science and Technology Ltd.s; Acrylic anhydride, acrylate chloride or 3-chlorpromazine chloride to be radically reformed Chemical Co., Ltd. purchased from Changzhou.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises formula I described in first aspect present invention or its pharmacy acceptable salt or solvate, and optional one or more pharmaceutically acceptable carrier or vehicle.
Fourth aspect present invention provides the compound shown in first aspect present invention formula I and pharmacy acceptable salt thereof, solvate is being used for the treatment of or/and prevent the purposes in the medicine of disease that Mammals (comprising people) is relevant to receptor tyrosine kinase or illness.
Fifth aspect present invention provides pharmaceutical composition described in third aspect present invention being used for the treatment of or/and prevent the purposes in the medicine of disease that Mammals (comprising people) is relevant to receptor tyrosine kinase or illness.
Sixth aspect present invention provides a kind of for treating and/or preventing the disease relevant to receptor tyrosine kinase or the method for illness in Mammals in need (comprising people), and the method comprises to the pharmaceutical composition described in the third aspect present invention of compound, its pharmacy acceptable salt, solvate or effective dose shown in the formula I of administration treatment significant quantity in need.
The present inventor is shown by biological test, compound shown in formula I described in first aspect present invention all show powerful inhibit activities to EGFR sudden change (EGFR-delE746-A750) cell strain (HCC827) and EGFR-T790M medicament-resistant mutation cell strain H1975, and it is more weak to Wild type EGFR overexpression cell line A431 restraining effect, therefore it is expected to the compounds of this invention and pharmaceutical composition thereof and can be used for EGFR sudden change and EGFR-T790M resistance receptor tyrosine kinase is independent or the treatment of the disease of part mediate, and avoid or reduce because the larger toxic side effect produced EGFR wild type kinase extra-inhibitory is (as skin acne, diarrhoea, vomiting etc.).The compounds of this invention mainly through suppressing one or more EGFR family tyrosine-kinase enzyme mutants, or produces the effect of anti-tumour cell proliferative, migration or short apoptosis of tumor cells by the kinase whose activity of mutation inhibiting.
In the present invention, in method described in purposes described in particularly in the present invention fourth, fifth and the 6th, described " disease relevant to receptor tyrosine kinase or illness " be " tumour mediated by receptor tyrosine kinase ", " propagation of the tumour cell driven by receptor tyrosine kinase and migration " or " EGFR receptor tyrosine kinase susceptible neoplasms preferably.Wherein, the tumour that described " EGFR receptor tyrosine kinase cancer susceptible " preferred EGFR family high expression level and EGF drive, include but not limited to lack activated mutant body and/or the mutant mediated tumour of EGFR-delE746-A750 by EGFRL858R mutant and/or EGFR-T790M mutant and/or Exon19, or to the tumour of EGFR inhibitor as resistances such as Gefitinib (Gefitinib) or Erlotinibs (Erlotinib), specifically comprise noumenal tumour, as bile duct, bone, bladder, central nervous system (as brain), breast, Colon and rectum, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus (as carcinoma of endometrium) and vulva etc., and non-solid tumors, as leukemia, multiple myeloma or lymphoma etc.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.Those skilled in the art can pass through the actual dose level changing each activeconstituents in pharmaceutical composition of the present invention, so that the active compound amount of gained effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level need according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In the present invention, described pharmaceutical composition can to become with solid or liquid form is for oral administration, for parental injection or for rectal administration by particular formulation especially.
Compound or its pharmacy acceptable salt shown in the formula I of the present invention that term " treats and/or prevents significant quantity " refer to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment and/or prevention.But it should be understood that total daily dosage portion of compound shown in formula I or its pharmacy acceptable salt and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, compound shown in formula I or its pharmacy acceptable salt are used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
Compound shown in formula I of the present invention can use with other medicines active ingredient combinations, as long as it does not produce other detrimental actions, and such as anaphylaxis.
Compound shown in formula I can separately as cancer therapy drug use, or can with one or more other antitumor drug conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacy acceptable salt.Term " pharmacy acceptable salt " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacy acceptable salt is well known in the art.Described salt, by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, is prepared at the final abstraction and purification process situ of the compounds of this invention or prepares separately.
Formula I also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with pharmaceutically acceptable solvent.
Embodiment
The present invention is further described below by concrete preparation embodiment and biological experiment, but, should be appreciated that these embodiments and biological experiment are only used for the use specifically described, and should not be understood as limiting the present invention in any form.It will be apparent to those skilled in the art that hereinafter, if not specified, material used and working method are well known in the art.Unless otherwise indicated, wherein: (i) temperature represents with degree Celsius (DEG C), operation is at room temperature carried out, and described room temperature refers generally to 15-35 DEG C, preferred 20-30 DEG C, more preferably 20-25 DEG C; (ii) organic solvent anhydrous sodium sulfate drying, the removal of solvent adopts Rotary Evaporators reduction vaporization, and bath temperature is not higher than 60 DEG C; (iii) reaction process thin-layer chromatography (TLC) is followed the tracks of; (iv) end product have satisfied hydrogen nuclear magnetic resonance spectrum ( 1h-NMR), nuclear magnetic resonance of carbon spectrum ( 13and mass spectrum (MS) data C-NMR).
embodiment 1:2-((2-acrylamido-5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 1):
a.3-the synthesis of (the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl)-1-Methyl-1H-indole
By 5-(trifluoromethyl) pyrimidine-2; 2-(1H; 3H)-diketone (18g; 0.1mol) join in the three-necked bottle of 250ml; add phosphorus oxychloride (45.8ml; 5eq); phosphoric acid (0.1eq) is added under nitrogen protection; heat in oil bath, between 85 DEG C ~ 90 DEG C, slowly drip diisopropyl ethyl amine (16ml), drip finish be warming up to 100 DEG C reaction backflow 36h; evaporated under reduced pressure solvent; namely column chromatography obtains oily liquids 2,4-bis-chloro-5-(trifluoromethyl) pyrimidine (3.8g, yield 17.7%).
By 2; the chloro-5-of 4-bis-(trifluoromethyl) pyrimidine (2.16g; 10mmol) join in the single port bottle of 150ml; add 30ml dry ethylene glycol dimethyl ether, under nitrogen protection, when being warming up to 60 DEG C, add 1-skatole (1.31g fast; 10mmol) with FERRIC CHLORIDE ANHYDROUS (2g); continue maintenance 60 DEG C reaction, after TLC detection reaction completes, add water/methyl alcohol (V water: V methyl alcohol=5:2) mixed solvent 30ml, stirring at room temperature, filter, filter cake anhydrous methanol washs, dry, obtains 3-(the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl)-1-Methyl-1H-indole (yield 24.8%).
b.N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2- the synthesis of amine:
By 3-(the chloro-5-of 2-(trifluoromethyl) pyrimidine-4-yl)-1-Methyl-1H-indole (1.07g, 1.0eq), the fluoro-5-N-methyl-p-nitroaniline of 2-methoxyl group-4-(639mg, 1.0eq) join in the single port bottle of 250ml, add propyl carbinol 75ml, tosic acid (709mg is added under stirring at room temperature, 1.2eq), pass into nitrogen protection, be heated to 105 DEG C of stirring reactions, after TLC detection reaction completes, Temperature fall, solid is had to separate out, filter, filter cake propyl carbinol washs, be drying to obtain N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-amine (805mg, yield 50.8%).
c.2-((5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitro phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester:
By N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-amine (922mg, 1.0eq),-the N of single Boc protection, N '-dimethyl quadrol (500mg), diisopropyl ethyl amine (2ml), trifluoroethanol 20ml joins in microwave tube, 100 DEG C of microwave reaction 2h, evaporated under reduced pressure solvent, rapid column chromatography obtains 2-((5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (1.13g, yield 90%).
d.2-((2-acrylamido-5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2- base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 1):
Getting 2-((5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (1.1g) joins in the single port bottle of 500ml, add anhydrous methanol (250ml), first nitrogen replacement, add 10%Pd/C (100mg), hydrogen exchange for several times, stirring at room temperature reaction 4h, after TLC detection reaction completes, suction filtration, filtrate reduced in volume removes solvent and obtains amine.Gained amine is dissolved in 20ml methylene dichloride, add triethylamine (900mg) wherein, be cooled to less than 0 DEG C, slowly drip acrylic anhydride (910mg) wherein, drip after finishing and naturally rise to room temperature reaction 1h, TLC detection reaction is complete, add 100ml water, equivalent dichloromethane extraction 3 times, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure rapid column chromatography obtains target product 2-((2-acrylamido-5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 1) (354mg, yield 31%), ESI-MS (m/z): [M+H] +654.3.
embodiment 2:N-(4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3- base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 2):
Gained compound in embodiment 11 (354mg) is dissolved in 5ml methylene dichloride, adds trifluoroacetic acid 3ml, stirring at room temperature 2h, it is complete that TLC detects raw material reaction, be cooled to less than 0 DEG C, add 50ml saturated sodium bicarbonate and 50ml methylene dichloride, stir 30min, separatory, aqueous phase equivalent dichloromethane extraction 3 times, merges organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains target product (compound 2) (246mg, yield 82%).
1H-NMR(400MHz,DMSO-d6,δppm)：9.48(s,1H),9.10(s,1H),8.64(s,3H),8.25(s,1H),8.13(m,1H),7.88(s,1H),7.48(d,1H，J＝7.2Hz),7.22(s,1H),7.05(s,1H),6.98(s,1H),6.78(m,1H)，6.24(d,1H，J＝17.2Hz),5.75(m,1H),3.89(s,3H),3.80(s,3H),3.24(s,2H),3.10(s,2H),2.60(s,3H)2.59(s,3H),；
13C-NMR(100MHz,DMSO-d6,δppm)：163.8,162.4,160.9,158.9,158.6,157.43，157.37,151.0，142.3，137.2,133.6,133.5，132.6,127.2,127.0,126.9,126.0,124.4,123.6,123.0,122.9,121.4,119.2,116.2,110.7，110.5，109.0,108.7，105.6，56.4,51.4,46.2,42.9,33.5,33.0；
ESI-MS(m/z):[M+H] +554.5。
embodiment 3:2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 3):
A. the synthesis of the fluoro-5-N-methyl-p-nitroaniline of 2-oxyethyl group-4-:
By fluoro-for 5-2-nitrophenols (6g, 1eq), salt of wormwood (15.8g, 3eq) be suspended in 150mlN, in dinethylformamide, instillation monobromethane (8.3g, 2eq), be warming up to 37 DEG C of stirring reactions, after TLC detection reaction, system poured in frozen water, product is separated out, the fluoro-2-nitrophenetol of 5-(6.8g, yield 97%) is washed to obtain in filtration.
Fluoro-for 5-2-nitrophenetol (6.8g) is dissolved in 150ml methyl alcohol, after adding 10%Pd/C (680mg), hydrogen exchange, stirring at room temperature hydrogenation, after TLC detection reaction, filter, filtrate decompression steams solvent and obtains the fluoro-2-phenetidine of 4-(5.2g, productive rate 92%).
Less than 0 DEG C, fluoro-for 4-2-phenetidine (3g) is dissolved in the 5ml vitriol oil, saltpetre (2.2g) is added system in batches, then naturally stirring at room temperature is risen to, processing reaction after LC-MS detection reaction, system is slowly poured in 100ml frozen water, instillation strong aqua adjust pH is to 7-8, add dichloromethane extraction for several times, organic phase adopts anhydrous sodium sulfate drying, after concentrating under reduced pressure, column chromatography obtains the fluoro-5-N-methyl-p-nitroaniline of 2-oxyethyl group-4-(1.4g, yield 36%).
b.2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 3):
Method similar to Example 1, with the fluoro-5-N-methyl-p-nitroaniline of 2-oxyethyl group-4-for raw material can obtain 2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 3), yield 22%.ESI-MS(m/z):[M+H] +600.2。
embodiment 4:N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3- base)-pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 4):
Gained compound in embodiment 33 (1.2g) is dissolved in 10ml methylene dichloride, adds trifluoroacetic acid 5ml, stirring at room temperature 2h, it is complete that TLC detects raw material reaction, be cooled to less than 0 DEG C, add 100ml saturated sodium bicarbonate and 100ml methylene dichloride, stir 30min, separatory, aqueous phase equivalent dichloromethane extraction 3 times, merges organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains target product (compound 4) (0.96mg, yield 96%).
1H-NMR(400MHz,DMSO-d6,δppm)：9.38(s,1H),8.99(s,1H),8.62(s,3H),8.34(d,1H，J＝4.8Hz),8.27(d,1H，J＝7.2Hz),7.87(s,1H),7.54(d,1H，J＝8.0Hz),7.25(m,2H),7.17(m,1H),6.98(s,1H),6.74(m,1H),6.31(d,1H，J＝16.8Hz)，5.80(d,1H，J＝10.4Hz),4.15(m,1H),3.91(s,3H),3.21(broads,2H),3.12(broads,2H),2.63(s,3H),2.59(s,3H),1.38(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.8,162.2,160.2,158.1,146.0,138.5,138.2,134.2,132.8,127.0,126.2,125.8,122.5,121.8,121.4,115.5,112.9,110.0,107.8,106.2，64.9,51.3,46.2,43.3,33.5,32.9,15.2.
ESI-MS(m/z):[M+H] +500.1。
embodiment 5:2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 5):
A. the synthesis of the fluoro-5-N-methyl-p-nitroaniline of 2-difluoro-methoxy-4-:
By fluoro-for 5-2-nitrophenols (5g, 1eq), salt of wormwood (6.6g, 1.5eq) be suspended in 150mlDMF with chlorodifluoroacetic acid sodium (7.2g), 90 DEG C of stirring reactions, after TLC detection reaction, decompression steams solvent, add 200ml water, equivalent dichloromethane extraction 3 times, merges organic layer, anhydrous sodium sulfate drying, after concentrating under reduced pressure, column chromatography obtains 4-fluoro-2-difluoro-methoxy oil of mirbane (3.1g, yield 45%).
Fluoro-for 4-2-difluoro-methoxy oil of mirbane (3.1g) is dissolved in 100ml methyl alcohol, hydrogen exchange is carried out after adding 10%Pd/C (350mg), stirring at room temperature hydrogenation, after TLC detection reaction, filter, filtrate reduced in volume is to doing to obtain the fluoro-2-difluoro-methoxy-aniline (2.6g) of 4-.
At 0 DEG C, be dissolved in the 5ml vitriol oil, add saltpetre (2.0g) in batches by fluoro-for 4-2-difluoro-methoxy-aniline (2.6g), stirring at room temperature is reacted, and after LC-MS detection reaction, system is slowly poured into the saturated NaHCO of 100ml 3in frozen water, solid is had to separate out, suction filtration, filtrate adds 100ml dichloromethane extraction 3 times, and filter cake filters after being dissolved in dichloromethane extraction liquid again, anhydrous sodium sulfate drying, after concentrating under reduced pressure, column chromatography obtains the fluoro-5-N-methyl-p-nitroaniline of 2-difluoro-methoxy-4-(2.1g, yield 65%).
b.2-((5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido)-2-nitrophenyl) (first base) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester:
Method similar to Example 1, with the fluoro-5-N-methyl-p-nitroaniline of 2-difluoro-methoxy-4-for raw material can obtain 2-((5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester, total recovery 61%.
c.2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) benzene base) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 5):
Getting 2-((5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (2.4g) joins in the single port bottle of 1000ml, add anhydrous methanol (400ml), first nitrogen replacement, add 10%Pd/C (200mg), hydrogen exchange for several times, stirring at room temperature reaction 4h, after TLC detection reaction completes, suction filtration, filtrate reduced in volume removes solvent and obtains amine (1.70g).
Above-mentioned gained amine (1.70g) is dissolved in 50ml acetone, add salt of wormwood (620mg wherein, 1.5eq), be cooled to less than-10 DEG C, slowly drip 3-chlorpromazine chloride (1.5eq) wherein, drip after finishing and naturally rise to room temperature reaction 1h, TLC detection reaction is complete.Reduced pressure at room temperature concentrates, and adds 20ml acetonitrile and dissolves, add triethylamine (3.0eq), and 83 DEG C of backflows 8h, LC-MS show raw material and transform completely.Add 50ml water, a large amount of solid is had to separate out, suction filtration obtains target product 2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 5) (1.47g, yield 79%).
ESI-MS(m/z):[M+H] +622.3。
embodiment 6:N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole -3-base)-pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 6):
Gained compound in embodiment 55 (1.47g) is dissolved in 10ml methylene dichloride, add trifluoroacetic acid 4ml, stirring at room temperature 2h, it is complete that TLC detects raw material reaction, is cooled to less than 0 DEG C, adds 50ml saturated sodium bicarbonate solution, equivalent dichloromethane extraction 3 times, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure obtains target product (compound 6) (1.11g, yield 90%).
1H-NMR(400MHz,DMSO-d6,δppm)：9.39(s,1H),8.90(s,1H),8.87(s,1H),8.76(s,2H),8.55(s,1H),8.30(d,1H，J＝4.8Hz),8.23(m,1H),7.54(d,1H，J＝7.6Hz),7.26(m,2H),7.23(s,1H),7.13(m,1H),6.76(m,1H),6.29(d,1H，J＝16.8Hz)，5.80(d,1H，J＝10.4Hz),3.89(s,3H),3.20(s,4H),2.64(s,3H),2.61(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：164.0,159.3,140.2,157.9,138.3,135.1,132.5,131.0,127.6,125.9,122.8,122.3,121.7,119.9,119.0,117.3,114.8,113.7,112.7,111.1,107.7,51.4，46.0,42.7,33.6,33.0；
ESI-MS(m/z):[M+H] +522.1。
embodiment 7:2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoro methyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 7) synthesis:
a.2-((5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2- nitrophenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester:
Method similar to Example 1, with the fluoro-5-N-methyl-p-nitroaniline of 2-difluoro-methoxy-4-(synthetic method is as described in example 5 above) for raw material can obtain 2-((5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester, yield 47%.ESI-MS(m/z):[M+H] +498.1。
b.2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)- pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 7):
The synthetic method similar with compound 5 in embodiment 5,2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 7) can be obtained, total recovery 55%.ESI-MS(m/z):[M+H] +690.3。
embodiment 8:N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole -3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 8):
With method similar in embodiment 2, compound 7 in embodiment 7 is sloughed Boc, obtain N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide (compound 8), yield 81%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.95(s,1H),9.51(s,1H),9.35(s,2H),8.65(s,1H),8.30(s,1H),8.12(s,1H),7.89(s,1H),7.49(d,1H，J＝7.6Hz),7.32(m,1H),7.28(s,1H),7.23(m,1H),7.06(m,2H),7.03(m,1H),6.24(d,1H，J＝16.8Hz)，5.72(d,1H，J＝10.0Hz),3.90(s,3H),3.25(s,2H),3.10(s,2H),2.61(s,3H),2.53(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：164.2,162.5，161.0，157.6,143.0,142.8,137.2,133.7,133.0，130.8,127.1,126.9,126.1,124.3,123.0,122.9,122.7，121.5，119.9,117.4,114.8,112.8,110.6,109.3,109.0，51.1，45.8,42.6,33.6,32.8；
ESI-MS(m/z):[M+H] +590.1。
embodiment 9:2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) -pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 9):
a.2-((5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitro phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester:
Method similar to Example 1, with the fluoro-5-N-methyl-p-nitroaniline of 2-oxyethyl group-4-(synthetic method is as described in example 3 above) for raw material can obtain 2-((5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester, yield 68%.MS(m/z):[M+H] +476.3。
b.2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2- base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 9):
The synthetic method similar with compound 5 in embodiment 5,2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 9) can be obtained, total recovery 73%.ESI-MS(m/z):[M+H] +668.4。
embodiment 10:N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3- base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 10):
With method similar in embodiment 2, compound 9 in embodiment 9 is sloughed Boc, obtain N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide (compound 10), yield 86%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.48(s,1H),9.01(s,1H),8.65(s,2H),8.24(s,1H),8.12(s,1H),7.88(s,1H),7.49(d,1H，J＝8.0Hz),7.21(m,1H),7.04(s,1H),6.95(s,1H),6.79(dd,1H),6.24(d,1H，J＝16.8Hz)，5.74(d,1H，J＝11.6Hz),4.05(m,2H)，3.89(s,3H),3.23(s,2H),3.10(s,2H),2.59(s,6H),1.22(m,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.9,162.3，160.9，157.3,150.0,142.1,137.2,133.6,132.6，127.1,126.9,125.9,124.3,124.0,122.9,121.4，121.2，110.7,110.6,108.8,106.7,64.6，51.1，46.1,43.0,33.6,32.9，15.1；
ESI-MS(m/z):[M+H] +568.3。
embodiment 11:2-((2-acrylamido-5-methoxyl group-4-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amine base) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 11):
a.3-the synthesis of (2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole
By iodo-for 3-1-methyl isophthalic acid H indazole (11.6g; 45mmol), duplex tetramethyl ethylene ketone boric acid ester (22.8g, 89.8mmol); Potassium ethanoate (13.2g; 3eq) be suspended in the anhydrous Isosorbide-5-Nitrae-dioxane of 150ml, after nitrogen replacement; add tetrakis triphenylphosphine palladium (5.2g; 10%eq), after being warming up to 90 DEG C of reaction 10h, TLC detection reaction under nitrogen protection.Be cooled to room temperature, suction filtration, filter cake ethyl acetate has children outside the state plan washing for several times, merging organic concentrated rear rapid column chromatography of pressure that subtracts each other and obtains 1-methyl isophthalic acid H-indazole-3-ylboronic acid pinacol ester crude product (15g), directly carrying out next step reaction without being further purified.
By 1-methyl isophthalic acid H-indazole-3-ylboronic acid pinacol ester crude product (12g); 2; 4-dichloro pyrimidine (9g; 60.4mmol) with cesium carbonate (30g; 92mmol) be suspended in 1; in 4-dioxane (100ml) and water (20ml) mixed solvent, after nitrogen replacement, add lower Pd (dppf) Cl of protection 2(3.4g; 10%eq); the lower 98 DEG C of reaction 8h of nitrogen protection; after TLC detection reaction; be cooled to room temperature; filter, filter cake methylene dichloride excusing from death washing several, after merging filtrate concentrating under reduced pressure, column chromatography must obtain 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole (3.7g).
b.2-((2-acrylamido-5-methoxyl group-4-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 11):
Method similar to Example 1, be that raw material can obtain 2-((2-acrylamido-5-methoxyl group-4-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 11), yield 85% with 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole.ESI-MS(m/z):[M+H] +587.2。
embodiment 12:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole -3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 12):
Method similar to Example 2, sloughs Boc by gained compound 11 in embodiment 11 with trifluoroacetic acid and obtains compound 12, yield 94%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.50(s,1H),8.45(m,5H),7.71(d,1H，J＝8.0Hz),7.44(m,2H),7.17(m,1H),7.00(s,1H),6.68(m,1H),6.24(d,1H,J＝16.8Hz)，5.76(m,1H),4.15(s,3H),3.84(s,3H),3.25(m,2H),3.12(m,2H),2.63(m,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.9,161.2,160.7,158.7,149.4,141.7,140.7,140.2,132.5,127.1,126.9,125.8,125.0,123.7,122.5,122.2,119.4,110.6,107.6,105.4,56.5，51.3,46.3,43.2,36.5,33.1；ESI-MS(m/z):[M+H] +487.1。
embodiment 13:2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amine base)-5-methoxyl group) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 13):
a.3-the synthesis of (2-chloropyrimide-4-base) fluoro-1-Methyl-1H-indole of-5-
Get N, dinethylformamide (DMF, 400ml) join in the three-necked bottle of 2L, add 60%NaH (59.2g) in batches, at being cooled to 0 DEG C after stirring at room temperature 10min, slowly drip the DMF solution (100ml) of 5-fluoro-1-hydrogen indoles (50g), drip and finish, after reacting 2h at 0 DEG C, instillation methyl iodide (100ml), TLC detects to raw material complete reaction.Add water 1000ml, equivalent extraction into ethyl acetate 3 times, organic layer anhydrous sodium sulfate drying, and after concentrating under reduced pressure, column chromatography obtains the fluoro-1-Methyl-1H-indole of 5-(49.8g, yield 90.3%).
By 2; 4-dichloro pyrimidine (17.8g, 1.2eq) is dissolved in dry ethylene glycol dimethyl ether (250ml), under nitrogen protection; be warming up to 60 DEG C; add the fluoro-1-Methyl-1H-indole (14.9g, 1eq) of 5-and FERRIC CHLORIDE ANHYDROUS (19.4g, 1.2eq) fast; finish; 60 DEG C of reactions, TLC detects to having reacted, and add water/methyl alcohol (V water: V methyl alcohol=5:2) mixed solvent 250ml, stirring at room temperature, filter, filter cake anhydrous methanol washs, dry, obtains 3-(2-chloropyrimide-4-base) the fluoro-1-Methyl-1H-indole of-5-(11.8g, yield 45.3%).
b.2-((5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-nitrophenyl) (first base) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester:
Method similar to Example 1,2-((5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-nitrophenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester can be obtained, total recovery 63% by 3-(2-chloropyrimide-4-base)-5-fluoro-1-Methyl-1H-indole.
c.2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-methoxy base) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 13):
The synthetic method similar with compound 5 in embodiment 5,2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-methoxyl group) phenyl) (methyl) amido can be obtained) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 13), total recovery 81%.ESI-MS(m/z):[M+H] +604.3。
embodiment 14:N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-methoxyl group-2-(first base (2-(methylamino) ethyl) amido)-phenyl) synthesis of acrylamide (compound 14):
Method similar to Example 2, gained compound 13 in embodiment 13 is sloughed Boc with trifluoroacetic acid and obtains N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide (compound 14), yield 95%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.32(s,1H),8.72(s,3H),8.62(s,1H),8.52(s,1H),8.29(d,1H，J＝4.8Hz),8.05(m,1H),7.54(m,1H),7.22(d,1H，J＝4.8Hz),7.09(m,1H),7.02(s,1H),6.74(m,1H),6.26(d,1H，J＝16.8Hz),5.76(d,1H，J＝10.0Hz),3.90(s,3H),3.86(s,3H),3.24(s,2H),3.15(s,2H),2.63(s,3H),2.61(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.7,162.8,160.0,159.6,159.2,158.9,157.6，156.0,148.4,139.9,136.1,134.9,132.7,126.8,126.4,124.9,119.1,117.5,116.1,112.8,112.7,112.3,112.2,111.0,110.7，107.6,107.4，107.1,105.6，56.5,51.3,46.1,43.0,33.9,32.9；ESI-MS(m/z):[M+H] +504.3。
embodiment 15:2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amine base)-5-oxyethyl group) phenyl) (methyl) amido) synthesis of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 15):
The synthetic method similar with compound 13 in embodiment 13, with 2-oxyethyl group-4-fluoro-5-N-methyl-p-nitroaniline (synthetic method is as described in example 3 above) for raw material can obtain 2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-oxyethyl group) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 15), total recovery 21%.ESI-MS(m/z):[M+H] +618.4。
embodiment 16:N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-oxyethyl group-2-(first base (2-(methylamino) ethyl) amido)-phenyl) synthesis of acrylamide (compound 16):
Method similar to Example 2, gained compound 15 in embodiment 15 is sloughed Boc with trifluoroacetic acid and obtains N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide (compound 16), yield 89%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.30(s,1H),9.10(s,1H),8.72(s,3H),8.65(s,1H),8.29(d,1H，J＝4.8Hz),8.00(s,1H),7.58(m,1H),7.30(d,1H，J＝4.8Hz),7.12(m,1H),7.03(s,1H),6.75(m,1H),6.25(d,1H，J＝16.8Hz),5.76(d,1H，J＝10.0Hz),4.11(m,2H),3.92(s,3H),3.23(s,2H),3.16(s,2H),2.63(s,3H),2.61(s,3H),1.26(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.7,160.2,159.1,158.8,157.8148.1,140.6,137.4,135.0,132.7,126.9,126.5,126.4,126.3,117.9,115.8,112.5,111.3,111.0，107.8,107.5，106.9,64.7,51.3,46.1,42.9,34.0,32.9，15.1；
ESI-MS(m/z):[M+H] +518.3。
embodiment 17:2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amine base)-5-(difluoro-methoxy) phenyl) (methyl) amido) conjunction of ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 17) become:
The synthetic method similar with compound 13 in embodiment 13, with 2-difluoro-methoxy-4-fluoro-5-N-methyl-p-nitroaniline (synthetic method is as described in example 5 above) for raw material can obtain 2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-(difluoro-methoxy) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 17), total recovery 14%.ESI-MS(m/z):[M+H] +640.2。
embodiment 18:N-(4-(difluoro-methoxy)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2- base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) synthesis of acrylamide (compound 18):
Method similar to Example 2, gained compound 17 in embodiment 17 is sloughed Boc with trifluoroacetic acid and obtains N-(4-(difluoro-methoxy)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide (compound 18), yield 86%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.34(s,1H),9.26(s,1H),8.73(s,2H),8.66(s,1H),8.60(s,1H),8.29(d,1H，J＝4.8Hz),7.96(d,1H，J＝8.8Hz),7.55(m,1H),7.29(m,1H),7.22(s,1H),7.09(m,1H),6.78(m,1H),6.26(d,1H，J＝16.8Hz)，5.78(d,1H，J＝10.0Hz),3.89(s,3H),3.20(s,4H),2.64(s,3H),2.61(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：164.0,162.2,160.1,159.2,158.8,158.5,157.7,141.0,136.8,135.0,132.5,131.3,127.5,127.2,126.5,126.3,119.8,119.6,118.5,117.3,115.6,114.7,113.8,112.5,112.4,112.3,111.2,110.9,107.9,107.7,107.2,51.4,45.9,42.6,34.0,32.9；
ESI-MS(m/z):[M+H] +540.3。
embodiment 19:2-((2-acrylamido-5-oxyethyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5- (trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (chemical combination thing 19) synthesis:
a.3-the synthesis of the fluoro-1-Methyl-1H-indole of (the chloro-5-of 2-(trifluoromethyl)-pyrimidine-4-yl)-5-
By 2; the chloro-5-of 4-bis-(trifluoromethyl)-pyrimidine (10.8g; 50mmol) be dissolved in dry ethylene glycol dimethyl ether (150ml), under nitrogen protection, be warming up to 60 DEG C; add the fluoro-1-Methyl-1H-indole of 5-(7.3g fast; 49mmol) with FERRIC CHLORIDE ANHYDROUS (8.1g, 50mmol), continue stirring reaction; TLC detects to having reacted, and add water/methyl alcohol (V water: V methyl alcohol=5:2) mixed solvent 150ml, stirring at room temperature, filter, filter cake use water/methyl alcohol (V water: V methyl alcohol=5:2) mixed solvent washing, dry, obtain the fluoro-1-Methyl-1H-indole of 3-(the chloro-5-of 2-(trifluoromethyl)-pyrimidine-4-yl)-5-(7.1g, yield 43%).
b.2-((2-acrylamido-5-oxyethyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 19)
The synthetic method similar with compound 13 in embodiment 13, be that raw material can obtain 2-((2-acrylamido-5-oxyethyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 19), total recovery 17% with 2-oxyethyl group-4-fluoro-5-N-methyl-p-nitroaniline and 3-(the chloro-5-of 2-(trifluoromethyl)-pyrimidine-4-yl)-5-fluoro-1-Methyl-1H-indole.ESI-MS(m/z):[M+H] +686.3。
embodiment 20:N-(4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2- base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) synthesis of acrylamide (compound 20):
Method similar to Example 2, gained compound 19 in embodiment 19 is sloughed Boc with trifluoroacetic acid and obtains N-(4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide (compound 20), yield 79%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.39(s,1H),9.18(s,1H),8.64(s,3H),8.20(s,1H),7.97(s,1H),7.89(m,1H),7.51(d,1H，J＝3.6Hz),7.07(m,1H),6.96(s,1H),6.77(m,1H),6.20(d,1H，J＝16.8Hz),5.72(d,1H，J＝10.0Hz),4.05(m,2H),3.90(s,3H),3.21(s,2H),3.11(s,2H),2.59(s,6H),1.18(s,3H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.7,162.4,160.4,159.9,158.6,158.3，157.6，157.3，150.3,142.2,135.31,135.25,133.9,132.7,127.7,127.6,127.0,126.8，126.2，124.4,123.9,121.7，121.3,116.3,111.9,111.8,111.3，111.0，110.5，108.5,108.3，108.0，107.0，64.5,51.3,46.1,42.8,33.9,32.9，15.1；
ESI-MS(m/z):[M+H] +586.2。
embodiment 21:2-((2-acrylamido-5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5- (trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (chemical combination thing 21) synthesis:
The synthetic method similar with compound 13 in embodiment 13, with 2-methoxyl group-4-fluoro-5-N-methyl-p-nitroaniline and 3-(the chloro-5-of 2-(trifluoromethyl)-pyrimidine-4-yl)-5-fluoro-1-Methyl-1H-indole (synthetic method as described in example 19 above) for raw material can obtain 2-((2-acrylamido-5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester (compound 21), total recovery 23%.ESI-MS(m/z):[M+H] +672.3。
embodiment 22:N-(4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2- base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) synthesis of acrylamide (compound 22):
Method similar to Example 2, gained compound 21 in embodiment 21 is sloughed Boc with trifluoroacetic acid and obtains N-(4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide (compound 22), yield 85%.
1H-NMR(400MHz,DMSO-d6,δppm)：9.30(s,1H),9.26(s,1H),8.67(s,3H),8.62(s,1H),8.16(s,1H),7.96(s,1H),7.51(d,1H，J＝4.0Hz),7.08(m,1H),7.00(s,1H),6.72(m,1H),6.21(d,1H，J＝16.4Hz),5.74(m,1H),3.90(s,3H),3.80(s,3H),3.24(s,2H),3.14(s,2H),2.60(s,6H)；
13C-NMR(100MHz,DMSO-d6,δppm)：163.7,162.5,160.4,159.9,158.9,158.6，157.6，157.5，157.4,151.4,142.4,135.3,133.9,132.5,127.7,127.6,127.0,126.1，124.4,123.6,121.7，119.2,111.9,111.8,111.3，111.0，110.5，108.2,108.0,105.9，56.3,51.1,46.0,42.8,33.9,32.8；
ESI-MS(m/z):[M+H] +572.4。
embodiment 23:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(1-methyl -1H-indol-3-yl)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) conjunction of acrylamide (compound 23) become:
a.N 1 -(2-(dimethylin) ethyl)-5-methoxyl group-N 1 -methyl-N 4 -(4-(1-Methyl-1H-indole-3- base)-5-(trifluoromethyl) pyrimidine-2-base) synthesis of-2-nitrophenyl-Isosorbide-5-Nitrae-diamines:
By N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-amine (300mg, 1.0eq) (synthetic method as described in Example 1), N, N, N '-trimethylammonium ethylenediamine-hydrochloride (500mg), diisopropyl ethyl amine (1.2ml, 10.0eq), trifluoroethanol 15ml joins in microwave tube, 100 DEG C of microwave reaction 30min, evaporated under reduced pressure solvent, rapid column chromatography obtains N 1-(2-(dimethylin) ethyl)-5-methoxyl group-N 1-methyl-N 4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base)-2-nitrophenyl-Isosorbide-5-Nitrae-diamines (350mg).
b.N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(1-Methyl-1H-indole -3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) synthesis of (compound 23):
Get N 1-(2-(dimethylin) ethyl)-5-methoxyl group-N 1-methyl-N 4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base)-2-nitrophenyl-1,4-diamines (350mg) joins in the single port bottle of 100ml, add the mixed solvent of dehydrated alcohol (15ml) and water (5ml), iron powder (200mg is added under stirring at room temperature, 5.0eq) with ammonium chloride (178mg), 65 DEG C of stirring reactions, water 100ml is added after TLC detection reaction completes, ethyl acetate equivalent extracts 3 times, merge organic layer, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains amine (307mg).Gained amine is dissolved in 15ml methylene dichloride, add triethylamine (526mg) wherein, be cooled to less than 0 DEG C, slowly drip acrylic anhydride (262mg) wherein, drip after finishing and naturally rise to room temperature reaction 1h, TLC detection reaction is complete, add 80ml water, equivalent dichloromethane extraction 3 times, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure rapid column chromatography obtains target product N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (193mg, yield 56.9%).
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.67(s,1H),9.83(s,1H),9.11(s,1H),8.64(s,1H),8.24(s,1H),8.10(m,1H),7.87(s,1H),7.47(m,1H),7.21(m,1H),7.07(m,1H),6.96(m,1H),6.21(d,1H,J＝15.2Hz),5.68(d,1H，J＝10.0Hz),4.03(m,1H),3.88(s,3H),3.80(s,3H),3.30(m,4H),3.06(m,1H),2.70(s,6H),2.62(s,3H),1.99(s,1H),1.18(m,2H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：164.0,162.5,160.9,157.4,151.0,142.4,137.2,133.6,133.5,133.0,127.2,127.1,126.5,126.0,123.3,123.0,122.9,122.0,121.4,110.7,110.5,105.3,60.2,56.4,53.9,49.6,45.9,43.1,33.6,21.2,14.6,8.9；
MS(m/z):[M+H] +568.3。
embodiment 24:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(5-fluoro-1-methyl isophthalic acid H- indol-3-yl) pyrimidine-2-base amido)-4-p-methoxy-phenyl) synthesis of acrylamide (compound 24):
The method similar with embodiment 23, N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-p-methoxy-phenyl) acrylamide (compound 24) can be obtained, yield 15.3% by 3-(2-chloropyrimide-4-base)-5-fluoro-1-Methyl-1H-indole (synthetic method as described in Example 13).
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.12(s,1H),8.97(s,1H),8.63(s,1H),8.30(d,1H，J＝5.2Hz),8.09(m,1H),8.03(m,1H),7.53(m,1H),7.18(d,1H，J＝5.2Hz),7.10(m,1H),7.05(m,1H),6.47(m,1H),6.24(m,1H)，5.74(m,1H),3.90(s,3H),3.84(s,3H),2.94(m,2H),2.71(s,3H),2.43(m,2H),2.29(s,6H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.0,161.9,160.7,159.8,158.0,157.5，147.4,138.6,135.5,134.9,132.9,128.6,127.9,126.5,126.3,126.2,125.7,115.2,113.0,112.9,112.1,112.0,110.7，110.4，107.4,107.2，105.9，56.4,45.3,43.0,33.7；
MS(m/z):[M+H] +518.3。
embodiment 25:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-methyl -1H-indol-3-yl) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 25):
The method similar with embodiment 23, be that raw material can obtain N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 25), yield 30% with 2-oxyethyl group-4-fluoro-5-N-methyl-p-nitroaniline (synthetic method as described in Example 3) and 3-(the chloro-pyrimidine-4-yl of 2-)-1-Methyl-1H-indole.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.21(s,1H),9.23(s,1H),8.74(s,1H),8.35(d,1H，J＝5.2Hz),8.22(d,1H，J＝8.0Hz),7.86(s,1H),7.53(d,1H，J＝8.4Hz),7.25(m,2H),7.18(m,1H),7.03(s,1H),6.47(m,1H),6.29(d,1H，J＝16.8Hz)，5.78(d,1H，J＝11.6Hz),4.13(m,1H),3.93(s,3H),2.90(m,2H),2.70(s,3H),2.33(m,2H),2.23(s,6H),1.36(m,3H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：162.9,162.0,160.2,158.3,145.3,138.2,137.6,134.5,132.9,128.2,126.5,126.3,125.8,122.4,121.6,121.4,113.4,112.9,110.0,107.7,106.9，64.8,57.2,55.9,45.5,43.2,33.4,15.2；
MS(m/z):[M+H] +514.2。
embodiment 26:N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amine base)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 26) synthesis:
The method similar with embodiment 23, be that raw material can obtain N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 26), yield 30% with 2-difluoro-methoxy-4-fluoro-5-N-methyl-p-nitroaniline (synthetic method as described in Example 5) and 3-(the chloro-pyrimidine-4-yl of 2-)-1-Methyl-1H-indole.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.29(s,1H),8.95(s,1H),8.51(s,1H),8.37(s,1H),8.30(d,1H，J＝5.6Hz),8.24(d,1H，J＝8.0Hz),7.51(d,1H，J＝8.0Hz),7.23(m,3H),7.10(m,1H),6.46(m,1H),6.26(m,1H)，5.79(m,1H),3.89(s,3H),2.88(m,2H),2.72(s,3H),2.36(m,2H),2.26(s,6H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.4,162.4,160.8,157.9,139.4,139.3,138.1,133.9,132.5,128.6,127.4,125.9,122.5,122.2,121.2,120.0,117.4,116.9,114.9,114.2,112.8,110.9,107.8,57.3，56.2,45.7,42.5,33.5；
MS(m/z):[M+H] +536.2。
embodiment 27:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-isopropoxy-5-(4-(1-first base-1H-indol-3-yl) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 27):
The method similar with embodiment 23, be that raw material can obtain N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-isopropoxy-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 27), yield 27% with 2-isopropoxy-4-fluoro-5-N-methyl-p-nitroaniline (synthetic method is similar executes example 3) and 3-(the chloro-pyrimidine-4-yl of 2-)-1-Methyl-1H-indole.MS(m/z):[M+H] +528.4。
embodiment 28:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl -1H-indazole-3-base) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 28):
a.3-the synthesis of (2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole
By iodo-for 3-1-methyl isophthalic acid H indazole (5.16g, 20mmol), hexa methyl ditin (19g, 3eq), tetrakis triphenylphosphine palladium (Pd (PPh 3) 4, 2.1g, 10%eq) be suspended in the anhydrous Isosorbide-5-Nitrae-dioxane of 200ml, under nitrogen protection after back flow reaction 16h, TLC detection reaction.Be cooled to room temperature, in reaction system, add 60mlKF solution (1M) and 200ml ethyl acetate and stir 0.5h.Filter, filtrate uses equivalent water washing 2 times, organic phase anhydrous sodium sulfate drying, and concentrating under reduced pressure obtains pale solid 1-methyl-3-trimethyl-tin-radical-1H-indazole crude product (4.04g, yield 68%), not purifiedly directly carries out next step reaction.
By 1-methyl-3-trimethyl-tin-radical-1H-indazole (2.96g, 10mmol), 2,4-dichloro pyrimidine (1.48g, 10mmol) and tetrakis triphenylphosphine palladium (Pd (PPh 3) 41.1g; 10%eq) be suspended in 60ml toluene; under nitrogen protection after back flow reaction 14h, TLC detection reaction, be cooled to room temperature; add 100ml saturated ammonium chloride solution; equivalent extraction into ethyl acetate 3 times, merge organic phase and drying, concentrating under reduced pressure column chromatography obtains 1.2g3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole.
b.N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl isophthalic acid H-indazole -3-base) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 28):
The method similar with embodiment 23, be that raw material can obtain N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl isophthalic acid H-indazole-3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 28), yield 38% with 3-(2-chloropyrimide-4-base)-1-methyl isophthalic acid H-indazole.
1H-NMR(600MHz,DMSO-d 6,δ ppm)：10.16(s,1H),8.65(s,1H),8.49(s,1H),8.43(m,1H),8.40(m,1H),7.69(d,1H，J＝8.4Hz),7.41-7.44(m,2H),7.12(m,1H),7.05(s,1H),6.42(m,1H),6.17(d,1H,J＝16.8Hz)，5.72(d,1H,J＝10.2Hz),4.15(s,3H),3.80(s,3H),2.91(m,2H),2.75(s,3H),2.34(m,2H),2.22(s,6H)；
13C-NMR(125MHz,DMSO-d 6,δ ppm)：162.9,161.4,160.6,158.6,149.2,141.6,132.6,127.7,126.9,126.6,124.8,123.8,122.2,121.1,118.0,110.5,107.2,105.9,57.4，56.2,45.7,42.8,36.4；MS(m/z):[M+H] +501.3。
embodiment 29:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-methyl -1H-indol-3-yl)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) synthesis of acrylamide (compound 7):
The method similar with embodiment 24, N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 29), yield 28% can be obtained.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.02(s,1H),9.06(s,1H),8.65(s,1H),8.42(s,1H),8.10(s,1H),7.89(s,1H),7.47(m,1H),7.20(m,1H),6.99(m,2H),6.53(m,1H),6.21(m,1H)，5.72(m,1H),4.03(m,2H),3.88(s,3H),2.96(m,2H),2.70(s,3H),2.30(s,6H),1.20(m,3H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：167.8,163.2,162.5,160.8,157.3,149.8,141.7,137.2,133.6,132.7,130.7,130.4,128.7,127.5,127.2,126.7,124.4,124.0,123.0,122.8,121.2,120.0,110.8,110.5,107.4,64.5，56.7,55.0,45.2,42.6,33.5，1,5.1；MS(m/z):[M+H] +582.3。
embodiment 30:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(fluoro-1-of 5- methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 30) synthesis:
The method similar with embodiment 25, N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 30), yield 25% can be obtained.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：9.91(s,1H),9.20(s,1H),8.64(s,1H),8.34(s,1H),7.97(s,1H),7.50(m,1H),7.06(m,1H),6.98(m,1H),6.72(m,1H),6.20(m,1H),5.70(d,1H，J＝10.8Hz),3.90(s,3H),4.03(m,2H),3.04(s,3H),2.60-2.80(m,4H),2.44(s,6H),1.18(s,3H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.4,162.6,160.3,159.9,157.6,157.4，150.1,142.0,135.3,135.2,133.9,132.7,127.8,127.6,126.6,124.4,123.8,120.4,111.7,111.8,111.2,111.0，110.6，110.5,108.3,108.0，107.3，64.4,55.8,44.4,42.5,33.9,15.1；MS(m/z):[M+H] +600.3。
embodiment 31:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(fluoro-1-of 5- methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 31) synthesis:
The method similar with embodiment 24, N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 31), yield 35% can be obtained.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.78(s,1H),9.76(s,1H),9.29(s,1H),8.63(s,1H),8.19(s,1H),8.02(s,1H),7.50(m,1H),7.28(m,1H),7.06(m,1H),6.97(m,1H),6.18(d,1H，J＝16.8Hz),5.65(d,1H，J＝10.0Hz),3.90(s,3H),3.80(s,3H),3.32(s,3H),3.02(m,4H),2.72(s,6H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：164.0,162.6,160.4,159.9,157.6,157.4，151.3,142.6,135.3,135.2,133.9,133.1,127.8,127.6,126.5,126.3,126.1,124.4,123.1,122.1,111.9,111.8,111.2,111.0，110.6，110.5,108.3,108.0，105.5，56.2,53.7,45.8,42.9,33.9；MS(m/z):[M+H] +586.3。
embodiment 32:N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(fluoro-1-of 5- methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 32) synthesis:
The method similar with embodiment 28, N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(5-fluoro-1-methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 32), yield 23% can be obtained.MS(m/z):[M+H] +601.3。
embodiment 33:N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amine base)-2-((2-(dimethylin) ethyl) (methyl) amido-4-ethoxyl phenenyl)-acrylamide (compound 33) synthesis:
The method similar with embodiment 25, N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-ethoxyl phenenyl)-acrylamide (compound 33), yield 28% can be obtained.
1H-NMR(600MHz,DMSO-d 6,δ ppm)：10.09(s,1H),8.65(s,1H),8.61(s,1H),8.48(s,1H),8.35(s,1H),8.00(m,1H),7.50(m,1H),6.97-7.08(m,2H),6.37(m,1H),6.16(d,1H，J＝16.4Hz)，5.71(d,1H，J＝11.4Hz),4.02(m,2H),3.90(s,3H),2.87(m,2H),2.72(s,3H),2.33(m,2H),2.20(s,6H),1.16(m,3H)；
13C-NMR(125MHz,DMSO-d 6,δ ppm)：162.9,159.7,157.8,157.6,157.4,149.1,140.7,136.8,133.7,132.7,128.0,127.6,127.5,126.5,125.0,118.3,114.4,111.7,111.6,111.1,110.9,110.4,109.0,64.4，57.9,56.4,45.8,42.4,33.9，15.1；MS(m/z):[M+H] +566.2。
embodiment 34:N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amine base)-2-((2-(dimethylin) ethyl) (methyl) amido-4-p-methoxy-phenyl)-acrylamide (compound 34) synthesis:
The method similar with embodiment 25, N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-p-methoxy-phenyl)-acrylamide (compound 34), yield 20% can be obtained.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.07(s,1H),8.68(s,1H),8.64(s,1H),8.44(s,1H),8.34(s,1H),8.03(m,1H),7.50(m,1H),7.06(m,1H),7.03(s,1H),6.36(m,1H),6.16(d,1H，J＝16.8Hz)，5.71(d,1H，J＝10.4Hz),3.90(s,3H),3.75(s,3H),2.88(m,2H),2.74(s,3H),2.34(m,2H),2.21(s,6H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：160.8,157.7,155.7,155.5,155.4,148.1,138.9,134.7,131.6,130.5,125.8,125.5,125.4,124.4,122.4,116.8,112.3,109.5,109.4,109.0,108.8,108.3,106.9,106.6,104.3,55.3，54.3,54.0,43.7,40.2,31.7；MS(m/z):[M+H] +552.2。
embodiment 35:N-(4-methoxyl group)-5-(4 (1-Methyl-1H-indole-3-base) pyrimidine-2-base amine base)-2-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) synthesis of acrylamide (compound 35):
a.3-the synthesis of (2-chloropyrimide-4-base)-1-Methyl-1H-indole
By 2; 4-dichloro pyrimidine (2.84g; 1.2eq) be dissolved in dry ethylene glycol dimethyl ether (38ml), under nitrogen protection, be warming up to 60 DEG C; add 1-Methyl-1H-indole (2.25g) and FERRIC CHLORIDE ANHYDROUS (3.09g fast; 1.2eq), finish, 60 DEG C of reactions; TLC detects to having reacted, and add water/methyl alcohol (V water: V methyl alcohol=5:2) mixed solvent 30ml, stirring at room temperature, filter, filter cake anhydrous methanol washs, dry, obtains 3-(2-chloropyrimide-4-base)-1-Methyl-1H-indole (1.12g, yield 27%).
b.N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base) pyrimidine-2-amine synthesis:
The method similar with embodiment 23, can obtain N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base) pyrimidine-2-amine (yield 52%).
c.6-methoxyl group-N 1 -(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base)-4-(tetrahydrofuran (THF)-3-base oxygen base) ethyl) synthesis of phenyl-1,3-diamines:
3-hydroxyl tetrahydrofuran 4ml is dissolved in 50mlTHF, add the NaH (1.1g) of 60%, room temperature reaction 0.5h, be cooled to 10 DEG C, N-(the fluoro-2-methoxyl group of 4--5-nitrophenyl)-4-(1-Methyl-1H-indole-3-base) pyrimidine-2-amine (2g) is joined in reaction system, naturally rise to room temperature reaction 5h, TLC detects complete to raw material reaction.30 DEG C are evaporated to dry, add 500ml water, a large amount of orange solid is had to separate out, decompress filter, filter cake massive laundering washs dry N-(2-methoxyl group-5 nitro-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl-4-(1-Methyl-1H-indole-3-base) pyrimidine-2-amine (1g).
By N-, (2-methoxyl group-5 nitro-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl-4-(1-Methyl-1H-indole-3-base) pyrimidine-2-amine (1g) is suspended in 500ml ethanol/water (V water: V methyl alcohol=1:1) in mixed solvent, add iron powder 2g, NH 4cl (2g), 60 DEG C of reactions 6h, TLC detect raw material reaction completely, suction filtration, a large amount of washed with dichloromethane of filter cake, use equivalent dichloromethane extraction 6 times, no longer include product to water layer after filtrate 60 DEG C of concentrating under reduced pressure.Anhydrous sodium sulfate drying after dichloromethane layer merges, is evaporated to dry 6-methoxyl group-N 1-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base)-4-(tetrahydrofuran (THF)-3-base oxygen base) ethyl) phenyl-1,3-diamines (800mg).
d.N-(4-methoxyl group)-5-(4 (1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-2-(tetrahydrofuran (THF) -3-base oxygen base) phenyl) synthesis of acrylamide (compound 35):
The method similar with embodiment 23, N-(4-methoxyl group)-5-(4 (1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-2-(tetrahydrofuran (THF)-3-base oxygen base) phenyl can be obtained) acrylamide (compound 35), yield 34%.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：9.18(s,1H),8.66(s,1H),8.48(s,1H),8.28(d,1H，J＝4.0Hz),7.91(s,1H),7.51(d,1H，J＝8.0Hz),7.13-7.25(m,3H),6.82(s,1H),6.66(m,1H),6.22(d,1H，J＝16.8Hz)，5.72(d,1H，J＝10.4Hz),5.10(s,1H),3.86-3.94(m,10H),3.79(m,1H),2.19(m,1H),2.11(m,1H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.5,162.3,160.7,157.9,148.0,145.1,138.1,133.8,132.8,126.5,125.9,122.5,122.2,121.3,120.8,118.4,113.0,110.9,107.3,100.1,79.8,72.6,66.9,56.7,33.4,33.0；
MS(m/z):[M+H] +486.2。
embodiment 36:N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amine base)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 36) synthesis:
The method similar with embodiment 25, N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido) phenyl) acrylamide (compound 36, yield 30% can be obtained.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.27(s,1H),8.84(s,1H),8.56(s,1H),8.50(s,1H),8.28(d,1H，J＝7.2Hz),8.01(m,1H),7.51(s,1H),6.87-7.20(m,4H),6.41(m,1H),6.24(d,1H，J＝16.4Hz)，5.78(d,1H，J＝9.2Hz),3.88(s,3H),2.86(m,2H),2.72(s,3H),2.36(m,2H),2.22(m,6H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.4,162.2,161.1,159.8,157.8,157.4,140.2,139.8,135.1,134.8,132.5,132.4,128.4,127.3,126.4,126.3,120.0,117.5,117.4,114.9,114.2,112.8,112.0,111.9,110.8,110.5,107.7,107.5,107.3,57.4,56.5,45.9,42.2,33.8；MS(m/z):[M+H] +554.1。
embodiment 37:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl -1H-indol-3-yl)-1,3,5-triazines-2-base amido) phenyl) synthesis of acrylamide (compound 37):
The method similar with embodiment 25, N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-1 can be obtained, 3,5-triazine-2-base amido) phenyl) acrylamide (compound 37), yield 12%.MS(m/z):[M+H] +501.3。
embodiment 38:N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amine base)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acryloyl the synthesis of amine (compound 38):
The method similar with embodiment 25, N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide (compound 38) can be obtained, yield 32%.
1H-NMR(600MHz,DMSO-d 6,δ ppm)：10.24(s,1H),9.54(s,1H),8.66(s,1H),8.49(s,1H),7.89(s,1H),7.49(d,1H，J＝8.4Hz),7.22(m,2H),7.21(s,1H),6.45(m,1H),6.25(m,1H)，5.79(m,1H),3.89(s,3H),2.86(m,2H),2.72(s,3H),2.38(m,2H),2.22(s,6H)；
13C-NMR(125MHz,DMSO-d 6,δ ppm)：163.5,162.5,160.9,157.5,142.6,142.1,137.2,133.7,132.2,127.6,127.1,126.5,124.7,122.8,121.2,120.7,119.0,117.3,115.6,114.0,110.6,57.2,56.2,45.8,41.8,33.5；MS(m/z):[M+H] +604.2。
embodiment 39:N-(2-(4-(dimethylin) piperidin-1-yl)-4-methoxyl group-5-(4-(1-methyl isophthalic acid H- indol-3-yl) pyrimidine-2-base aminocarbonyl phenyl) synthesis of acrylamide (compound 39):
The method similar with embodiment 25, N-(2-(4-(dimethylin) piperidin-1-yl)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base aminocarbonyl phenyl) acrylamide (compound 39), yield 37% can be obtained.
1H-NMR(600MHz,DMSO-d 6,δ ppm)：9.08(s,1H),8.84(s,1H),8.58(s,1H),8.30(d,1H，J＝5.4Hz),8.27(d,1H，J＝7.2Hz),7.89(s,1H),7.52(d,1H，J＝8.4Hz),7.16-7.26(m,3H),6.87(s,1H),6.72(m,1H),6.25(d,1H，J＝16.0Hz)，5.75(m,1H),3.90(s,3H),3.86(s,3H),3.05(m,2H),2.69(m,2H),2.29(m,6H),1.86(m,2H),1.72(m,2H)；
13C-NMR(125MHz,DMSO-d 6,δ ppm)：163.3,162.1,160.4,158.0,147.0,139.8,138.1,134.1,132.9,126.6,125.8,125.0,124.7,122.4,121.9,121.4,116.4,112.9,110.9,107.5,103.6,62.0,56.4,51.7,41.8,33.4,28.6；MS(m/z):[M+H] +526.3。
embodiment 40:N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(5-fluoro-1-methyl isophthalic acid H- indol-3-yl) pyrimidine-2-base amido)-4-ethoxyl phenenyl) synthesis of acrylamide (compound 40):
The method similar with embodiment 25, N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-ethoxyl phenenyl) acrylamide (compound 40) can be obtained, yield 31%.
1H-NMR(400MHz,DMSO-d 6,δ ppm)：10.64(s,1H),9.74(s,1H),8.86(s,1H),8.61(s,1H),8.31(s,1H),8.04(s,2H),7.54(m,1H),6.97-7.20(m,4H),6.22(d,1H，J＝16.0Hz),5.70(d,1H，J＝7.2Hz),4.13(m,2H),3.90(s,3H),3.27(m,2H),2.73(s,6H),2.60(m,2H),1.32(m,3H)；
13C-NMR(100MHz,DMSO-d 6,δ ppm)：163.9,161.9,160.5,159.8,158.0,157.5,146.6,139.0,135.5,134.9,133.3,126.3,126.1,125.7,116.7,112.9,112.2,112.1,110.7,110.5,107.3,107.1,106.2,64.7,54.0,49.9,43.4,42.6,33.8,15.2；MS(m/z):[M+H] +532.3。
Following compound also can be obtained by the similar synthetic method in above-described embodiment:
Biological experiment
1) cancer cell multiplication inhibition test:
Following test can be used to measure the inhibited proliferation of part of compounds of the present invention to people's squamous epidermal carcinoma A431 (EGFR-wt high expression level), Non-small cell lung carcinoma NCI-H1975 (EGFRT790M sudden change) and HCC827 Non-small cell lung carcinoma cell (EGFRE746-A750del).
A) the compounds of this invention is to EGFR-wt high expression level A431 cell inhibitory effect function analysis
The compounds of this invention measures the Proliferation Ability of EGFR high expression level people squamous epidermal carcinoma A431 (purchased from ATCC) and adopts SRB method, SRB (Sulforhodamine B) is a kind of pink anionic dyestuff, in acid condition can specifically in cell the basic aminoacids of constitutive protein matter be combined, absorption peak is produced, light absorption value and the linear positive correlation of cell concentration under 540nm wavelength.
A431 cell containing in the DMEM in high glucose substratum of 10% foetal calf serum, 2mM glutamine and non-essential amino acid, 37 DEG C, cultivate under the condition of 5%CO2, application trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from Tissue Culture Flask.Cell adds 96 porocyte culture plates with 3000/ hole (100 μ l substratum), 37 DEG C, adherent culture is spent the night in 5%CO2 cell culture incubator, add the fresh culture (100 μ l) of different concns testing compound, the ultimate density of DMSO is 0.2%, by Tissue Culture Plate at 37 DEG C, the CO of 5% 2incubation 72h under condition, remove nutrient solution, then add TCA (i.e. trichoroacetic acid(TCA)) solution (10%, w/v) of 4 DEG C of precoolings, standing 5min moves in 4 DEG C of refrigerators and fixes 1h, and take out and use deionized water rinsing 5 times, room temperature is dried.After drying under 96 orifice plate room temperatures, every hole adds SRB dye liquor (peracetic acid formulation of 1%) the 50 μ L of 0.4% (w/v), outwells dye liquor, rinse 5 times with 1% (v/v) acetic acid after dyeing 30min, remove unconjugated dyestuff, room temperature is dried.
Dissolve the dyestuff be combined with cell protein with 100 μ L non-buffered Tris-base alkali lye (10mM, pH=10.5), horizontal shaker vibrates 20min, adopts microplate reader 540nm place to measure absorbance value, adopts GraphPadPrism4 analytical data, ask IC 50, result is as shown in table 1.
Table 1: the compounds of this invention is to the restraining effect of A431 cell proliferation
Tester IC 50(nM)
Compound 2 342.9
Compound 4 631.0
Compound 6 410.4
Compound 8 357.1
Compound 10 427.7
Compound 12 495.0
Compound 14 382.0
Compound 16 604.1
Compound 18 334.4
Compound 20 478.7
Compound 22 375.6
Compound 23 52.7
Compound 24 43.6
Compound 25 32.2
Compound 26 57.3
Compound 28 161.6
Compound 29 71.3
Compound 30 98.2
Compound 31 83.9
Compound 33 67.4
Compound 34 34.3
Compound 36 134.2
Compound 37 75.6
Compound 38 98.0
Compound 40 149.3
Positive control 43.5
Note: positive control medicine: AZD-9291.
B) the compounds of this invention is to the inhibited proliferation analysis of drug-resistant cell strain NCI-H1975
The proliferation inhibition activity of the compounds of this invention to drug-resistant cell strain NCI-H1975 (this cell is the non-small cell lung cancer cell of EGFRT90M sudden change, to EGFR tyrosine kinase inhibitor resistances such as Gefitinib, Tarceva, lapatinibditosylates) (purchased from Shanghai cell institute) adopts SRB method to measure.
NCI-H1975 containing 10% foetal calf serum, 2mM glutamine and non-essential amino acid RPMI1640 substratum in, 37 DEG C, 5%CO 2condition under cultivate, application trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from Tissue Culture Flask.Cell adds 96 porocyte culture plates, at 37 DEG C, 5%CO with 5000/ hole (100 μ l substratum) 2in cell culture incubator, adherent culture is spent the night, and add the fresh culture (100 μ l) of different concns testing compound, the ultimate density of DMSO is 0.25%, by Tissue Culture Plate at 37 DEG C, and the CO of 5% 2incubation 72h under condition, remove nutrient solution, then add TCA (i.e. trichoroacetic acid(TCA)) solution (10%, w/v) of 4 DEG C of precoolings, standing 5min moves in 4 DEG C of refrigerators and fixes 1h, and take out and use deionized water rinsing 5 times, room temperature is dried.After drying under 96 orifice plate room temperatures, every hole adds SRB dye liquor (peracetic acid formulation of 1%) the 50 μ L of 0.4% (w/v), outwells dye liquor, rinse 4 times with 1% (v/v) acetic acid after dyeing 30min, remove unconjugated dyestuff, room temperature is dried.
Dissolve the dyestuff be combined with cell protein with 100 μ L non-buffered Tris-base alkali lye (10mM, pH=10.5), horizontal shaker vibrates 20min, adopts microplate reader 540nm place to measure absorbance value, adopts GraphPadPrism4 analytical data, ask IC 50, result is as shown in table 2.
Table 2: the compounds of this invention is to the inhibited proliferation of NCI-H1975 cell
Tester IC 50(nM) Selectivity a
Compound 2 1.3 263.8
Compound 4 16.5 38.2
Compound 6 4.0 102.6
Compound 8 2.3 155.3
Compound 10 3.5 122.2
Compound 12 4.5 110.0
Compound 14 7.3 52.3
Compound 16 20.4 29.6
Compound 18 4.6 72.7
Compound 20 4.6 104.1
Compound 22 3.2 117.4
Compound 23 1.4 37.6
Compound 24 0.5 87.2
Compound 25 0.3 107.3
Compound 26 1.2 47.8
Compound 28 3.0 53.9
Compound 29 1.2 59.4
Compound 30 1.3 75.5
Compound 31 0.4 209.8
Compound 33 0.9 74.9
Compound 34 0.7 49.0
Compound 36 1.9 70.6
Compound 37 3.6 21.0
Compound 38 2.1 46.7
Compound 40 3.8 39.3
Positive control b 2.3 18.9
Note: a, Selectivity are that compound is to EGFR-wt high expression level A431 cell inhibitory activity (IC 50) and to EGFR-T790M mutant drug-resistant NCI-H1975 cell inhibitory activity (IC 50) ratio, this ratio represents the selectivity to EGFR-T790M medicament-resistant mutation, and ratio is larger, and selectivity is better, for more weak to EGFR-wt kinase inhibitory activity under the equal effective dose of medicament-resistant mutation, the toxic side effect caused because EGFR-wt kinases crosses high inhibition therefore can be reduced; B, positive control medicine: AZD-9291.
C) the compounds of this invention is to HCC827 cell inhibitory effect function analysis
The compounds of this invention adopts SRB method to measure to the proliferation inhibition activity of HCC827 (EGFRE746-A750del) (Shanghai Inst. of Life Science, CAS cellular resources center).
HCC827 at 37 DEG C, 5%CO 2incubator in cultivate, to growth logarithmic phase after, be inoculated in 96 orifice plates by 5000/hole.After adherent culture 24h, add the tested material (starting point concentration 1000nM, 3 times of dilutions, totally 8 concentration) of different concns, each concentration establishes 2 multiple holes, establishes blank simultaneously.Continue culturing cell to 72h.
After cell cultures terminates, discard substratum, every hole adds the TCA of 10% (w/v) of 100 μ L precoolings, 4 DEG C of fixing 1h.Then use washed with de-ionized water 5 times, room temperature is dried.Dry the SRB solution that rear every hole adds the 4mg/mL of 100 μ L, room temperature dyeing 30min, then use the Glacial acetic acid of 1% (v/v) to clean 5 times, room temperature is dried.Dry the Tris adding 150 μ L10mM in rear every hole, fully mix, under microplate reader 550nm wavelength, measure OD value, adopt GraphPadPrism4 analytical data, ask IC 50, result is as shown in table 3.
Table 3: the compounds of this invention is to the inhibited proliferation of HCC-827 cell
Tester IC 50(nM)
Compound 2 7.8
Compound 4 10.1
Compound 6 5.5
Compound 8 4.2
Compound 10 7.4
Compound 12 4.2
Compound 14 5.6
Compound 16 14.9
Compound 18 8.9
Compound 20 6.5
Compound 22 7.8
Compound 23 11.0
Compound 24 3.3
Compound 25 6.6
Compound 26 1.4
Compound 27 10.8
Compound 28 5.6
Compound 29 17.7
Compound 30 20.7
Compound 31 4.7
Compound 33 21.5
Compound 34 9.4
Compound 36 7.4
Compound 37 6.9
Compound 38 5.8
Compound 40 6.0
Positive control 5.0
Note: positive control medicine: AZD-9291.
Can see from above-mentioned experimental result, the propagation of the compounds of this invention to EGFRT790M mutant drug-resistant cell strain H1975 or HCC827 (EGFRE746-A750del) cell has stronger inhibit activities, and it just effectively can suppress the propagation of EGFR-T790M high expression level H1975 or HCC827 cell under nmole (nmol/L) concentration.The compounds of this invention also has certain restraining effect to EGFR-wt high expression level A431 tumour cell, but activity is lower than the inhibit activities to EGFRT790M mutant drug-resistant cell.In addition, most of the compounds of this invention such as compound 2,6,8,10 etc. shows the selectivity higher than AZD-9291 for EGFR-T790M resistance.
2) stability test of compound in different genera blood plasma
The stability test of test-compound in people, SD rat, Beagle dog and nude mouse blood plasma:
Preparation cumulative volume is the plasma containing drug solution of 300 μ L, and comprise the blank plasma that medium is 285 μ L, the standard solution of 15 μ L, final concentration counts 100ng/mL with each compound.After vortex mixing, divide and get the EP pipe that 90 μ L enter 0.5mL, hatch 1.0h for 37 DEG C.After reaction terminates, add 400 μ L ice-cold acetonitrile termination reactions.Get reaction terminating liquid, vortex 1min, centrifugal 10min under 12000rpm; Get supernatant liquor 100 μ L, add 200 μ L acetonitrile-waters (50/50, v/v), vortex 1min, centrifugal 10min under 12000rpm, get the analysis of supernatant liquor 2.0 μ L sample introduction.Adopt LC/MS/MS method to detect the residue content of medicine to be measured, result is as table 4.
Table 4: the stability of the compounds of this invention in different genera blood plasma
Note: positive control medicine: AZD-9291.
Can see from above-mentioned experimental result, most compounds of the present invention such as compound 2,4,10,16,20,22 etc. demonstrates the characteristic more stable than AZD-9291 in different genera blood plasma.Especially, in human plasma, all test compounds stability is all significantly better than AZD-9291.

Claims (10)

1. the compound shown in formula I and pharmacy acceptable salt thereof:
Wherein, R 1be selected from hydrogen, C 1-4the C of alkyl, halo 1-4alkyl, C 1-4heterocyclylalkyl, halogen, preferred hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-2-base, fluorine, chlorine, bromine, more preferably methyl, ethyl, difluoromethyl, trifluoromethyl, most preferable, ethyl, difluoromethyl;
R 2be selected from hydrogen, C 1-3the C of alkyl, halo 1-3alkyl, halogen, preferred hydrogen, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, trichloromethyl, dichloromethyl, fluorine, chlorine, bromine, more preferably hydrogen, methyl, fluorine, chlorine, most preferably hydrogen, fluorine;
R 3be selected from tetrahydrofuran (THF)-3-base oxygen base, tetrahydrofuran (THF)-2-base oxygen base ,-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2,-N (CH 3) CH 2cH 2n (Boc) CH 3, 4-methylpiperazine-1-yl, 4-(dimethylin) piperidin-1-yl, 2-(cyclopropyl (2-(dimethylin) ethyl) amido, 2-((2-(nitrogen heterocyclic ethyl-1-base) ethyl) (methyl) amido, preferably-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2,-N (CH 3) CH 2cH 2n (Boc) CH 3, 4-methylpiperazine-1-yl, more preferably-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is selected from CH, C-CH 3, N, preferred CH, N, more preferably CH;
Y is selected from N, CH, C-Cl, C-F, C-CF 3, C-CHF 2, C-CH 3, C-CCl 3, preferred N, CH, C-Cl, C-CF 3, more preferably CH, C-Cl, C-CF 3;
R 7be selected from methyl, ethyl, methoxyethyl, preferable methyl, ethyl, more preferably methyl;
And work as R 1during for methyl, X is not CH, or Y is not CH, C-Cl, C-CH 3, or R 2be not hydrogen; Preferably, R is worked as 1during for methyl, X is selected from C-CH 3, N, or Y is selected from N, C-F, C-CF 3, C-CHF 2, C-CCl 3, or R 2for fluorine.
2. compound according to claim 1 and pharmacy acceptable salt thereof, is characterized in that, R 1be selected from methyl, ethyl, difluoromethyl;
R 2be selected from hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is selected from CH, N, preferred CH;
Y is selected from N, CH, C-Cl, C-CF 3, preferred CH, C-Cl, C-CF 3;
R 7be selected from methyl;
And work as R 1during for methyl, X is N, or Y is selected from N, C-CF 3, or R 2for fluorine;
In a preferred technical scheme of the present invention, R 1be selected from methyl, ethyl, difluoromethyl;
R 2be selected from hydrogen, fluorine;
R 3be selected from-N (CH 3) CH 2cH 2-NH-CH 3,-N (CH 3) CH 2cH 2-N (CH 3) 2;
X is CH;
Y is selected from CH, C-Cl, C-CF 3;
R 7be selected from methyl;
And work as R 1during for methyl, Y is C-CF 3, or R 2for fluorine.
3. compound according to claim 1 and 2 and pharmacy acceptable salt thereof, it is selected from following compounds:
2-((2-acrylamido-5-methoxyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-difluoro-methoxy-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-difluoro-methoxy-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-5-methoxyl group-4-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-5-(4-(1-methyl isophthalic acid H-indazole-3-base)-pyrimidine-2-base amido) phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-methoxyl group) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-methoxyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-oxyethyl group) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-4-oxyethyl group-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-5-(difluoro-methoxy) phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-(difluoro-methoxy)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-5-oxyethyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
2-((2-acrylamido-5-methoxyl group-4-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido)-phenyl) (methyl) amido) ethyl (methyl) the amidocarbonic acid tert-butyl ester;
N-(4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-trifluoromethvl-Dvrimidin-2-base amido)-2-(methyl (2-(methylamino) ethyl) amido)-phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-p-methoxy-phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-isopropoxy-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-methyl isophthalic acid H-indazole-3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(5-fluoro-1-methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-ethoxyl phenenyl)-acrylamide;
N-(5-(the chloro-4-of 5-(the fluoro-1-Methyl-1H-indole of 5--3-base)-pyrimidine-2-base amido)-2-((2-(dimethylin) ethyl) (methyl) amido-4-p-methoxy-phenyl)-acrylamide;
N-(4-methoxyl group)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-2-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-(4-(dimethylin) piperidin-1-yl)-4-methoxyl group-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base aminocarbonyl phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-ethoxyl phenenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-methoxyethoxy phenyl) acrylamide;
N-(2-(cyclopropyl (2-(dimethylin) ethyl) amido)-4-methoxyl group-5-(4-(1-(2-methoxyethyl)-1H-indoles-3-yl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(nitrogen heterocyclic ethyl-1-base) ethyl) (methyl) amido)-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base) pyrimidine-2-base amido)-4-p-methoxy-phenyl) acrylamide;
N-(4-(difluoro-methoxy)-2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base)-5-methyl-pvrimidine-2-base amido) phenyl) acrylamide;
(S)-N-(2-((2-(dimethylin) ethyl) (methyl) amido)-5-(4-(1-Methyl-1H-indole-3-base) pyrimidine-2-base amido)-4-(tetrahydrofuran (THF)-3-base oxygen base) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-methoxyl group-5-(4-(5-fluoro-1-methyl isophthalic acid H-indazole-3-base)-5-(trifluoromethyl) pyrimidine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-5-chloropyrimide-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(1-Methyl-1H-indole-3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-oxyethyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
N-(2-((2-(dimethylin) ethyl) (methyl) amido)-4-methoxyl group-5-(4-(the fluoro-1-Methyl-1H-indole of 5--3-base)-1,3,5-triazine-2-base amido) phenyl) acrylamide;
Or its pharmacy acceptable salt.
4. the formula I described in any one of claim 1-3 and a preparation method for pharmaceutically-acceptable salts thereof, the method comprises the following steps:
(1) in the presence of a lewis acid, in high boiling point anhydrous solvent, intermediate compound IV is obtained by reacting by compound shown in compound and formula III shown in formula II:
Or, by compound shown in formula II and formula III ' shown in compound react under catalyst action and prepare intermediate compound IV:
(2) intermediate compound IV obtains intermediate VI with compound V under suitable acid exists, and intermediate VI reacts under suitable alkali effect, then reduces to obtain intermediate VII through reductive agent:
(3) intermediate VII and acrylate chloride or acrylic anhydride are obtained by reacting formula I:
Or intermediate VII and 3-chlorpromazine chloride react, then through eliminating to obtain formula I:
And optionally,
(4) formula I and corresponding acid-respons obtain formula I pharmacy acceptable salt, or obtain the base of corresponding formula I through alkali tune;
Wherein, R 1-R 3and R 7, X, Y have aforementioned identical implication, Z is boric acid base group, borate group or tin trimethyl group.
5. preparation method according to claim 4, is characterized in that, in step (1), described high boiling point anhydrous solvent is selected from glycol dimethyl ether, dimethylbenzene; Described Lewis acid is selected from anhydrous AlCl 3, FeCl 3; Described catalyzer is palladium catalyst, preferred Pd/C, tetrakis triphenylphosphine palladium, [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride;
In step (2), described suitable acid is selected from tosic acid, hydrochloric acid, Hydrogen bromide, preferred tosic acid; Described suitable alkali is selected from organic bases or mineral alkali, preferred triethylamine, diisopropyl ethyl amine, sodium hydride, potassium hydride KH and hydrolith; Described reductive agent is selected from SnCl 2concentrated hydrochloric acid, Zn powder acetic acid, Fe powder acetic acid, iron powder ammonium chloride, Pd/C shortening; Preferred Pd/C shortening, Fe powder ammonium chloride.
6. a pharmaceutical composition, it comprises formula I described in any one of claim 1-3 or its pharmacy acceptable salt, and one or more optional pharmaceutically acceptable vehicle.
7. the compound described in any one of claim 1-3 and pharmacy acceptable salt thereof for the preparation for the treatment of or/and purposes in the medicine of prevention Mammals (the comprising people) disease relevant to receptor tyrosine kinase or illness.
8. pharmaceutical composition according to claim 6 is being used for the treatment of or/and prevent the purposes in the medicine of disease that Mammals (comprising people) is relevant to receptor tyrosine kinase or illness.
9. the purposes according to any one of claim 7-8, described " disease relevant to receptor tyrosine kinase or illness " be " tumour mediated by receptor tyrosine kinase ", " propagation of the tumour cell driven by receptor tyrosine kinase and migration " or " EGFR receptor tyrosine kinase susceptible neoplasms preferably.
10. purposes according to claim 9, it is characterized in that, the tumour that described " EGFR receptor tyrosine kinase cancer susceptible " preferred EGFR family high expression level and EGF drive, include but not limited to lack activated mutant body and/or the mutant mediated tumour of EGFR-delE746-A750 by EGFRL858R mutant and/or EGFR-T790M mutant and/or Exon19, or to the tumour of EGFR inhibitor as resistances such as Gefitinib (Gefitinib) or Erlotinibs (Erlotinib), specifically comprise noumenal tumour, as bile duct, bone, bladder, central nervous system (as brain), breast, Colon and rectum, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus (as carcinoma of endometrium) and vulva etc., and non-solid tumors, as leukemia, multiple myeloma or lymphoma etc.
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CN111303123A (en) * 2020-03-31 2020-06-19 南京雷正医药科技有限公司 2- (2,4, 5-substituted anilino) pyrimidine compound and application thereof
WO2021259316A1 (en) 2020-06-23 2021-12-30 深圳福沃药业有限公司 Crystalline form of compound
WO2021259315A1 (en) 2020-06-23 2021-12-30 深圳福沃药业有限公司 Salt of compound and pharmaceutical composition containing salt
WO2022033455A1 (en) * 2020-08-13 2022-02-17 上海和誉生物医药科技有限公司 Triazine derivative having egfr inhibitory activity, preparation method therefor and use thereof
CN115260195A (en) * 2021-04-30 2022-11-01 上海齐鲁制药研究中心有限公司 EGFR degradation agent
CN113387935B (en) * 2021-07-23 2022-06-10 苏州雅深智慧科技有限公司 Compound for inhibiting triple-mutation epidermal growth factor receptor tyrosine kinase and application thereof
CN113387935A (en) * 2021-07-23 2021-09-14 苏州雅深智慧科技有限公司 Compound for inhibiting triple-mutation epidermal growth factor receptor tyrosine kinase and application thereof
CN116407540A (en) * 2023-02-17 2023-07-11 杭州邦顺制药有限公司 Application of medicine in preventing and treating HER2 expression positive solid tumor

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