CN109280048A - A kind of pyrimidines of the structure of acrylamide containing substituted-phenyl and its application - Google Patents

A kind of pyrimidines of the structure of acrylamide containing substituted-phenyl and its application Download PDF

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CN109280048A
CN109280048A CN201811363921.9A CN201811363921A CN109280048A CN 109280048 A CN109280048 A CN 109280048A CN 201811363921 A CN201811363921 A CN 201811363921A CN 109280048 A CN109280048 A CN 109280048A
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methyl
base
amino
ethyl
acrylamide
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朱五福
郑鹏武
赵兵兵
徐珊
肖珍
胡晓晗
周志辉
何洁
赖罗根
杨琪
田发娟
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Jiangxi Science and Technology Normal University
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses a kind of pyrimidines of structure of acrylamide containing substituted-phenyl, its geometric isomer and its pharmaceutically acceptable salt, hydrate, solvate or prodrugs.The pyrimidines of the present invention structure of acrylamide containing substituted-phenyl, and its pharmaceutically acceptable salt, hydrate or solvate are as active ingredient, it is prepared by mixing into composition with pharmaceutically acceptable carrier or excipients, and is prepared into clinically acceptable dosage form.The application in proliferative disease drug is treated and/or prevented to the compounds of this invention in preparation, and the application in the drug of preparation treatment and/or pre- anti-cancer is treated and/or prevented in the drug of lung cancer, prostate cancer, breast cancer and cervical carcinoma in preparation and applied.

Description

A kind of pyrimidines of the structure of acrylamide containing substituted-phenyl and its application
Technical field
The present invention relates to a kind of pyrimidines of structure of acrylamide containing substituted-phenyl, in particular to one kind containing substitution The pyrimidines of phenylacryloyl amine structure and its application.
Background technique
Malignant tumour seriously endangers human health, every year because the number of cancer mortality is being continuously increased.Therefore it researches and develops anti- Tumour medicine becomes the research hotspot of current field of medicinal chemistry.In recent years, with the continuous development of molecular biology, it is various Technological means are constantly applied to during the diagnosing and treating of tumour, have further deepened researcher to oncobiology The understanding of characteristic finds a variety of new anti-tumor targets, wherein EGF-R ELISA (Epidermal Growth Factor Receptor, EGFR) signal path plays an important role during the occurrence and development of tumour, and the access is controllable The tune of cell is died, is proliferated, breaking up, migrating and cell cycle circulation, and the formation and deterioration with tumour are closely bound up.Therefore research and development are made Inhibitor for the signal path has become the hot spot of tumor prevention and therapy field.Now, the research and development of EGFR inhibitor Hot spot is had become in molecular targeted therapy human cancer field.It is optionally targeted by the micromolecular inhibitor of target of EGFR Tyrosine kinase catalytic domain intracellular, the active pocket of kinases is competitively combined with ATP, thus inhibit the phosphorylation of tyrosine, Interrupt kinase catalytic caused downstream signaling pathway.Currently, successively listing (following structural formula institute there are many EGFR inhibitor Show), in these micromolecular inhibitors, there are many EGFR micromolecular inhibitors that there is excellent anti-tumor activity, such as Ji is non-replaces Buddhist nun (Fukuoka.M, Yano.S, Giaccone G, et al.J. Clin.Oncol.21 (2003) 2237-2246.)；Ah method replaces Buddhist nun (Suda.K, Murakami.I, Katayama.T, et al.Clin.Cancer.Res.16 (2010) 5489-5498.)； AZD9291(D.A. Cross,S.E.Ashton,S.Ghiorghiu,et al.Cancer Discov.,4(2014)1046- 1061.) in order to filter out the excellent EGFR inhibitor of anti-tumor activity, C-5 introducing halogens, methoxyl group, cyanogen on pyrimidine ring The small molecules substituent group such as base, wherein compound A is demonstrated by excellent external antikinase activity, to EGFRWTKinase activity IC50 For 46nM, to EGFRTLKinase activity IC50For 0.9nM.Document (H.Gao, Z.Yang, X.Yang, et al.Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors[J], Bioorg.Med.Chem., 25 (2017) 4553-4559 report the pyrimidines B of side chain list oxidation to EGFRTLKinases IC50For 6.4nM.Furthermore document (G.Xia, W.Chen, J.Zhang, et al.A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and Pharmacokinetic profiles [J], J.Med.Chem., 57 (2014) 9889-9900) also reported to include small molecule The pyrimidines C for the acrylamide structure that alkyl or halogen replace shows very good anti-tumor activity.
For the present invention on the basis of bibliography, design has synthesized a series of pyrimidine of structures of acrylamide containing substituted-phenyl Class compound, this series compound remains the pyrimidine amine structure of AZD9291, while drawing on pyrimidine ring and acrylamide side chain Lower alkyl side chain and halogen isoreactivity group are entered, have designed and synthesized a variety of containing substituted-phenyl acrylamide structure Pyrimidines.And the present invention focus on investigate be the different substituted amine structures containing phenylacryloyl pyrimidines Anti-tumor activity, to filter out activity and selectivity more preferably anti-tumor drug.
Summary of the invention
It is an object of the invention to provide a kind of pyrimidines of structure of acrylamide containing substituted-phenyl and its preparations Methods and applications.
The present invention provides that a kind of pyrimidines of the structure of acrylamide containing substituted-phenyl as shown in general formula I, its is several What isomers and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, structure is as shown in the following general formula I:
Wherein:
R1Selected from aromatic ring, hetero-aromatic ring, and the aromatic ring, heteroaromatic contain 1-3 selected from hydrogen, halogen, trifluoromethyl, cyanogen Base, trifluoromethoxy, (C1~C4) alkyl substituent group；
R2、R3It is same or different, separately it is selected from hydrogen, halogen, trifluoromethyl, cyano, trifluoromethoxy, (C1~ C4) alkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkoxy methyl, (C1~ C4) alkyl acyl, (C1~C4) alkylthio group or R2、R3It forms one and contains CH2, O, NH, S, SO or SO2Five yuan of atom (group) Or hexa-atomic cycloaliphatic ring or aliphatic heterocycle；
R4Selected from hydrogen, (C1~C10) alkyl, (C3~C10) naphthenic base, (C1~C4) alcoholic extract hydroxyl group,
-N(CH3)R5It is selected from
R6Selected from hydrogen, (C1~C4) alkyl and halogen；
R7、R8It is identical or different, separately it is selected from (C1~C6) alkyl or (C3~C6) naphthenic base, ethoxy, sulfydryl Ethyl or R7And R85~10 yuan of saturated heterocyclyls are formed together with the nitrogen-atoms being connect with them, the saturated heterocyclyl removes And R7And R8Outside the nitrogen-atoms of connection, the hetero atom of O, N and S are optionally selected from containing 1~3.
N is 0~3；
Present invention is preferably related to such as above-mentioned compounds of formula I, its geometric isomer and its pharmaceutically acceptable salt, Hydrate, solvate or prodrug, in which:
R1The heterocycle of thick sum is selected from:
R1’Selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl, Ethyl, propyl, butyl, cyclopropane, ethylene, propylene, acetylene, propine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth oxygen Base or azido；
R2、R3It is same or different, separately it is selected from hydrogen, halogen, trifluoromethyl, cyano, trifluoromethoxy, (C1~ C4) alkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkoxy methyl, (C1~ C4) alkyl acyl, (C1~C4) alkylthio group or following heterocycle structure:
R4Selected from hydrogen, (C1~C10) alkyl, (C3~C10) naphthenic base, (C1~C4) alcoholic extract hydroxyl group,
-N(CH3)R5It is selected from
R6Selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine；
It is selected from:
N is 0~3.
In the present invention, a kind of pyrimidines of structure of acrylamide containing substituted-phenyl, it is characterised in that: institute Stating compounds of formula I is selected from one of following compounds, but these compounds are not meant to of the invention any Limitation:
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide, N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- Base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) -2- chloro- third Acrylamide, (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (diformazan Base amino) ethyl) (methyl) amino) -4- methoxyphenyl) but-2-enamides, (Z)-N- (5- ((5- cyano -4- (1- first Base -1H- indol-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group Phenyl) amyl- 2- acrylamide, (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (diformazan Base amino) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide, N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) benzene Base) the chloro- acrylamide of -2-, (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- Methyl -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) but-2-enamides, (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) ((4- methyl -6- (1- Methyl-1H-indole -3- base base) is phonetic by -4- methoxyl group -5- Pyridine -2- base) amino) phenyl) amyl- 2- acrylamide, (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- first Oxygroup -5- ((4- methyl -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) the amyl- 2- alkene of -4- methyl Amide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide, (Z)-N- (2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -4- methoxyl group Phenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- acrylamide, N- (5- ((5- cyano -4- (the fluoro- 1- first of 5- Base -1H- indol-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group Phenyl) acrylamide,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) hex- 2- acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) the chloro- acrylamide of -2-,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) the amyl- 2- alkene of -4- methyl Amide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) but-2-enamides,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) -2- is chloro- Acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) Amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-1 H- Yin of 5- Diindyl -3- base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) - The amyl- 2- acrylamide of 4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) but-2-ene Amide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) amyl- 2- alkene Amide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl-1 H- Indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) -4- methyl Amyl- 2- acrylamide.
Following synthetic route describes the preparation of the pyrimidines of general formula I of the present invention, and all raw materials are all logical Cross mode described in synthetic route, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or can quotient Purchase.The final pyrimidines of whole of the invention are all by method described in synthetic route or by similar Method preparation, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole applied in synthetic route is variable Definition in factor definition as follows or such as claim.
With (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl - 1H- indol-3-yl) pyrimidine -2-base) amino) phenyl) for hex- 2- acrylamide, synthetic method is as follows, and all raw materials are equal It is pure for commercially available analysis.
With (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- methyl - 1H- indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) for but-2-enamides, close As follows at method, all raw materials are that commercially available analysis is pure.
With N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole-of 5- 3- yl) -6,6- dioxy -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) -2- chloro- third For acrylamide, synthetic method is as follows, and all raw materials are that commercially available analysis is pure.
According to some usual methods of the art, the pyrimidines of above-mentioned general formula I can be in the present invention Pharmaceutically acceptable salt is generated with acid.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, with following sour addition Salt is particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, two sulphur of naphthalene Acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is spreading out for above-mentioned general formula I Biology, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as it is logical Cross metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" naphthenic base " Refer to substituted or unsubstituted naphthenic base.
The present invention can contain the pyrimidines and its pharmaceutically acceptable salt, hydrate or molten of above-mentioned general formula I Agent compound is prepared by mixing into composition as active ingredient, with pharmaceutically acceptable carrier or excipients, and is prepared into clinic Upper acceptable dosage form, above-mentioned pharmaceutically acceptable excipients refer to any diluent that can be used for pharmaceutical field, adjuvant And/or carrier.Derivative of the invention can be applied in combination with other active ingredients, as long as they do not generate other unfavorable works With, such as allergic reaction.
Clinical dosage of the pyrimidines of the above-mentioned general formula I of the present invention for patient can basis: active constituent is in body Age, gender, the disease phase of interior therapeutic efficiency and bioavilability, their metabolism and discharge rate and patient fit Work as adjustment, but adult daily dosage generally should be 10~500mg, preferably 50~300mg.Therefore, when of the invention When pharmaceutical composition is made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation should be above-mentioned containing 10~500mg The pyrimidines of general formula I, preferably 50~300mg.According to the guidance of doctor or pharmacist, these preparations can be between certain Every a point administration (preferably one to six time) several times.
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common figurations in drug field Agent.Several dosage form as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive, profit Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix etc.. Pharmaceutical preparation can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
It has also been found that the pyrimidines of the above-mentioned structure of acrylamide containing substituted-phenyl are in preparation treatment and/or in advance Application in anti-proliferative disease drug.Reactive compound of the invention or its officinal salt and its solvate can be used as uniquely Anti-proliferate drug be used alone, or can with the anti-proliferate Drug combination that has listed, for treating and/or Prevent proliferative disease, such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
It has also been found that the pyrimidines of the above-mentioned structure of acrylamide containing substituted-phenyl are in preparation treatment and/or in advance Application in the drug of anti-cancer.The compounds of this invention has inhibition tumor cell growth activity in vitro, and therefore, it may be used as The drug of preparation treatment and/or pre- anti-cancer, such as lung, mammary gland, liver, kidney, colon, rectum, stomach, prostate, bladder, son Palace, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma Deng.
It has also been found that a kind of pyrimidines of above-mentioned structure of acrylamide containing substituted-phenyl preparation treatment and/ Or the application in the drug of prevention lung cancer, prostate cancer and breast cancer.
By inhibiting lung cell A549, human lung carcinoma cell H1975, human lung carcinoma cell HCC827, human lung carcinoma cell in vitro PC-9, human breast cancer cell line Bcap-37, Human Prostate Cancer Cells PC-3 and the test of cervical cancer cell Hela isoreactivity, of the present inventionization Conjunction object, which has lung carcinoma cell, prostate gland cancer cell, breast cancer cell and cervical cancer cell, significantly inhibits effect, it is especially useful in The drug of preparation treatment and/or prevention prostate cancer, lung cancer and cervical carcinoma.
By to EGFRWTAnd EGFRTLKinase activity test discovery, the compounds of this invention have significant inhibition EGFRTL, And there is certain selectivity to EGFR kinases, it is thin to the highly expressed lung carcinoma cell of EGFR, Human Prostate Cancer Cells, breast cancer Born of the same parents and cervical cancer cell etc. have stronger inhibiting effect, it is especially useful in the drug of preparation treatment and/or prevention lung cancer.
It is independent that reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-tumor drug It uses, or can be with the anti-tumor drug (such as the platinum medicine cis-platinum, camptothecine Irinotecan, Changchun that have listed Flower bases drug Noviburn, deoxidation born of the same parents' former times class drug gemcitabine, etoposide, taxol etc.) it is used in combination.Combination therapy is logical Cross each therapeutic component simultaneously, sequence or separate administration to realize.
The present invention is carried out antitumor activity screening to a variety of EGFR inhibitor overexpression cell lines in vitro, the results showed that tool There are stronger anti-tumor activity and selectivity, many compounds have also carried out EGFRTLAnd EGFRWTThe activity in vivo of kinases is tested. Experiment shows that certain compounds have efficient anti-tumor activity.
Specific embodiment
In order to better explain the present invention, below in conjunction with specific embodiment, the present invention is described in further detail, but Limiting the invention for they.
Embodiment is intended to illustrate and be not intended to limit the scope of the invention.The nuclear magnetic resonance spectroscopy Bruker of derivative ARX-400 measurement, mass spectrum Waters Quadrupole Time of Flight Tandem Mass Spectrometry (QTOF-MS) it measures；Agents useful for same is that analysis is pure or chemical pure.
A kind of pyrimidines of structure of acrylamide containing substituted-phenyl of general formula I:
The structural formula of the embodiment of the present invention 1~34 is as shown in table 1 below.
The structural formula of 1 Examples 1 to 34 of table
The synthesis of step A 1- methyl indol (1)
50g (430mmol) indoles is dissolved into 500mL tetrahydrofuran (THF), under condition of ice bath, is stirred 34.4g (860mmol) sodium hydride is added slowly in above-mentioned mixed solution, and 91g (645mmol) iodine first is slowly added dropwise in 0 DEG C of stirring 30min Alkane, after being added dropwise, 30 DEG C of reaction 1.5h.After reaction, most of solvent is recycled by vacuum distillation, residue adds 100mL methylene chloride dissolution, with saturation NaHCO3Aqueous solution extraction, organic layer are used saturated common salt water washing again, are evaporated under reduced pressure back It receives solvent and obtains 53.9g pale yellowish oil liquid, yield 95.7%, 1HNMR (CDCl3,400MHz), δ: 7.65 (1H, d), 7.33(1H,d),7.23(1H,d),7.11(1H,d),7.05(1H, dd),3.90(3H,s)。
The synthesis of step B (2- chlorine pyrimidine-4-yl) -1- Methvl-indole (2)
56.8g (381mmol) 2,4- dichloro pyrimidine is dissolved in 500mL glycol dimethyl ether (DME), in N2Protection Under the conditions of be added 50.1g (381mmol) anhydrous AlCl3, stir 5min, be added 50g (381mmol) intermediate 2, be heated to 80 DEG C Stir 3h.After reaction, it is cooled to room temperature, above-mentioned mixed solution is added drop-wise in the water that 500mL is vigorously stirred, is stirred at room temperature 3h filters, obtains dark red solid, and filter cake is washed with water and methanol, until filter cake becomes white, it is dry, obtain 65.1g white Solid, yield 70.1%, 194.7~197.2 DEG C of mp.1HNMR (DMSO-d6,400MHz), δ: 8.56~8.49 (2H, m), 8.41 (1H, d), 7.83 (1H, d), 7.58 (1H, d), 7.35~7.24 (2H, m), 3.90 (3H, s).
Step C N- (the fluoro- 2- methoxyl group -5- nitrobenzophenone of 4-) -4- (1- methyl indol -3- base) pyrimidine -2- amine (3) Synthesis
By the 500mL Isosorbide-5-Nitrae-dioxane dissolution of 60g (246mmol) intermediate 2, states in mixed solution and add upwards in turn Enter the fluoro- 2- methoxyl group -5- nitroaniline of 45.8g (246mmol) 4-, 50.8g (295 mmol) p-methyl benzenesulfonic acid is heated to 85 DEG C Stir 3h.After reaction, it is cooled to room temperature, 10mL weak aqua ammonia quenching reaction is added into reaction solution, then above-mentioned mixing is molten Drop is added in 500mL water, and 3h is stirred at room temperature, and is filtered, and filtration cakes torrefaction obtains 93.6g chartreuse solid, yield 96.7%, 254.3~257.9 DEG C of mp.1HNMR(DMSO-d6, 400MHz), δ: 9.40 (1H, s), 8.79 (1H, d), 8.63 (1H, s), 8.35 (1H, d), 8.21 (1H, t), 7.60 (1H, d), 7.33~7.56 (2H, m), 7.31~7.36 (1H, m), 7.11 (1H, dd),4.11(3H,s),3.92(3H,s)。
Step D N'- (2- dimethyl aminoethyl) -2- methoxyl group-N'- methyl-N- [4- (1- methyl indol -3- base) Pyrimidine -2-base] -5- nitrobenzene -1,4- diamines (4) synthesis
By the 500mL N of 90g (229mmol) intermediate 31,N1Dimethyl acetamide (DMA) dissolution, is stated mixed upwards in turn It closes and 59.2g (458mmol) N is added in solution1,N1Diisopropylethylamine (DIPEA), 46.8g (458mmol) N1, N1, N2- three Methyl-1,2- ethylenediamine are heated to 110 DEG C of stirring 2.5h.To after reaction, be cooled to room temperature, reaction solution is added drop-wise to In 500mL water, it is vigorously stirred 3h under room temperature, filters, filtration cakes torrefaction obtains 79.7g Orange red solid, yield 73.2%, 125.9~131.1 DEG C of mp.1HNMR(DMSO-d6, 400MHz), δ 8.61 (1H, s), 8.39-8.29 (3H, m), 8.12 (1H, S), 7.52 (1H, d), 7.29~7.19 (2H, m), 7.11 (1H, t), 6.84 (1H, s), 3.95 (3H, s), 3.87 (3H, s), 3.27(2H,t),2.86(3H,s),2.50(4H,s), 2.16(6H,s)。
Step E N1- (2- dimethyl aminoethyl) -5- methoxyl group-N1- methyl-N4- [4- (1- methyl indol -3- base) Pyrimidine -2-base] benzene -1,2,4- triamine (5) synthesis
It takes 60g (126mmol) intermediate 4 to be dissolved in 500mL ethyl alcohol, 4.7g is added into above-mentioned mixed solution respectively (88.2mmol)NH4Cl, 49.4g (756mmol) zinc powder, 150mL water is finally added at one time into mixed solution, is heated to 105 DEG C of stirring 3h.To after reaction, filter while hot, filter cake is washed with 150mL dehydrated alcohol, is collected filtrate, is added thereto Proper amount of active carbon is heated to 80 DEG C of reflux 30min, filters while hot, and filter cake is washed with 300mL dehydrated alcohol, collects filtrate, decompression Most of solvent is distilled off, residue is recrystallized with tetrahydrofuran, is filtered, and filtration cakes torrefaction obtains 44.8g light gray solid, Yield 79.8%, 121.4~127.1 DEG C of mp.1HNMR(DMSO-d6, 400MHz), δ: 8.42 (1H, d), 8.30 (1H, s), 8.27 (1H, d), 7.78 (1H, s), 7.51 (1H, d), 7.48 (1H, s), 7.21~7.27 (1H, m), 7.12~7.19 (2H, m), 6.76(1H,s),4.58(2H,br s),3.88(3H,s),3.74(3H,s),2.88(2H,t),2.63(3H,s), 2.36(2H,t),2.17(6H,s)。
The synthesis of step F 4- oxo tetrahydro -2H- thiapyran -3- carboxylate methyl ester (a1)
2.7098g NaH (60%) is added in the dry three-neck flask of 250mL, is added 40mL anhydrous tetrahydro furan (THF), 10min is stirred at room temperature, and the THF of 3,3'- thio-2 acid dimethyl ester (10.1015g, 0.049mol) is then slowly added dropwise (30mL) solution, about 1h are added dropwise, rear that 10mL THF rinse dropping funel, the reaction was continued 1-2h, end of reaction is added.Instead Answer liquid with 2% dilute hydrochloric acid adjust pH be 6-7, then be added methylene chloride extraction (50mL*3), merge organic layer and be saturated Sodium chloride solution washs (50mL*3), and collected organic layer filters after sufficient anhydrous sodium sulfate drying is added, and filtrate decompression removes Solvent obtains yellow oily liquid 8.52, yield 99.9%.1H NMR(400MHz,CDCl3)δ 3.73(s,3H),3.67(s,1H), 3.27 (s, 2H), 2.75 (t, J=6.0Hz, 2H), 2.52 (t, J=5.9Hz, 2H).
The synthesis of step G 7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2,4- glycol (a2)
Metallic sodium (16.2252g, 0.7mol) is added in 300mL dehydrated alcohol stirring under ice bath and urea is added to after dissolving (32.7178g, 0.54mol), and 80 DEG C are heated to, 31.3050g (0.18mol) intermediate a1, reaction are added after urea dissolution About stop reaction afterwards for 24 hours, be removed under reduced pressure solvent after being cooled to room temperature, residue is added ice water, with second acid for adjusting pH is 6- under ice bath 7, there is white solid precipitation, filters, filter cake is washed with ice water, white powdery solids 13.6333g is obtained after dry, yield: 41.2%.M.p.:184.3-185.7 DEG C.ESI-MS m/z:[M-H]+:188.1；1H NMR(400MHz,CDCl3)δ3.81 (s, 2H), 3.23 (t, J=5.9Hz, 2H), 2.96 (t, J=6.0Hz, 2H).
The synthesis of the chloro- 7,8- dihydro -5H- thiapyran of step H 2,4- bis- simultaneously [4,3-d] pyrimidine (a3)
3.0293g (0.016mol) intermediate a2 is added in dry 50mL round-bottomed flask, and 20mL trichlorine oxygen is then added Phosphorus is stirred and is heated, and is stopped reaction after the 3h that flows back at 110 DEG C, is cooled to room temperature.Reaction solution is slowly added in trash ice, and acutely Yellow particle shape solid is precipitated in stirring, filters, and filter cake is washed with massive laundering, obtains yellow particle shape solid 3.1174g after dry, Yield 85.7%.M.p.:87.1-87.9 DEG C.ESI-MS m/z:[M+H]+:219.9,1H NMR(400MHz,CDCl3)δ 3.81 (s, 2H), 3.23 (t, J=5.9Hz, 2H), 2.96 (t, J=6.0Hz, 2H).
The conjunction of the chloro- 7,8- dihydro -5H- thio-pyrylium of step I 2,4- bis- simultaneously [4,3-d] pyrimidine 6,6- dioxide (a4) At
4.03g (0.02mol) compound a 3 is added in 250mL round-bottomed flask with 60mL methanol and is stirred at room temperature, so Sodium tungstate 0.65g (0.002mol) is weighed afterwards to be dissolved in the hydrogen peroxide of 5mL 30%, then is slowly added dropwise in reaction solution, room temperature Lower stirring 2-3 hours.Light yellow solid 3.91g, yield: 87.0%, m.p.:117.1-118.9 DEG C are filtered to obtain after reaction. ESI-MS m/z:[M+H]+:251.9。
Embodiment 1 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- first Base -1H- indol-3-yl) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide
White solid, yield 60%, m.p:185.2-186.7 DEG C of1H NMR(400MHz,DMSO-d6) δ10.02(s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.32 (d, J=5.3Hz, 1H), 8.24 (d, J=7.8Hz, 1H), 7.90 (s, 1H), 7.53 (d, J=8.2Hz, 1H), 7.24 (t, J=6.7Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 7.03 (s, 1H), 6.81 (dtd, J=11.0,6.9,3.8Hz, 2H), 6.11 (d, J=15.3Hz, 1H), 5.80-5.72 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.90 (s, 2H), 2.71 (s, 3H), 2.36 (s, 2H), 2.24 (d, J=7.5Hz, 6H), 2.14 (dd, J=13.7,6.5Hz, 2H), 1.50-1.42 (m, 2H), 0.93 (dd, J=13.5,6.2Hz, 3H)；TOF MS ES+(m/z): (M+ H)+,calcd for C31H39N7O2:541.3165,found,543.3245。
2 N- of embodiment (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) the chloro- acrylamide of -2-
White solid, yield 71%, m.p:152.3-153.1 DEG C of1H NMR(400MHz,DMSO-d6) δ10.03(s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.24 (s, 1H), 7.53 (d, J=7.6Hz, 1H), 7.33- 7.20(m,1H),7.14(s,1H),6.47(s,1H),6.29(s,1H),6.07(s, 1H),5.86(s,1H),3.92(s, 3H),3.78(s,3H),3.26–3.19(m,2H),2.76(s,2H), 2.72(s,3H),2.47(s,6H)；TOF MS ES+ (m/z):(M+H)+,calcd for C29H31ClN8O2:558.2259,found,559.2337。
Embodiment 3 (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) butyl- 2- acrylamide
White solid, yield 63%, m.p.158.2-160.5 DEG C of .TOF MS ES+ (m/z): (M+H)+, calcd for C31H36N8O2:538.6560,found,539.6721。
Embodiment 4 (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) amyl- 2- acrylamide
White solid, yield 60%, m.p:128.5-130.1 DEG C of1H NMR(400MHz,DMSO-d6) δ9.92(s, 1H), 9.41 (d, J=9.0Hz, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.51 (d, J=7.5Hz, 1H), 7.23 (s, 1H), 7.06 (s, 1H), 6.91-6.73 (m, 2H), 6.05 (d, J=15.4Hz, 1H), 5.74 (d, J= 15.6Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.91 (s, 2H), 2.74 (d, J=10.9Hz, 3H), 2.39 (s, 2H), 2.23 (d, J=5.8Hz, 6H), 2.20-2.14 (m, 2H), 1.02 (dd, J=9.8,7.5Hz, 3H) .TOF MS ES+ (m/ z):(M+H)+,calcd for C31H36N8O2:552.6830,found,553.3048。
Embodiment 5 (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 61%, m.p:160.3-162.1 DEG C of1H NMR(400MHz,CDCl3)δ 9.35(s,1H), 9.26 (s, 1H), 8.65 (s, 1H), 8.49 (s, 2H), 7.78 (s, 1H), 7.36 (d, J=7.3Hz, 1H), 7.33-7.27 (m, 2H), 6.92 (d, J=16.8Hz, 2H), 6.72 (s, 1H), 3.91 (d, J=6.6Hz, 6H), 3.29 (s, 2H), 3.01 (s, 2H), 2.74 (d, J=11.2Hz, 9H), 2.53 (d, J=6.8Hz, 1H), 1.10 (d, J=6.8Hz, 6H)；TOF MS ES+ (m/z):(M+H)+,calcd for C32H38N8O2:566.3118,found,567.3203。
Embodiment 6 (Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide
White solid, yield 64%, m.p:158.1-160.6 DEG C of1H NMR(400MHz,DMSO-d6) δ9.92(s, 1H), 9.40 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.51 (d, J=8.2Hz, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 6.82-6.69 (m, 2H), 6.07 (d, J=15.3Hz, 1H), 5.75 (d, J=15.5Hz, 1H), 3.90 (s, 3H), 3.72 (s, 3H), 2.91 (s, 2H), 2.74 (s, 3H), 2.41 (d, J=5.8Hz, 2H), 2.23 (s, 6H), 2.17–2.13(m,2H),1.45–1.41(m, 2H),0.89–0.87(m,3H).TOF MS ES+(m/z):(M+H)+,calcd for C32H38N8O2: 556.3118,found,567.3192。
7 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) the chloro- acrylamide of -2-
Faint yellow solid, m.p:164.5-165.7 DEG C of1H NMR(400MHz,DMSO-d6)δ9.94(s, 1H),9.12 (s, 1H), 8.53 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.69 (s, 1H), 7.43 (d, J=8.1Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 7.09 (t, J=7.8Hz, 2H), 6.99 (s, 1H), 6.49 (d, J=2.1Hz, 1H), 6.03 (d, J= 2.1Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.18 (t, J=7.0Hz, 2H), 2.82 (t, 2H), 2.57 (s, 3H), 2.40(s,6H),2.29(s,3H).TOF MS ES+(m/z):(M+H)+,calcd for C29H34ClN7O2:547.2463, found,548.2544
Embodiment 8 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl - 6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) but-2-enamides
White solid, yield 58%, m.p.179.2-181.6 DEG C, TOF MS ES+ (m/z): (M+H)+, calcd for C31H36N8O2:527.6830,found,528.6048。
According to the method for embodiment 17 and 18, embodiment 19-24 compound is made by similar reaction.
Embodiment 9 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl - 6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) amyl- 2- acrylamide
White solid, yield 54%, m.p:189.7-191.2 DEG C of1H NMR(400MHz,DMSO-d6) δ9.83(s, 1H), 9.15 (s, 1H), 8.57 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.54 (s, 1H), 7.33 (d, J=8.1Hz, 1H), 7.09-7.01 (m, 1H), 6.97 (t, J=7.2,5.5Hz, 2H), 6.82 (s, 1H), 6.69 (ddt, J=21.8, 15.5,6.3Hz,2H),3.73(s,3H),3.67(s,3H),2.70(t, 2H),2.36–2.28(m,3H),2.19(s,3H), 2.16 (t, J=6.2Hz, 2H), 2.06 (s, 6H), 2.01-1.95 (m, 2H), 0.88 (t, J=7.4Hz, 3H)；TOF MS ES +(m/z):(M+H)+, calcd for C31H39N7O2:576.2854,found,577.2935。
Embodiment 10 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- first Base -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 51%, m.p:172.3-173.5 DEG C of1H NMR(400MHz,DMSO-d6) δ9.86(s, 1H), 9.20 (s, 1H), 8.58 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.53 (s, 1H), 7.33 (d, J=8.2Hz, 1H), 7.04 (t, J=7.7Hz, 1H), 6.98 (d, J=4.6Hz, 2H), 6.82 (s, 1H), 6.63 (ddd, J=6.5,15.5, 30.9Hz, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 2.69 (t, J=5.7Hz, 2H), 2.34 (t, J=11.4,13.2Hz, 3H), 2.17 (d, J=22.2Hz, 6H), 2.06 (s, 6H), 0.89 (d, J=6.7Hz, 6H) .TOF MS ES+ (m/z): (M+ H)+,calcd for C32H41N7O2:555.3322,found,556.3405。
Embodiment 11 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- first Base -6- (1- Methyl-1H-indole -3- base base) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide
White solid, yield 61%, m.p:129.4-131.1 DEG C of1H NMR(400MHz,DMSO-d6) δ9.80(s, 1H), 9.15 (s, 1H), 8.57 (s, 1H), 8.04 (d, J=8.0Hz, 1H), 7.54 (s, 1H), 7.33 (d, J=8.1Hz, 1H), 7.04 (t, J=7.4Hz, 1H), 7.00-6.94 (m, 2H), 6.83 (s, 1H), 6.66-6.56 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 2.72 (t, J=5.7Hz, 2H), 2.31 (t, J=1.9Hz, 3H), 2.20 (d, J=4.5Hz, 5H), 2.09 (s, 6H), 2.05-2.01 (m, 2H), 1.31 (q, J=7.4Hz, 2H), 0.75 (t, J=7.4Hz, 3H)；TOF MS ES +(m/z):(M+H)+, calcd for C32H41N7O2:555.3322,found,556.3400。
Embodiment 12 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 51%, m.p:123.7-125.1 DEG C of1H NMR(400MHz,DMSO-d6) δ9.83(s, 1H), 8.57 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.54 (s, 1H), 7.33 (d, J=8.1Hz, 1H), 7.07-7.01 (m, 1H), 6.97 (q, J=7.2,5.5Hz, 3H), 6.82 (s, 1H), 6.68 (tt, J=15.5,6.5Hz, 2H), 3.73 (s, 3H),3.67(s,3H),2.73–2.68(m,2H), 2.35–2.29(m,3H),2.15(s,2H),2.06(s,6H),2.01– 1.95 (m, 2H), 0.80 (t, J=7.4 Hz, 3H) .TOF MS ES+ (m/z): (M+H)+,calcd for C31H38FN7O2: 559.3071, found,560.3161。
Embodiment 13 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- acrylamide
White solid, yield 51%, m.p:194.6-195.7 DEG C of1H NMR(400MHz,DMSO-d6) δ9.87(s, 1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.29 (d, J=4.7Hz, 1H), 8.05 (d, 1H), 7.54 (s, 1H), 7.23 (d, J =5.7Hz, 1H), 7.09 (d, J=7.4Hz, 3H), 6.58 (s, 1H), 6.09 (s, 1H), 3.91-3.87 (m, 7H), 3.18- 3.13(m,2H),2.73(s,9H),2.66(s,2H)；13C NMR(400MHz,DMSO-d6)δ170.82,166.45, 160.21,157.01,156.87,144.89, 143.21,133.77,132.12,129.88,128.96,122.53, 122.31,115.03,113.26,112.87, 112.43,111.12,108.98,104.53,98.23,58.67,56.78, 55.96,47.18×2,41.25, 33.68,20.05,13.89.TOF MS ES+(m/z):(M+H)+,calcd for C30H36FN7O2: 545.2915,found,546.2995。
Embodiment 14 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- acrylamide
White solid, yield 51%, m.p:211.9-213.4 DEG C of1H NMR(400MHz,DMSO-d6) δ9.93(s, 1H), 8.92 (s, 1H), 8.62 (s, 1H), 8.28 (d, J=5.3Hz, 1H), 8.09 (s, 1H), 8.02 (d, J=10.7Hz, 1H), 7.53 (dd, J=9.0,4.5Hz, 1H), 7.17 (d, J=5.3Hz, 1H), 7.12-7.04 (m, 1H), 7.01 (s, 1H), 6.78 (dd, J=15.5,6.1Hz, 1H), 6.11 (d, J=15.4Hz, 1H), 2.95 (s, 2H), 2.69 (s, 3H), 2.53 (s, 3H),2.35(s,6H),1.07(s,3H), 1.05(s,3H)；TOF MS ES+(m/z):(M+H)+,calcd for C31H38FN7O2:559.3071, found,560.3150。
15 N- of embodiment (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) - 2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide
White solid, yield 51%, m.p:155.8-159.3 DEG C of1H NMR(400MHz,DMSO-d6) δ10.70(s, 1H), 9.97 (s, 1H), 8.78 (s, 1H), 8.25 (s, 2H), 7.58 (d, J=8.0Hz, 1H), 7.37 (d, J=6.6Hz, 1H), 7.27 (d, J=6.3Hz, 2H), 7.01 (s, 1H), 6.20 (d, J=17.0 Hz, 1H), 5.69 (d, J=10.3Hz, 1H),3.92(s,3H),3.85(s,3H),3.34(s,2H),2.75 (s,3H),2.64(s,2H),2.50(s,6H).TOF MS ES+(m/z):(M+H)+,calcd for C29H31FN8O2:542.2554,found,543.2632。
Embodiment 16 (Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) ammonia Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 51%, m.p:179.8-181.2 DEG C of1H NMR(400MHz,DMSO-d6) δ9.66(s, 1H),9.42(s,1H),8.51(s,1H),8.35(s,1H),8.05(s,1H),7.35(s,1H), 6.94(s,2H),6.32 (s, 1H), 6.09 (s, 1H), 5.87 (s, 1H), 5.62 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.19 (d, J= 7.1Hz, 2H), 2.88 (d, J=7.2Hz, 2H), 2.52 (s, 3H), 2.50 (s, 6H), 2.33 (s, 2H), 1.01 (s, 3H)； TOF MS ES+(m/z):(M+H)+,calcd for C32H37FN8O2:584.3204,found,585.3102。
Embodiment 17 (Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) ammonia Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) amyl- 2- acrylamide
White solid, yield 51%, m.p:135.1-136.7 DEG C of1H NMR(400MHz,DMSO-d6) δ9.66(s, 1H),9.42(s,1H),8.51(s,1H),8.35(s,1H),8.05(s,1H),7.35(s,1H), 6.94(s,2H),6.32 (s, 1H), 6.09 (s, 1H), 5.87 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.19 (t, J=7.0Hz, 2H), 2.88 (t, J=7.3Hz, 2H), 2.54 (d, J=14.9Hz, 3H), 2.50 (s, 6H), 2.33 (s, 2H), 1.02 (t, J=9.3Hz, 3H)；TOF MS ES+(m/z):(M+H)+, calcd for C31H35FN8O2:570.2867,found,571.2950。
Embodiment 18 (Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) ammonia Base) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide
White solid, yield 51%, m.p:141.7-142.5 DEG C of1H NMR(400MHz,DMSO-d6) δ9.71(s, 1H), 9.57 (s, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.53 (s, 1H), 7.05 (d, J=25.2Hz, 2H), 6.75 (ddd, J=31.4,15.5,6.3Hz, 2H), 6.34 (d, J=15.9Hz, 1H), 3.90 (s, 3H), 3.74 (s, 3H),3.10(s,2H),2.86(s,2H),2.68(s,3H), 2.50(s,6H),2.44–2.40(m,1H),1.20(s,6H)； TOF MS ES+(m/z):(M+H)+, calcd for C32H37FN8O2:584.3204,found,585.3107。
Embodiment 19 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 51%, m.p:208.5-209.4 DEG C of1H NMR(400MHz,DMSO-d6) δ9.35(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.48 (m, 2H), 7.35 (dd, J=7.5,5.0Hz, 1H), 7.04 (td, J=7.8,1.5Hz, 1H), 6.38 (s, 1H), 6.22 (dd, J=11.0,0.9Hz, 1H), 6.02 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.69 (t, J=7.1Hz, 2H), 3.00 (s, 3H), 2.74 (t, J=7.1Hz, 2H), 2.66 (m, 1H), 2.42 (s, 3H), 2.34 (s, 6H), 1.04 (dd, J=6.8,1.1Hz, 6H)；TOF MS ES+(m/z):(M +H)+,calcd for C32H40FN7O2:573.3228,found,574.3306。
Embodiment 20 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) amyl- 2- acrylamide
White solid, yield 51%, m.p:239.7-240.1 DEG C of1H NMR(400MHz,DMSO-d6) δ9.24(s, 1H), 8.73 (s, 1H), 7.86 (s, 1H), 7.51-7.40 (m, 3H), 7.34 (dd, J=7.5,4.9Hz, 1H), 7.04 (td, J =7.7,1.5Hz, 1H), 6.38 (s, 1H), 6.22-6.15 (m, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.69 (t, J= 7.1Hz, 2H), 3.00 (s, 3H), 2.74 (t, J=7.1Hz, 2H), 2.45-2.36 (m, 5H), 2.33 (s, 6H), 1.08 (m, 3H).TOF MS ES+(m/z):(M+ H)+,calcd for C31H38FN7O2:559.3071,found,560.3145。
Embodiment 21 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) hex- 2- acrylamide
White solid, yield 58%, m.p:195.7-196.6 DEG C of1H NMR(400MHz,DMSO-d6) δ9.21(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.48-7.40 (m, 2H), 7.35 (dd, J=7.5,5.0Hz, 1H), 7.04 (td, J=7.8,1.5Hz, 1H), 6.38 (s, 1H), 6.28 (dt, J=10.8,6.1Hz, 1H), 6.20-6.14 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.69 (t, J=7.1 Hz, 2H), 3.00 (s, 3H), 2.74 (t, J=7.1Hz, 2H), 2.42 (s, 3H), 2.35-2.27 (m, 8H), 1.49 (m, 2H), 0.89 (t, J=8.0Hz, 3H) .TOF MS ES+ (m/ z):(M+H)+,calcd for C32H40FN7O2:573.3228,found,574.3312。
22 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-of 5- 1H- indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) -2- chloro- third Acrylamide
White solid, yield 52%, m.p:219.7-221.1 DEG C.1H NMR(400MHz,DMSO-d6)δ 9.84(s, 1H), 8.75 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.80 (d, J=10.4Hz, 1H), 7.50-7.46 (m, 1H), 7.04 (t, J=9.2,2.6Hz, 1H), 6.99 (s, 1H), 6.82-6.73 (m, 1H), 6.03 (d, J=15.3Hz, 1H), 3.90 (s, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 3.00 (dt, J=10.2,5.2Hz, 6H), 2.89 (s, 3H), 2.68 (s, 4H),2.36(s,2H),2.21–2.15(m,2H)。 TOF MS ES+(m/z):(M+H)+,calcd for C31H35ClFN7O2S:623.2284,found, 624.3205。
Embodiment 23 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- Acrylamide
White solid, yield 50%, m.p:234.2-236.8 DEG C.TOF MS ES+(m/z):(M+H)+, calcd for C33H34FN7O2S:617.1986,found,618.2013。
Embodiment 24 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) -4- first The amyl- 2- acrylamide of base
White solid, yield 52%, m.p:232.1-233.5 DEG C.1H NMR(400MHz,DMSO-d6)δ 9.87(s, 1H), 8.76 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.79 (d, J=11.0Hz, 1H), 7.48 (dd, J=8.9, 4.6Hz, 1H), 7.04 (d, J=8.7Hz, 1H), 6.99 (s, 1H), 6.72 (dd, J=15.1,6.4Hz, 1H), 5.99 (d, J =16.1Hz, 1H), 3.90 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.05-2.97 (m, 4H), 2.89 (s, 2H), 2.68 (s, 3H), 2.45 (s, 2H), 2.28 (s, 6H), 2.18 (t, J=7.5Hz, 1H), 1.05 (d, J=6.8Hz, 6H).TOF MS ES+(m/z):(M+H)+, calcd for C34H42FN7O2S:631.3185,found,640.1238。
Embodiment 25 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- Acrylamide
White solid, yield 52%, m.p:238.6-240.2 DEG C.1H NMR(400MHz,DMSO-d6)δ9.78(s,1H), 8.72 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.80 (d, J=10.7Hz, 1H), 7.48 (dd, J=8.9,4.6Hz, 1H), 7.07-7.01 (m, 1H), 6.99 (d, J=5.5Hz, 1H), 6.71 (dt, J=14.7,6.8Hz, 1H), 6.12 (s, 1H), 3.90 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.00 (dd, J=7.8,4.4Hz, 5H), 2.66 (s, 4H), 2.33 (s, 6H), 2.18 (q, J=6.5Hz, 4H), 1.46 (d, J=7.3Hz, 2H), 0.91 (t, J=7.3Hz, 3H).TOF MS ES+(m/z):(M+ H)+,calcd for C34H42FN7O2S:631.2584,found,632.0815。
Embodiment 26 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) but-2-enamides
White solid, yield 41%, m.p:182.5-183.9 DEG C.1H NMR(400MHz,DMSO-d6)δ 10.23(s, 1H), 9.85 (s, 1H), 8.672 (s, 1H), 8.08 (d, J=8.0Hz, 1H), 8.03 (s, 1H), 7.62 (dd, J=8.0, 4.7Hz, 1H), 7.51 (d, J=8.3Hz, 1H), 7.22 (t, J=7.6Hz, 1H), 7.13 (t, J=7.5Hz, 1H), 6.92 (s, 1H), 6.78 (d, J=5.4Hz, 1H), 3.95 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.35 (s, 4H), 3.13 (d, J=5.9Hz, 3H), 3.02 (d, J=6.1Hz, 2H), 2.75 (s, 6H), 2.72 (s, 2H), 2.66 (s, 2H).TOF MS ES+(m/z):(M+H)+, calcd for C32H39N7O2S:585.2798,found,586.1035。
Embodiment 27 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) the amyl- 2- of -4- methyl Acrylamide
White solid, yield 48%, m.p:192.3-194.1 DEG C.TOF MS ES+(m/z):(M+H)+, calcd for C34H43N7O2S:613.4021,found,614.2358。
Embodiment 28 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide
White solid, yield 47%, m.p:194.3-196.2 DEG C.1H NMR(400MHz,DMSO-d6)δ 9.84(s, 1H), 8.89 (s, 1H), 8.04 (d, J=8.1Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.47 (d, J=8.2Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.04 (t, J=7.7Hz, 1H), 6.98 (s, 1H), 6.76 (dt, J=14.7, 6.9Hz, 1H), 6.07 (d, J=15.2Hz, 1H), 3.90 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.06-2.97 (m, 4H), 2.90 (s, 2H), 2.67 (s, 3H), 2.42 (s, 2H), 2.32-2.13 (m, 8H), 1.47 (dt, J=14.6,7.3Hz, 2H), 0.92 (t, J=7.3Hz, 3H). TOF MS ES+(m/z):(M+H)+,calcd for C34H43N7O2S:613.3185, found, 613.3962。
29 N- of embodiment (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- methyl-of 5- 1H- indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyl group Phenyl) the chloro- acrylamide of -2-
White solid, yield 46%, m.p:238.9-39.7 DEG C.TOF MS ES+(m/z):(M+H)+,calcd for C31H35ClN7O2S:655.2165,found,656.0286。
Embodiment 30 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxy Base phenyl) amyl- 2- acrylamide
White solid, yield 49%, m.p:237.1-238.6 DEG C.TOF MS ES+(m/z):(M+H)+, calcd for C33H40FN7O4S:649.3582,found,650.5420。
Embodiment 31 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- first of 5- Base -1H- indol-3-yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxy Base phenyl) the amyl- 2- acrylamide of -4- methyl
White solid, yield 43%, m.p:241.5-242.6 DEG C.1H NMR(400MHz,DMSO-d6)δ 10.12(s, 1H), 9.42 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H), 7.79 (d, J=10.6Hz, 1H), 7.50 (dd, J=8.9, 4.6Hz, 1H), 7.43-7.34 (m, 1H), 7.07-7.01 (m, 1H), 6.95 (s, 1H), 6.73 (dd, J=15.2,6.2Hz, 1H), 4.48 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.58 (t, J=6.6Hz, 3H), 3.27 (d, J=5.4Hz, 6H), 2.73 (s, 6H), 2.58 (s, 3H), 1.04 (d, J=6.7Hz, 6H).TOF MS ES+(m/z):(M+H)+,calcd for C34H42FN7O4S:663.3158,found,664.2083。
Embodiment 32 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) But-2-enamides
White solid, yield 55%, m.p:212.3-213.8 DEG C.1H NMR(400MHz,DMSO-d6)δ 9.63(s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.93 (s, 1H), 7.47 (d, J=8.3Hz, 1H), 7.18 (t, J=7.7Hz, 1H), 7.05 (t, J=7.5Hz, 1H), 6.93 (s, 1H), 6.74 (dt, J=14.6, 6.7Hz, 2H), 4.46 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.57 (t, J=6.7Hz, 2H), 3.28 (d, J= 6.5Hz, 4H), 3.22-3.02 (m, 3H), 2.59 (s, 8H), 1.84 (d, J=6.0Hz, 3H).TOF MS ES+(m/z):(M+ H)+,calcd for C32H39N7O4S:617.2138,found,618.1823。
Embodiment 33 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) Amyl- 2- acrylamide
White solid, yield 57%, m.p:219.7-221.5 DEG C.1H NMR(400MHz,DMSO-d6)δ 9.56(s, 1H), 8.53 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=7.8Hz, 1H), 7.95 (s, 1H), 7.50 (d, J=7.8Hz, 1H),7.23–7.17(m,1H),7.12–7.05(m,1H),6.94(s,1H), 6.87–6.75(m,1H),6.67(s,1H), 4.49(s,2H),3.88(s,3H),3.85(s,3H),3.62– 3.55(m,2H),3.31–3.23(m,4H),2.71(s,6H), 2.58 (s, 3H), 2.26-2.14 (m, 2H), 1.30 (s, 2H), 1.06 (t, J=7.1Hz, 3H).TOF MS ES+(m/z):(M +H)+,calcd for C33H41N7O4S:631.3102,found,632.2087。
Embodiment 34 (Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole -3- base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) benzene Base) the amyl- 2- acrylamide of -4- methyl
White solid, yield 57%, m.p:225.4-227.1 DEG C.TOF MS ES+(m/z):(M+H)+, calcd for C34H43N7O4S:645.3896,found,646.2312。
The pharmacological research of product of the present invention
In vitro cytotoxic effect
External inhibition has been carried out to a kind of pyrimidines of structure of acrylamide containing substituted-phenyl of general formula I of the present invention Lung cell A549, lung cancer mutant cell H1975, HepG-2 cell screening active ingredients, reference substance AZD9291 is according to patent text (WO201314448A1) the method is offered to be prepared.
1) after 2~3 stabilizations of cell recovery and passage, it is made to disappear from culture bottle bottom with trypsin solution (0.25%) Change is got off.After cell dissociation buffer is poured into centrifuge tube, culture solution is added later to terminate digestion.By centrifuge tube in 800r/min 5mL culture solution is added after discarding supernatant liquid in lower centrifugation 10min, and piping and druming mixes cell, draws 10 μ L cell suspensions and cell is added It is counted in tally, adjustment cell concentration is 104A/hole.Except the hole A1 is that blank well is not added extracellularly in 96 orifice plates, remaining all adds Enter 100 μ L cell suspensions.96 orifice plates are put into incubator and are cultivated for 24 hours.
2) with 50 μ L dmso solution given the test agent, appropriate culture solution is then added, sample is made to be dissolved into 2mg/mL Then sample is diluted to 20,4,0.8,0.16,0.032 μ g/mL in 24 orifice plates by medical fluid.
3 holes are added in each concentration, wherein surrounding two rows, two column cell growing way is affected by environment larger, it only and is blanc cell Hole uses.96 orifice plates are put into incubator and cultivate 72h.
3) band medicine culture solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole MTT (tetrazole) (0.5mg/mL) 100 μ L is added to be put into incubator after 4h, discards MTT solution, 100 μ of dimethyl sulfoxide is added L.Oscillation dissolves survivaling cell sufficiently with MTT reaction product formazan on magnetic force oscillator, is put into microplate reader and measures knot Fruit.Drug IC can be found out by Bliss method50Value.
Lung cell A549, mutation lung carcinoma cell H1975, the HepG-2 cell Activity Results of compound are shown in Table 2.
EGFRWT、EGFRT790M/L858REnzymatic activity experiment
1, solution is prepared
1) untested compound adds 1mL DMSO, is made into 10mM storage solutions.Positive compound AZD9291 storing liquid concentration For 10mM (being dissolved in DMSO), the storing liquid concentration of positive compound cis-platinum is 2mM (being dissolved in DMSO).
2) DMSO diluted compounds storing liquid is used, 2mM solution (100X) is made into.
3) the 2mM solution of 2 μ L is taken, 18 μ L reaction solution diluted compounds are added to 200 μM of (10X) solution.
4) the above-mentioned solution of 2 μ L and 18 μ L reaction solutions are added in working plate, are made into 10X solution.
5) it takes with 1 μ L of solution in upper plate to detection plate.
6) 1 μ L kinase reaction liquid is added in the full inhibition control and null suppression control wells of detection plate, so that the concentration of DMSO It is 10%.
2, experimental procedure
1) layout of orifice plate
384 orifice plates is needed to arrange according to experiment, in which:
A) HPE (complete to inhibit control): kinases and compound is not added, adds ATP, substrate and 1%DMSO.
B) ZPE (null suppression control): compound is not added, adds kinases, ATP, substrate and 1%DMSO.
C) positive reference compound hole: add kinases, ATP, substrate and various concentration positive compound.
D) untested compound hole: add kinases, ATP, substrate and untested compound.
2) agents useful for same is prepared
4XATP: ATP is diluted to 4X with reaction solution.
4X substrate solution: substrate is diluted to 4X with reaction solution.
2.5X kinase solution: with reaction solution by kinase dilution to 2.5X.
3) kinase reaction
A) 1 μ L10X compound (positive control of untested compound or various kinases) solution is added according to the every hole of arrangement, It is complete to inhibit control and null suppression control wells that 1 μ L reaction solution is added.
B) 4 μ L2.5X kinase solutions are added according to the every hole of arrangement.It is complete to inhibit control wells that 4 μ L reaction solutions are added.
C) it will test plate 1000rpm centrifugation to mix.
D) 4XATP solution is mixed in equal volume with 4X substrate solution, obtains 2XATP- substrate solution.
E) the above-mentioned 2X ATP- substrate solution of 5 μ L is added according to the every hole of arrangement.
F) it will test plate 1000rpm centrifugation to mix.
G) it will test plate and be placed in 30 DEG C of reactions 1 hour.
H) 10 μ L Kinase glo plus or ADP-Glo reaction reagents are added in every hole, and 27 DEG C are placed 20 minutes.
I) 20 μ L Kinase Detection reagents are added in every hole, and 27 DEG C are placed 30 minutes.
J) Envision reads fluorescence values.
Note: needing preset room temperature before the use of Kinase glo plus, ADP-Glo and Kinase Detection reagent Half an hour.
4) primary data analysis
Prism5.0 analyzes initial data.
The IC of compound is calculated according to Bliss method50
Inhibiting rate (%)=(Ratio665/620 control wells-Ratio665/620 dosing holes)/Ratio665/620 pairs According to hole × 100%
Experimental result is as shown in table 2.IC in table 150>=80%, is indicated with " +++ ", 80% > IC50>=60%, with " ++ " It indicates, 60% > IC50>=40%, is indicated with "+", IC50≤ 40%, it is indicated with "-", " NA " indicates inactive, and " ND " is indicated It does not test.Table 3 is the anti-EGFR kinase activity result of partial target compound
2 target compound enzymatic activity of table and anti tumor activity in vitro
From above-mentioned test result it can be clearly seen that the compound of the claimed general formula I of the present invention, has good External antiproliferation and anti-EGFR kinase activity.From the data in table 2 it is found that the pyrimidine of the structure containing substituted acrylamide Class AZD9291 derivative shows preferable cellular antiproliferative activity to three plants of tumour cells, and big as can be seen from the table Part of compounds is to EGFRT790M/L858RDouble mutant kinases have fine rejection ability, and the bis- mutation of selective depression EGFR swash Enzyme.As can be seen from the above table data, relative to anti-EGFR wild type kinase activity, the bis- mutant kinases of the anti-EGFR of Compound of Example Active selectivity reaches 10-200 times or more, and also provable Compound of Example targeting is good for this, and selectivity is high.It can thus be concluded that going out Conclusion, the compound of formula of I of the present invention may be potential EGFR inhibitor.
The compound of formula of I of the present invention can be administered alone, but usually give with pharmaceutical carrier mixture, described medicinal The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various drug agent of such compound Type, such as the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, Illustrate its new opplication in pharmaceutical field.
Application examples 1: tablet
100 are pressed into, often after adding auxiliary material 20g to mix according to the general pressed disc method of pharmacy with 1 compound 10g of embodiment Slice weight 300mg.
Application examples 2: capsule
With 3 compound 10g of embodiment be packed into hollow glue after auxiliary material 20g being mixed according to the requirement of pharmacy capsule Capsule, each capsule weight 300mg.
Application examples 3: injection
Activated carbon adsorption is carried out according to pharmacy conventional method with 5 compound 10g of embodiment, is filtered through 0.65 μm of micropore After film filtering, hydro-acupuncture preparation is made in filling nitrogen gas tank, and every dress 2mL is filling 100 bottles total.
Application examples 4: aerosol
It after distilled water and other spoke material are added, is made after the dissolution of appropriate propylene glycol with 10 compound 10g of embodiment The clear solution of 500mL to obtain the final product.
Application examples 5: suppository
With 13 compound 10g of embodiment, by finely ground addition glycerol it is appropriate, the glycerin gelatine melted is added after grinding well, Grinding uniformly, is poured into the model for having applied lubricant, and suppository 50 is made.
Application examples 6: film
With 16 compound 10g of embodiment, will be dissolved by heating after the stirrings such as polyvinyl alcohol, medicinal glycerin, water expansion, 80 meshes Net filtration, then 18 compound of embodiment is added to stirring and dissolving in filtrate, film applicator is film-made 100.
Application examples 7: pill
It is instilled in cryogenic liquid paraffin after being mixed with matrix 50g heating fusings such as gelatin with 19 compound 10g of embodiment, 1000 ball of dripping pill is made altogether.
Application examples 8: externally-applied liniment
With 20 compound 10g of embodiment, according to the auxiliary materials 2.5g mixed grinding such as conventional dose method and emulsifier, then plus Distilled water is obtained to 200mL.
Application examples 9: ointment
With 22 compound 10g of embodiment, ground well after finely ground with oleaginous bases 500g such as vaseline obtained.
Although describing the present invention by specific embodiment, modification and equivalent variations are for being proficient in this field It will be apparent from for technical staff, and they are included within the scope of the invention.

Claims (6)

1. a kind of pyrimidines of the structure of acrylamide containing substituted-phenyl, which is characterized in that structure such as the following general formula I institute Show:
Wherein:
R1Selected from aromatic ring, hetero-aromatic ring, and the aromatic ring, heteroaromatic contain 1-3 selected from hydrogen, halogen, trifluoromethyl, cyano, three Fluorine methoxyl group, (C1~C4) alkyl substituent group；
R2、R3It is same or different, separately it is selected from hydrogen, halogen, trifluoromethyl, cyano, trifluoromethoxy, (C1~C4) alkane Base, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkoxy methyl, (C1~C4) alkane Base acyl group, (C1~C4) alkylthio group or R2、R3It forms one and contains CH2, O, NH, S, SO or SO2Five yuan or hexa-atomic of atom (group) Cycloaliphatic ring or aliphatic heterocycle；
R4Selected from hydrogen, (C1~C10) alkyl, (C3~C10) naphthenic base, (C1~C4) alcoholic extract hydroxyl group,
-N(CH3)R5It is selected from
R6Selected from hydrogen, (C1~C4) alkyl and halogen；
R7、R8It is identical or different, separately it is selected from (C1~C6) alkyl or (C3~C6) naphthenic base, ethoxy, mercaptoethyl, Or R7And R8Be formed together 5~10 yuan of saturated heterocyclyls with the nitrogen-atoms being connect with them, the saturated heterocyclyl in addition to R7 And R8Outside the nitrogen-atoms of connection, the hetero atom of O, N and S are optionally selected from containing 1~3；
N is 0~3.
2. a kind of pyrimidines of structure of acrylamide containing substituted-phenyl according to claim 1, it is characterised in that:
R1The heterocycle of thick sum is selected from:
R1’Selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl, second Base, propyl, butyl, cyclopropane, ethylene, propylene, acetylene, propine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy Or azido；
R2、R3It is same or different, separately it is selected from hydrogen, halogen, trifluoromethyl, cyano, trifluoromethoxy, (C1~C4) alkane Base, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkoxy methyl, (C1~C4) alkane Base acyl group, (C1~C4) alkylthio group or following heterocycle structure:
R4Selected from hydrogen, (C1~C10) alkyl, (C3~C10) naphthenic base, (C1~C4) alcoholic extract hydroxyl group,
-N(CH3)R5It is selected from
R6Selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine；
It is selected from:
N is 0~3.
3. a kind of pyrimidines of structure of acrylamide containing substituted-phenyl according to claim 1, it is characterised in that: The compounds of formula I is selected from one of following compounds:
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide,
N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) second Base) (methyl) amino) -4- methoxyphenyl) the chloro- acrylamide of -2-,
(Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -4- methoxyphenyl) but-2-enamides,
(Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (5- ((5- cyano -4- (1- Methyl-1H-indole -3- base) pyrimidine -2-base) amino) -2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- methyl-1 H- Yin Diindyl -3- base base) pyrimidine -2-base) amino) phenyl) the chloro- acrylamide of -2-,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- methyl - 1H- indol-3-yl base) pyrimidine -2-base) amino) phenyl) but-2-enamides,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- methyl - 1H- indol-3-yl base) pyrimidine -2-base) amino) phenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- methyl - 1H- indol-3-yl base) pyrimidine -2-base) amino) phenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- methyl -6- (1- methyl - 1H- indol-3-yl base) pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) pyrimidine -2-base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- acrylamide,
N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino Base) ethyl) (methyl) amino) -4- methoxyphenyl) acrylamide,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (diformazan Base amino) ethyl) (methyl) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (diformazan Base amino) ethyl) (methyl) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (5- ((5- cyano -4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) pyrimidine -2-base) amino) -2- ((2- (diformazan Base amino) ethyl) (methyl) amino) -4- methoxyphenyl) hex- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6- methylpyrimidine -2- base) amino) -4- methoxyphenyl) hex- 2- acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) -7, 8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) the chloro- acrylamide of -2-,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) hex- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) but-2-enamides,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) the amyl- 2- acrylamide of -4- methyl,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -7,8 dihydro -5H- thiapyrans simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) hex- 2- acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indole -3- base of 5-) -6, 7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) the chloro- acryloyl of -2- Amine,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) amyl- 2- alkene Amide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (fluoro- 1- Methyl-1H-indole -3- of 5- Base) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) -4- methoxyphenyl) -4- first The amyl- 2- acrylamide of base,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) but-2-enamides,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) amyl- 2- acrylamide,
(Z)-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl group -5- ((4- (1- Methyl-1H-indole - 3- yl) -6,7-6 titanium dioxide -7,8- dihydro -5H- thiapyran simultaneously [4,3-d] pyrimidine -2-base) amino) phenyl) the amyl- 2- alkene of -4- methyl Amide.
4. a kind of pyrimidines of the structure of acrylamide containing substituted-phenyl as described in claim 1-3 are treated in preparation And/or the application in prevention proliferative disease drug.
5. a kind of pyrimidines of the structure of acrylamide containing substituted-phenyl as described in claim 1-3 are treated in preparation And/or the application in the drug of pre- anti-cancer.
6. a kind of pyrimidines of the structure of acrylamide containing substituted-phenyl as described in claim 1-3 are treated in preparation And/or prevention lung cancer, prostate cancer, breast cancer and cervical carcinoma drug in application.
CN201811363921.9A 2018-11-16 2018-11-16 A kind of pyrimidines of the structure of acrylamide containing substituted-phenyl and its application Pending CN109280048A (en)

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