CN103965120B

CN103965120B - Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application

Info

Publication number: CN103965120B
Application number: CN201410036231.8A
Authority: CN
Inventors: 夏广新; 俞永平; 陈文腾; 张永; 沈竞康
Original assignee: Zhejiang University ZJU; Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Zhejiang University ZJU; Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2013-01-25
Filing date: 2014-01-26
Publication date: 2016-08-17
Anticipated expiration: 2034-01-26
Also published as: CN103965120A

Abstract

The invention discloses quinoline and quinazoline derivant I, preparation method, intermediate C, compositions and application.This preparation method includes: method one: 1. in solvent, under the effect of alkali 1, is reacted with compound B by compound A, obtains compound C；2., in solvent, under the effect of alkali 2, product C step 1. obtained reacts with compound D；Method two: in solvent, under the effect of alkali 1, reacts compound A with compound E.Present invention also offers the application in the medicine preparing EGFR tyrosine kinase inhibitor, A431 or H1975 inhibition of cell proliferation or prevention or treatment tumor disease of above-mentioned compound of formula I or aforementioned pharmaceutical compositions.The compound that the present invention provides has preferably anti-tumor activity.

Description

Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application

Technical field

The present invention is specifically related to a kind of quinoline and quinazoline derivant, preparation method, intermediate, compositions and application.

Background technology

Protein kinase has important function in cellular signal transduction.Phosphate group can be transferred to function egg from ATP by it In white particular amino acid residue, cause a series of biochemical reaction.According to aminoacid classification as substrate in Phosphorylation events, Protein kinase can be divided into serine-threonine kinase (STKs) and tyrosine kinase (PTKs).Wherein PTKs can be divided three classes: 1. Receptor tyrosine kinase (receptor protein tyrosine kinases, RPTKs), for single pass transmembrane albumen, at vertebra Animal having been found that, more than 50 plant；2. cytoplasmic tyrosine kinase, such as Src family, Tec family, JAK family etc.；3. tyrosine in core Kinases such as Abl and Wee.

The extracellular region of RPTKs is binding partner domain, and part is the polypeptide that combines of solubility or film or protein hormone, Including various kinds of cell somatomedin (such as EGF).Intracellular section is the catalytic site of tyrosine protein kinase, and has autophosphorylation position Point.Part is combined with receptor outside born of the same parents and causes conformation change, causes Receptor dimerization to form homology or heterodimer, two Phosphorylation intracellular section tyrosine residue, the protein tyrosine kinase activity of activated receptor itself each other in aggressiveness.Great majority The peptide sequence that this receptoroid of cell growth factor contains tyrosine kinase mainly has EGFR, PDGFR, FGFR, VEGFR etc., is permitted The overexpression of different tyrosine kinase receptors seen from many tumors or excessive activation.Similarity according to peptide sequence and other Feature in some structures, these receptors are divided into some families: 1. epidermal growth factor (EGFR) family；2. Insulin receptor INSR Family；The most platelet-derived growth factor receptors (PDGFR) family；4. bfgf receptor (FGFR) family； 5. vascular endothelial growth factor receptor (VEGFR) family；6. Fibronectin type III receptor class；7. hepatic cell growth Factor acceptor (HGFR) class etc..The overexpression in different tumors respectively of these receptors, causes its Intracellular signals abnormal activation, Cause cell transformation, constantly breed, promote the generation of tumor, development, therefore use the inhibitor for above-mentioned protein kinase, spy It not that tyrosine kinase inhibitor can play antitumor action.Such as EGFR family, including EGFR, HER2, HER3, HER4 Deng, it is the more tyrosine kinase of a class research, they have high expressed in kinds of tumors, and their expression increases with cancerous cell Grow, the phenomenon such as transfer is correlated with, find the inhibitor with EGFR as target spot be antitumor drug research and development in recent years important directions it One.

EGFR tyrosine kinase inhibitor can be divided into reversible inhibitor and irreversible inhibitor two class.The most go up The gefitinib (Gefitinib) in city, erlotinib (Erlotinib) are reversible inhibitor, along with they are in clinic Using, reversible inhibitor gradually shows drug resistance problems.Irreversible inhibitor can be with EGFR tyrosine kinase with covalent bond In conjunction with, many preclinical studies show, the irreversible inhibitor in exploitation can resist T790M sudden change at present, overcomes T790M and draws The drug resistance risen；Meanwhile, just at some irreversible inhibitors (such as BIBW2992 and PF00299804 etc.) of clinical development, Multiple members of EGFR receptor family can be suppressed, especially for the effect of EGFR and HER 2, may be by blocking by with two Synergistic signal path that aggressiveness and heterodimer activate and strengthen inhibition (Oncologist, 2009,14 (11): 1116- 1130).

Summary of the invention

The technical problem to be solved is, it is provided that a kind of quinoline and quinazoline derivant, it pharmaceutically may be used The salt accepted and their enantiomer, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof Or prodrug, its preparation method, intermediate, compositions and application.The quinoline of the present invention and quinazoline derivant, it pharmaceutically can connect The salt being subject to and their enantiomer, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or Prodrug has preferably anti-tumor activity.

The invention provides a kind of quinoline shown in formula I or quinazoline derivant, its pharmaceutically acceptable salt, quinoline Or quinazoline derivant or the enantiomer of its salt, diastereomer, tautomer, raceme, solvate, metabolism Precursor or prodrug；

Wherein, Z is N or C-CN；X is halogen, preferably F or Cl；

R₁For substituted C_6～10Aryl, described in be substituted by one or more being selected from following group a)～c) and take Generation:

A) halogen, preferably F, Cl or Br；

B) substituted or unsubstituted C_1～3Alkoxyl, described substituted C_1～3Alkoxyl can be substituted or unsubstituted further C_5～6Aryl, substituted or unsubstituted C_5～6Heteroaryl or 3～6 yuan of cycloalkyl substituted；Wherein, described substituted C_5～6Aryl or Substituted C_5～6Heteroaryl also can be further by halogen (preferably F) or C_1～3Alkyl (preferably methyl) replaces；Preferably, C_5～6 Aryl is phenyl, C_5～6Heteroaryl is pyridine radicals, and 3～6 yuan of cycloalkyl are cyclopropyl；

C) substituted or unsubstituted C_5～8Heteroaryloxy, described substituted C_5～8Heteroaryloxy can be further by C_1～3Alkyl (preferably methyl) replaces；Described C_5～8Heteroaryloxy is preferably the C containing 1 nitrogen-atoms_5～8Heteroaryloxy, more preferably pyrrole Piperidinyl or indyl；

R₂For substituted or unsubstituted C_1～3Alkoxyl or 3～8 yuan of heterocyclic oxy groups；Described 3～8 yuan of heterocyclic oxy groups are preferably 3～8 yuan of heterocyclic oxy groups, more preferably tetrahydrofuran base epoxides containing oxygen atom, more preferably 3S-tetrahydrofuran base oxygen Base；Described substituted C_1～3Alkoxyl can be selected from following group d)～g) further and replace:

D) substituted or unsubstituted 3～8 yuan of heterocyclic radicals, described substituted 3～8 yuan of heterocyclic radicals can be further by C_1～5Alkyl (preferably C_1～3Alkyl, more preferably methyl or ethyl) replace；Described 3～8 yuan of heterocyclic radicals be preferably pyrrolidinyl, piperidyl, Piperazinyl or morpholinyl, more preferably piperidyl or morpholinyl；

E) substituted or unsubstituted amino, described substituted amino can be further by C_1～5Alkyl (preferably C_1～3Alkyl, More preferably methyl or ethyl) replace；

F) halogen, preferably F or Cl, more preferably F；

G) C_1～3Alkoxyl, preferably methoxyl group；

R₃And R₄It is each independently hydrogen or substituted or unsubstituted C_1～3Alkyl, described substituted C_1～3Alkyl can be further It is selected from following group h)～i) to replace:

H) substituted or unsubstituted amino, described substituted amino can be further by C_1～3Alkyl (preferably methyl) replaces；

I) 3～8 yuan of heterocyclic radicals, described 3～8 yuan of heterocyclic radicals are preferably 3～8 yuan of heterocyclic radicals containing 1 nitrogen-atoms, more excellent Elect piperidyl as；

Further, quinoline shown in formula I or quinazoline derivant, its pharmaceutically acceptable salt, quinoline or quinazoline spread out Biology or the enantiomer of its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug Do not include the compound with following structure:

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

(Z)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

(E)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base)-4-(dimethylamino Base)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-ethoxyquin oxazoline-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base)-2-fluoro-4-morpholinyl But-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-((3R)-oxolane-3-base epoxide) quinazoline-6-base)-4-(two Methylamino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-((tetrahydrochysene-2H-pyrans-4-base) methoxyl group) quinazoline-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base)-2-fluoro-4-(4-first Base piperazine-1-base) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-((2-methoxyethyl) (first Base) amino) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-(4-methyl piperazine-1- Base) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-((methyl) (tetrahydrochysene furan Mutter-3-base) amino) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(2-(dimethylamino) ethyoxyl)- 2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-3-(1-methylpyrrolidin-2 (S) base) acrylamide；

N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan Base amino)-2-fluorine but-2-enamides；

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino Base)-2-fluorine but-2-enamides；

The fluoro-N-of 4-(dimethylamino)-2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino)-7-methoxyl group quinoline azoles Quinoline-6-base) but-2-enamides；

4-(dimethylamino)-N-(4-(3-ethynyl phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluorine butyl-2- Acrylamide；

N-(4-(2,4-bis-chloro-5-Methoxyphenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)- 2-fluorine but-2-enamides；

N-(4-(5-chlorobenzene also [d] [1,3] dioxolanes-4-base amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan Base amino)-2-fluorine but-2-enamides；

N-(4-(4-chloro-3-(trifluoromethyl) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)- 2-fluorine but-2-enamides；

N-(4-(3-bromophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine but-2-ene acyl Amine；

N-(4-(3-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(4-bromo-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3-chloro-2,4 difluorobenzene base amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

N-(4-(3,4-bis-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

N-(4-(the bromo-3-of 4-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2- Fluorine but-2-enamides；

(Z)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides；

(E)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-2,4 difluorobenzene base amino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)- 2-fluoropropene amide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(piperidin-1-yl) butyl-2- Acrylamide；

(Z)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-(piperidin-1-yl) But-2-enamides；

(E)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-(piperidin-1-yl) But-2-enamides；

N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(diformazan ammonia Base)-2-fluorine but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base) the fluoro-4-of-2- Morpholinyl but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4-(diformazan Amino)-2-fluorine but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-ene acyl Amine；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-fluoro-4-(piperidin-1-yl) but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-(2-methoxyethyl) quinazoline-6-base) the fluoro-4-of-2-(piperidin-1-yl) But-2-enamides；

N-(the chloro-4-of 3-(2-pyridine benzyloxy) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(piperidines amino)-2- Fluorine but-2-enamides；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-4-(dimethylamino)-2-fluorine but-2-enamides；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-fluoro-4-morpholinyl-but-2-enamides；

N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(pyrrolidin-1-yl) butyl-2- Acrylamide；

(Z)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(diformazan Amino)-2-fluorine but-2-enamides；

(E)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(diformazan Amino)-2-fluorine but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-2- Fluoro-4-morpholinyl but-2-enamides；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-2- Fluoro-4-morpholinyl but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-ene Amide；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-ene Amide；

N-(4-(4-bromo-2-fluoroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,4-bis-fluoro-3-chloroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-3-ethynylphenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2-fluoro-3-chloroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,4-bis-chloro-5-methoxybenzene amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(3-bromoanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(the chloro-3-of 2-(3-fluorine benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

N-(4-(2-fluoro-3,4-dichloro-benzenes amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,4 difluorobenzene amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,3,4-trifluorophenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,4 dichloro benzene amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(2,4-bis-fluoro-3-chloroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-chloroacrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-chloroacrylamide；

N-(4-(2,4-bis-chloro-3-methoxybenzene amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(4-chloro-3-methoxybenzene amino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(the fluoro-3-of 2-chloro-4-bromoanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-ethoxyquin oxazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(piperidin-1-yl) propoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

The chloro-N-of 2-(4-(3-chloro-4-fluoroanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base) acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(dimethylamino) propoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

N-(4-(3-chlorine 4-fluoroanilino)-7-(3-(pyrrolidin-1-yl) propoxyl group) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(4-methylpiperazine-1-yl) propoxyl group) quinazoline-6-base)-2-fluorine Acrylamide；

(R)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(oxolane-3-ylmethoxy) quinazoline-6-base)-2- Fluoropropene amide；

(S)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(oxolane-3-ylmethoxy) quinazoline-6-base)-2- Fluoropropene amide；

N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(cyclobutylmethyl epoxide) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(cyclo propyl methoxy) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(1-methyl piperidine-4-epoxide) quinazoline-6-base)-2-fluoropropene acyl Amine；

(R)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluorine Acrylamide；

(S)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(3-bromoanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoropropene amide；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-fluoropropene amide；

N-(4-(3-trifluoromethyl phenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoropropene amide；

N-(4-(3-trifluoromethyl phenylamino)-7-ethoxyquin oxazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-chloroacrylamide；

N-(4-(3-trifluoromethyl phenylamino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-chlorine Acrylamide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene Amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene Amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2- Chloroacrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(piperidin-1-yl) ethyoxyl) quinazoline-6-base)-2-fluoropropene acyl Amine；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(piperidin-1-yl) ethyoxyl) quinazoline-6-base)-2-chloropropene acyl Amine；

N-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy phenylamino)-7-ethoxyquin oxazoline-6-base)-2-chloropropene acyl Amine；

N-(4-((the chloro-4-of 3-(cyclo propyl methoxy phenylamino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline- 6-yl)-2-chloroacrylamide；

N-(4-((the chloro-4-of 3-(cyclo propyl methoxy phenylamino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline- 6-yl)-2-fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-3-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-3-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-2-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-2-base) methoxyl group) quinazoline-6-base)-2- Fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-4-base) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(4-methylpiperazine-1-yl) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-morpholine ethyoxyl) quinazoline-6-base)-2-fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methylpyrrolidin-2-yl) ethyoxyl) quinazoline-6- Base)-2-fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methylpyrrolidin-2-yl) ethyoxyl) quinazoline-6- Base)-2-fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-2-base) ethyoxyl) quinazoline-6-base)- 2-fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-2-base) ethyoxyl) quinazoline-6-base)- 2-fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-3-base) ethyoxyl) quinazoline-6-base)- 2-fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-3-base) ethyoxyl) quinazoline-6-base)- 2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

N-(4-(3-bromoanilino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

(S)-N-(4-((3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)- 2-chloroacrylamide.

According to an embodiment of the invention, quinoline described in Formulas I or quinazoline derivant, it is pharmaceutically acceptable Salt, quinoline or quinazoline derivant or the enantiomer of its salt, diastereomer, tautomer, raceme, solvation Thing, metabolic precursor thereof or prodrug are the quinazoline derivant as shown in Formula Il:

Wherein,

X is halogen；R₁For substituted C_6～10Aryl, described in be substituted by by halogen, substituted or unsubstituted C_1～3Alkoxyl and Substituted or unsubstituted C_5～8One or more in heteroaryloxy replace；R₂For substituted or unsubstituted C_1～3Alkoxyl or 3～8 Unit's heterocyclic oxy group；R₃And R₄It is each independently hydrogen or substituted or unsubstituted C_1～3Alkyl；

X is preferably F or Cl；

R₁In, when described be substituted by halogen time, described halogen is preferably F, Cl or Br；

R₁In, it is substituted by substituted C when described_1～3During alkoxyl, described substituted C_1～3Alkoxyl be replaced further or Unsubstituted C_5～6Aryl, substituted or unsubstituted C_5～6Heteroaryl or 3～6 yuan of cycloalkyl substituted；Wherein, described substituted C_5～6 Aryl or substituted C_5～6Heteroaryl is replaced by halogen (preferably F) the most further；Preferably, described C_5～6Aryl is phenyl, institute State C_5～6Heteroaryl is pyridine radicals, and described 3～6 yuan of cycloalkyl are cyclopropyl；

R₁In, it is substituted by substituted C when described_5～8During heteroaryloxy, described substituted C_5～8Heteroaryloxy further by C_1～3Alkyl (preferably methyl) replaces；Described C_5～8Heteroaryloxy is preferably the C containing 1 nitrogen-atoms_5～8Heteroaryloxy, enters one Step is preferably pyridine radicals or indyl, more preferably pyridine radicals；

R₂In, described substituted C_1～33～8 yuan of heterocyclic radicals, replacements that alkoxyl is substituted or unsubstituted further or do not take The amino in generation, halogen or C_1～3Alkoxyl replaces；

R₂In, as described substituted C_1～3When 3～8 yuan of heterocyclic radicals that alkoxyl is substituted or unsubstituted further replace, institute Stating substituted 3～8 yuan of heterocyclic radicals can be further by C_1～5Alkyl (preferably C_1～3Alkyl, more preferably methyl or ethyl) replace； Described 3～8 yuan of heterocyclic radicals are preferably pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, more preferably piperidyl or morpholinyl；

R₂In, as described substituted C_1～3When the amino that alkoxyl is substituted or unsubstituted further replaces, described substituted Amino can be further by 1～2 C_1～5Alkyl (preferably C_1～3Alkyl, more preferably methyl or ethyl) replace；

R₂In, as described substituted C_1～3When alkoxyl is optionally substituted by halogen further, described halogen is preferably F or Cl, more excellent Elect F as；

R₂In, as described substituted C_1～3Alkoxyl is further by C_1～3When alkoxyl replaces, described C_1～3Alkoxyl is preferred For methoxyl group；

R₂In, described 3～8 yuan of heterocyclic oxy groups are preferably 3～8 yuan of heterocyclic oxy groups containing oxygen atom, more preferably Tetrahydrofuran base epoxide, more preferably 3S-tetrahydrofuran base epoxide；

R₃And R₄In, described substituted C_1～3Amino that alkyl can be substituted or unsubstituted further or 3～8 yuan of heterocyclic radicals Replace；Wherein, described substituted amino can be further by 1～2 C_1～3Alkyl (preferably methyl) replaces；Described 3～8 yuan miscellaneous Ring group is preferably 3～8 yuan of heterocyclic radicals, more preferably piperidyls containing 1 nitrogen-atoms；

Further, the quinazoline derivant shown in Formula II, its pharmaceutically acceptable salt, quinazoline derivant or its salt right Reflect isomer, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug and do not include following structure Compound:

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-fluoropropene amide；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

According to another implementation of the invention, quinoline described in Formulas I or quinazoline derivant, it is pharmaceutically acceptable Salt, quinoline or quinazoline derivant or the enantiomer of its salt, diastereomer, tautomer, raceme, solvent Compound, metabolic precursor thereof or prodrug are quinoline shown in following formula III:

Wherein,

X is preferably F or Cl；

R₁In, it is substituted by substituted C when described_5～8During heteroaryloxy, described substituted C_5～8Heteroaryloxy further by C_1～3Alkyl (preferably methyl) replaces；Described C_5～8Heteroaryloxy is preferably the C containing 1 nitrogen-atoms_5～8Heteroaryloxy, enters one Step is preferably pyridine radicals or indyl；

R₂It is preferably ethyoxyl；

R₃And R₄In, described substituted C_1～3Amino that alkyl can be substituted or unsubstituted further or 3～8 yuan of heterocyclic radicals Replace；Wherein, described substituted amino can be further by 1～2 C_1～3Alkyl (preferably methyl) replaces；Described 3～8 yuan miscellaneous Ring group is preferably 3～8 yuan of heterocyclic radicals, more preferably piperidyls containing 1 nitrogen-atoms.

As one of the present invention preferred embodiment, R₁It is the C at least containing 1 halogen_6～10Aryl；It is preferred that R₁ It it is the phenyl at least containing 1 halogen；More preferably,With halogen at R₁On each other in meta replace.

As the present invention another preferred embodiment, R₂For C_1～3Alkoxyl.

As the present invention another preferred embodiment, R₃And R₄In at least 1 be hydrogen；It is preferred that work as R₃And R₄ In only have 1 when being hydrogen, X is fluorine, works as R₃And R₄When being hydrogen, X is fluorine or chlorine.

Described quinoline shown in formula I or quinazoline derivant, its pharmaceutically acceptable salt, quinoline or quinazoline derivative Thing or the enantiomer of its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are excellent Select following situation: R₁For substituted C_6～10Aryl, described in be substituted by by halogen and/or substituted or unsubstituted C_1～3Alkoxyl takes Generation (described substituted C_1～3Alkoxyl can be further by C_5～6Heteroaryl replaces, described C_5～6Heteroaryl preferred 2-pyridine radicals)；R₂ For C_1～3Alkoxyl (preferably ethyoxyl)；R₃And R₄It is each independently hydrogen or substituted or unsubstituted C_1～3Alkyl (described replacement C_1～33～8 yuan of heterocyclic radicals or substituted or unsubstituted amino that alkyl can be substituted or unsubstituted further replace, wherein, and institute State substituted 3～8 yuan of heterocyclic radicals or substituted amino also can be further by C_1～3Alkyl replaces).

An embodiment more preferably as the present invention:

As Z=N, R₁Preferably

As Z=N, R₂Preferably methoxyl group, ethyoxyl, 3S-tetrahydrofuran base epoxide, 2-(N-methyl-4-piperidyl) ethoxy Base, 3-(4-morpholinyl) propoxyl group, 2-(N, N-lignocaine)-ethyoxyl, 2,2,2-trifluoro ethoxies or 2-(methoxyl group)-second Epoxide.

As Z=N, R₃And R₄Independently of one another preferably hydrogen,

As Z=C-CN, R₁It is preferably

As Z=C-CN, R₂It is preferably ethyoxyl.

As Z=C-CN, R₃And R₄It is preferably hydrogen, N, N-dimethylamino methyl or piperidino methyl independently of one another.

A most preferred embodiment as the present invention:

Work as Z=N, R₁During for 3-chloro-4-fluorophenyl, R₂It is preferably 3S-tetrahydrofuran base epoxide, 2-(N-methyl-4-piperidines Base) ethyoxyl, 2-(N, N-diethylamino)-ethyoxyl, 2,2,2-trifluoro ethoxy, 2-(methoxyl group)-ethyoxyl or ethoxy Base；R₃And R₄It is preferably hydrogen or piperidino methyl, more preferably R independently of one another₃And R₄In one be hydrogen, another is hydrogen Or piperidino methyl.

Work as Z=N, R₁During phenyl bromo-for 3-orTime, R₂It is preferably methoxyl group；R₃And R₄The most independent Ground is preferably hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R₃And R₄In one be hydrogen, another is 1- Piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R₁ForTime, R₂It is preferably ethyoxyl；R₃And R₄The most solely On the spot it is preferably hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R₃And R₄In one be hydrogen, another is Piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R₁ForTime, R₂It is preferably ethyoxyl or 3-(4-morpholinyl) propoxyl group；R₃And R₄Respectively From being preferably hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R independently₃And R₄In one be hydrogen, another Individual for hydrogen, piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R₁ForTime, R₂It is preferably 3-(4-morpholinyl) propoxyl group；R₃And R₄Independently of one another It is preferably hydrogen.

Work as Z=C-CN, R₁During for 3-chloro-4-fluorophenyl, R₂It is preferably as ethyoxyl；R₃And R₄It is preferably independently of one another Hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R₃And R₄In one be hydrogen, another is hydrogen, N, N-diformazan Amino methyl or piperidino methyl；

Work as Z=C-CN, R₁For the bromo-phenyl of 3-, Time, R₂It is preferably ethyoxyl；R₃And R₄It is hydrogen.

Work as Z=C-CN, R₁ForTime, R₂It is preferably ethyoxyl；R₃And R₄It is preferably hydrogen independently of one another Or N, N-dimethylamino methyl, more preferably R₃And R₄In one be hydrogen, another is hydrogen or N, N-dimethylamino methyl；

Work as Z=C-CN, R₁ForTime, R₂It is preferably ethyoxyl；R₃And R₄It is hydrogen.

Described quinoline shown in formula I or quinazoline derivant, its pharmaceutically acceptable salt, quinoline or quinazoline derivative Thing or the enantiomer of its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are excellent Select following 1～41 arbitrary compounds:

In above-claimed cpd 1～41, containing "Key " compound refer to that this compound is cis Yu trans mixing Thing.

Present invention also offers a kind of quinoline the most shown in formula I as above or quinazoline derivant, it pharmaceutically may be used The salt accepted, quinoline or quinazoline derivant or the enantiomer of its salt, diastereomer, tautomer, raceme, The preparation method of solvate, metabolic precursor thereof or prodrug, it is following either method:

Method one comprises the steps:, 1. in solvent, under the effect of alkali 1, to be reacted with compound B by compound A, Obtain compound C,；2., in solvent, under the effect of alkali 2, product C step 1. obtained reacts with compound D, Obtain compound I；

Method two comprises the steps: in solvent, under the effect of alkali 1, is reacted with compound E by compound A, To compound I；

Wherein, R₁、R₂、R₃、R₄、R₅, Z and X all as described above, R and R ' is each independently C_1～6Alkyl (preferably C_1～3Alkane Base).

1. method one step preferably includes following steps: compound A and alkali 1 is mixed and is dissolved in solvent ,-10 DEG C～10 React 15～60 minutes at DEG C, then mix with the solution of compound B, carry out reacting at 0 DEG C～80 DEG C.

Method one step 1. in, the solvent in the solution of described compound B is identical or different with the solvent of this reaction.Described The preferred N,N-dimethylformamide of solvent (DMF) in the solution of compound B, DMSO, CH₂Cl₂And CHCl₃In one or many Kind.

Method one step 1. in, the preferred DMF of described solvent (DMF), DMSO, CH₂Cl₂And CHCl₃In One or more.The consumption of described solvent does not the most affect being normally carried out of reaction, preferably 10～100ml/g compound A。

Method one step 1. in, described alkali 1 can be organic base or inorganic base.The preferred triethylamine of described organic base, N, N-bis- Wopropyl ethyl amine, pyridine or DMAP.The preferred sodium hydroxide of described inorganic base, potassium hydroxide, Lithium hydrate, carbonic acid Potassium, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.The mol ratio of described alkali 1 and compound A is preferably 1.0: 1～3.0:1.

Method one step 1. in, preferred 1.0:1～2.0:1 of mol ratio of compound B and compound A.

Method one step 1. in, the temperature of described reaction preferably 0 DEG C～50 DEG C.

Method one step 1. in, the process of described reaction can be monitored by TLC or HPLC, typically disappears with compound A Miss the season as the terminal reacted.

Method one step 1. in, after described reaction terminates, be further purified product also by last handling process.After described Processing procedure preferably includes following steps: cancellation is reacted, extractive reaction system, is dried organic facies, concentrates and carry out column chromatography.Institute State cancellation reaction preferably to carry out with alkaline aqueous solution.The condition of described column chromatography and step all can be by the column chromatographies of this area routine Condition and step select.

2. method one step preferably includes following steps: is mixed with compound D by compound C and is dissolved in solvent ,-10 DEG C ～react 30～60 minutes at 15 DEG C, then with the aqueous solution of alkali 2, react 0.5～24 hour at 10 DEG C～30 DEG C.

Method one step 2. in, one or more in described solvent preferred alcohol, methanol and isopropanol.Described solvent Consumption does not generally affect being normally carried out of reaction.

Method one step 2. in, the described preferred inorganic base of alkali 2.The preferred sodium hydride of described inorganic base, hydrofining, hydroxide Sodium, potassium hydroxide, Lithium hydrate, Feldalat NM, Sodium ethylate, potassium tert-butoxide or sodium tert-butoxide.Described alkali 2 and compound C mole Than preferred 1:1～10:1.

Method one step 2. in, preferred 1:1～5:1 of mol ratio of described compound D and compound C.

Method one step 2. in, if containing amino in compound D, described compound D can participate in reaction by the form of salt. Wherein, the preferred hydrochlorate of the salt of compound D.

Method one step 2. in, the process of described reaction can be monitored by TLC or LC-MS, typically disappears with compound C Miss the season as the terminal reacted.

Method one step 2. in, after described reaction terminates, be further purified product also by last handling process.After described Processing procedure preferably includes following steps: by the pH regulator of reaction system to less than 3.0, mixes with water after removing solvent, then will The pH regulator of system, to more than 10.0, extracts, and is dried organic facies, concentrates and carry out column chromatography purification.Described pH regulator to 3.0 with Under regulator be preferably inorganic aqueous acid, such as the aqueous hydrochloric acid solution of 4mol/L.The tune of described pH regulator to more than 10.0 The aqueous solution of the joint preferred inorganic base of agent, such as the sodium hydrate aqueous solution of 2mol/L.The organic solvent preferred acetic acid second of described extraction Ester.Described dry time use desiccant be preferably anhydrous sodium sulfate.Described column chromatography can be the column chromatography that this area is conventional, its Step and condition all can select according to conventional step and condition.

In method two, described reaction preferably includes following steps: mixed with solvent by compound A, obtains solution ,-10 DEG C～0 At DEG C, stir 5～10 minutes, be then added in the solution of compound E, then in system, add alkali 1, react 30～40 minutes, It is warming up to 10 DEG C～50 DEG C carry out reacting.

One or more in method two, in the preferred dichloromethane of described solvent, chloroform and dichloroethanes.Described molten The consumption of agent does not the most affect the carrying out of reaction.

In method two, described alkali 1 can be organic base or inorganic base.The preferred triethylamine of described organic base, N, N-diisopropyl Ethamine, pyridine or DMAP.The preferred sodium hydroxide of described inorganic base, potassium hydroxide, Lithium hydrate, potassium carbonate, carbon Acid sodium, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.Preferred 2:1～4:1 of mol ratio of described alkali 1 and compound A.

In method two, the temperature of described reaction preferably-10 DEG C～50 DEG C, more preferably 0 DEG C～30 DEG C.

In method two, the process of described reaction can be monitored by TLC or LC-MS, makees when typically disappearing with compound A Terminal for reaction.

In method two, after described reaction terminates, it is further purified product also by last handling process.Described post processing Journey preferably includes following steps: carry out column chromatography purification after concentrating reaction system.Described column chromatography can be the post that this area is conventional Chromatography, its step and condition can be selected by the step of this area routine and condition.

In described method one and method two, if the mixture that product I is cis-trans-isomer obtained, then can pass through chiral column The cis or trans product I that isolated is pure further.Described chiral column preferred AD-H chiral column.

Present invention also offers a kind of compound as shown in formula C,

Wherein, R₁、R₂, R, R ', X and Z all as described above.

Present invention also offers containing above-mentioned compound of formula I or its pharmaceutically acceptable salt, or their solvate Pharmaceutically useful compositions.

Wherein, described compositions is by one or more compound of formula I, or its pharmaceutically acceptable salt, or they Solvate forms with at least one pharmaceutic adjuvant.The selection of pharmaceutic adjuvant is different because of route of administration and action character, generally may be used For filler, diluent, binding agent, wetting agent, disintegrating agent, lubricant, emulsifying agent or suspending agent etc..

The pharmaceutical composition of the present invention can by oral, injection (in vein, muscle, subcutaneous and coronary artery), Sublingual, Buccal, per rectum, per urethra, transvaginal, per nasal, suction or topic route are used, and optimization approach is oral.

Present invention also offers above-mentioned compound of formula I or aforementioned pharmaceutical compositions at preparation EGFR tyrosine-kinase enzyme level Application in the medicine of agent, A431 or H1975 inhibition of cell proliferation or prevention or treatment tumor disease.

On the basis of common sense in the field, above-mentioned each optimum condition, can combination in any, obtain each preferable reality of the present invention Example.

Agents useful for same of the present invention and raw material are the most commercially.

The most progressive effect of the present invention is: the invention provides the new quinoline of a class or quinazoline derivant, its medicine Effect is learned embodiment test data and is shown: it is inhibited to EGFR tyrosine kinase, has bright to A431 and H1975 cell Aobvious Inhibit proliferaton activity.

Some technical terms of chemistry related in the present invention are explained as follows:

“C_1～3" refer to that in group defined in it (such as alkyl, alkoxyl, aryl, heteroaryl etc.), carbon atom number is 1,2 Or 3.Thus can deduce the implication of other terms described in a similar manner, such as " C_1～5”“C_6～10" etc..

" 3～8 yuan " refer to that surrounding this in its defined Guan Bi ring system group (such as heterocyclic radical, aryl, heteroaryl etc.) closes The atom number of cyclization skeleton itself is 3,4,5,6,6,7 or 8, can be according to the Guan Bi number of rings of ring system group, saturation and structure Atomic property becoming this ring etc. and take different numbers.Thus can deduce the implication of other terms described in a similar manner, as " 3～6 yuan ", " 4～6 yuan " etc..

" alkyl " refer to only to be made up of carbon atom and hydrogen atom, without unsaturated bond, have such as 1 to 12 carbon atom and By the hydrocarbon chain radical of the straight or branched that singly-bound is connected with the remainder of molecule.Generally, the example of alkyl includes but does not limits In methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 2-methyl butyl, 2,2- Dimethyl propyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl group, nonyl and decyl etc..

" alkoxyl " refers to formula-OR_aGroup, wherein R_aFor " alkyl " as defined above.Generally, the example of alkoxyl Include but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tertiary fourth Epoxide etc..

" cycloalkyl " refers to stable non-aromatic monocyclic or the multi-ring alkyl being only made up of carbon atom and hydrogen atom, can wrap Include fused ring system, bridged-ring system or spiro ring system, be generally of 3 to 15 carbon atoms.It can be via any suitable on ring Carbon atom is connected with the remainder of molecule by singly-bound.Generally, the example of cycloalkyl includes but not limited to cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, ring octyl group etc..For purposes of the invention, preferably there is the list of 3 to 6 carbon atoms The cycloalkyl of member ring systems.

" heterocyclic radical " refers to be collectively constituted selected from the hetero atom of nitrogen, oxygen and sulfur by 2 to 14 carbon atoms and 1 to 6 Stable 3 yuan are to 20 yuan of non-aromatic cyclic groups, and it can be monocycle, dicyclo, the member ring systems of three rings or more multi-ring, it is possible to bag Include fused ring system, bridged-ring system or spiro ring system.It can pass through single via carbon atom or the hetero atom of any suitable on ring Key is connected with the remainder of molecule.Nitrogen-atoms therein can optionally be further substituted with forming tertiary amine or quaternary ammonium by other groups Structure.Generally, the example of heterocyclic radical include but not limited to aziridinyl, azelidinyl, oxetanylmethoxy, pyrrolidinyl, Imidazolinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, tetrahydrofuran base, dioxolanes Base, oxacyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazine base, N-replacement homopiperazine base, piperidyl, N-take For piperidyl, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc..With regard to the purpose of the present invention Speech, preferably 3 yuan to 8 yuan and at least contain the heterocyclic radical of 1 heteroatomic single ring systems being selected from nitrogen or oxygen, further preferred 4 Unit is to 6 yuan and at least contain the heterocyclic radical of 1 heteroatomic single ring systems being selected from nitrogen or oxygen, and more preferably 4 yuan to 6 yuan and contain 1～2 selected from nitrogen or the heterocyclic radical of the heteroatomic single ring systems of oxygen.

" heterocyclic oxy group " refers to formula-OR_bGroup, wherein R_bFor " heterocyclic radical " as defined above.Generally, heterocyclic oxy group Example include but not limited to pyrrolidinyl epoxide, tetrahydrofuran base epoxide, dioxolanyl epoxide, morpholinyl epoxide, piperazine Base epoxide, piperidyl epoxide etc..

" aryl " or " aromatic ring " refers to the conjugation armaticity hydrocarbon ring system group with 6 to 18 carbon atoms, can be single Ring, dicyclo, three rings or more polycyclic system.It can be connected with the remainder of molecule by singly-bound via the atom on aromatic rings. Generally, the example of aryl includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl etc..For purposes of the invention, preferably There is the monocycle of 6 to 10 carbon atoms or the aryl of bicyclic system or aromatic ring.

" heteroaryl " or " hetero-aromatic ring " refers to be total to by 1 to 15 carbon atom and 1 to 6 hetero atom selected from nitrogen, oxygen and sulfur With 5 yuan to 16 yuan conjugation armaticity ring system groups of composition, can be monocycle, dicyclo, three rings or more polycyclic system, it can be via Atom on aromatic rings is connected with the remainder of molecule by singly-bound.Generally, the example of heteroaryl includes but not limited to pyrroles Base, furyl, thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, di azoly, isoxazolyl, triazol radical, four nitrogen Oxazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, indyl, isoindolyl, indazolyl, benzimidazolyl, BTA Base, quinolyl, isoquinolyl, benzothiazolyl, benzo pyridazinyl, quinazolyl, quinoxalinyl etc..With regard to the purpose of the present invention Speech, preferably 5 to 8 yuan and at least contain the monocycle of 1 nitrogen-atoms or the heteroaryl of bicyclic system or hetero-aromatic ring.

" heteroaryloxy " refers to formula-OR_cGroup, wherein R_cFor " heteroaryl " as defined above.Generally, heteroaryloxy Example include but not limited to furan epoxide, thiophene oxy, pyridyloxy, 2-pyrimidinyl oxy, indoxyl, quinoline oxy etc..

Detailed description of the invention

Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to described reality Execute among example scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product description selects.

Embodiment 1

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2- The preparation of fluorine but-2-enamides

Step 1 4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-6-(2-fluoro-2-diethoxy phosphate acetyl) ammonia The preparation of base-7-methoxyquinazoline hydrochloride

Raw material: ((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride presses document to 6-amino-4- Prepared by J.Med.Chem.2009,52,6880-6888 method.

Raw material: 2-fluoro-2-diethoxy phosphoryl chloroacetic chloride presses document Heterocycles, 2004,63,699-706 side Prepared by method.

By 6-amino-4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride (1eq.) (876mg) and Triethylamine (1.5eq.) (423 μ L) is dissolved in DMF (10ml), and this solution stirs 30min at 0 DEG C.By fluoro-for 2-2-diethoxy DMF (5ml) solution of phosphoryl chloroacetic chloride (1.5eq.) (640 μ L) is slowly dropped in above-mentioned solution, stirs the most at room temperature Mix reaction overnight.After reaction terminates, use saturated NaHCO₃Cancellation, EtOAc extracts, and organic facies is dried with anhydrous sodium sulfate, decompression It is concentrated to dryness to obtain crude product, obtains flaxen 4-((the chloro-4-of 3-(3-fluorine benzyloxy through column chromatography purification (flowing phase 40:1DCM/MeOH) Base) phenylamino)-6-(2-fluoro-2-diethoxy phosphate acetylamino)-7-methoxyquinazoline hydrochloride solid 0.621g.

¹H NMR(500MHz,DMSO)δ9.84(s,1H),9.66(s,1H),8.86(s,1H),8.50(s,1H),7.94 (s,1H),7.66(d,J=8.0Hz,1H),7.48-7.46(m,1H),7.34-7.31(m,3H),7.25(d,J=9.0Hz,1H), 7.19(t,J=8.0Hz,1H),6.03(dd,J=45.0,11.0Hz,1H),5.26(s,2H),4.20(q,J=7.0Hz,4H), 4.02(s,3H),1.31-1.26(m,6H)。HRMS(ESI):m/z calcd for(C₂₈H₂₈ClF₂N₄O₆P+H)⁺:621.1481; found:621.1475。

Step 2 N-4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan ammonia Base) preparation of-2-fluorine but-2-enamides

Raw material: 2-(dimethylamino)-acetaldehyde Asia hydrochlorate is prepared by document WO2007/85638 method.

By upper step product 4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-6-(2-fluoro-2-diethoxy phosphate acetyl Amino)-7-methoxyquinazoline hydrochloride (1eq.) (150mg) and 2-(dimethylamino)-acetaldehyde hydrochlorate (2.0eq.) (71mg), it is dissolved in In EtOH (10ml), stir 30min in 0 DEG C, add NaOH (112mg) and be dissolved in the solution of water (1mL), remove ice bath, natural Recover to room temperature, continue stirring reaction 0.5h.After reaction terminates, adjust pH to 1.0 with 4N hydrochloric acid, be spin-dried for solvent, add water, use Regulation pH to 12.0, the EtOAc extraction of 2NNaOH solution, organic facies is dried with anhydrous sodium sulfate, is evaporated to do to obtain crude product, warp Column chromatography purification (flowing phase 30:1DCM/MeOH) obtains flaxen N-4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-first Epoxide quinazoline-6-base)-4-(dimethylamino)-2-fluorine but-2-enamides 0.1g.

HRMS(ESI):m/z calcd for(C₂₈H₂₆ClF₂N₅O₃+H)+:554.1770;

LC/MS:

Peak 1 RT=5.32min,[M+H]+=554.1780

Peak 2 RT=5.38min,[M+H]+=554.1784

Rf value: 0.53,0.56(silica gel, methylene chloride/methanol=10:1；Two isomers are separately)

Embodiment 2

(Z)-N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan ammonia Base)-2-fluorine but-2-enamides and (E)-N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyquinazoline hydrochloride-6- Base) preparation of-4-(dimethylamino)-2-fluorine but-2-enamides sum

Use Thar SFC Pre80 Overcritical prepared chromatographic instrument that the mixture of the cis-trans-isomer that embodiment 1 obtains is entered Row separates.

Chromatographic column: AD-H (20 × 250mm, 5 μm, Tianjin Agela)

Monitoring wavelength: 254nm

Column temperature: 38 degree

Sample dissolves: methanol dissolves, and filters

Flowing phase: ethanol (containing 0.1%DEA): carbon dioxide=40:60

Collect retention time 5.09min component and obtain (Z)-type isomer (compound 2-1)；Retention time 8.61min component Obtain (E)-type isomer (compound 2-2).

(Z)-type isomer

¹H NMR(400MHz,DMSO)δ9.75(s,1H),9.69(s,1H),8.68(s,1H),8.53(s,1H),7.99 (d,J=2.8Hz,1H),7.71(dd,J=9.2,2.8Hz,1H),7.50-7.44(m,1H),7.34-7.30(m,3H),7.25 (d,J=9.2Hz,1H),7.20-7.16(m,1H),6.19(dt,J=36.0,7.2Hz,1H),5.25(s,2H),3.99(s, 3H),3.18-3.15(m,2H),2.19(s,6H)。

(E)-type isomer

¹H NMR(400MHz,DMSO)δ10.92(s,1H),9.70(s,1H),8.78(s,1H),8.51(s,1H),7.97 (d,J=2.4Hz,1H),7.69(dd,J=8.8,2.8Hz,1H),7.50-7.44(m,1H),7.34-7.30(m,3H),7.25 (d,J=9.2Hz,1H),7.21-7.16(m,1H),6.11(dt,J=23.6,6.8Hz,1H),5.25(s,2H),4.01(s, 3H),3.37(s,2H),2.23(s,6H)。

Embodiment 3～11

According to embodiment 1 same procedure, using different raw materials, prepare following compound, the product obtained is suitable Trans mixtures of isomers.

Embodiment 12～17

According to SFC equipment described in embodiment 2, the compound (cis-trans-isomer mixture) that embodiment 4,6 and 11 is obtained Separate respectively, prepare following compound:

Embodiment 18

(S)-N-(4-(3-chloro-4-Fluorophenylamino)-7-(oxolane-3-epoxide) quinazoline-6-base)-2-fluoropropene The preparation of amide

The preparation of step 1 4-(3-chloro-4-Fluorophenylamino)-6-nitro-7-(oxolane-3S-epoxide) quinazoline

Raw material: 6-nitro-4-(3-chloro-4-Fluorophenylamino)-7-Fluquinconazole quinoline presses document J.Med.Chem.2009,52, Prepared by 6880-6888 method.

By 6-nitro-4-(3-chloro-4-Fluorophenylamino)-7-Fluquinconazole quinoline (1eq.) (3.03g) and S-oxolane-3- Alcohol (1.5eq.) (1.2ml) is dissolved in DMSO (10ml), and this solution stirs 5min under water bath condition.By potassium tert-butoxide (3.0eq.) DMSO (5ml) solution of (3.36g) is slowly dropped in above-mentioned solution, the most at room temperature stirring reaction 30min. After reaction terminates, add the dilution of 100ml water, with concentrated hydrochloric acid regulation pH to neutral, stir 30min, separate out a large amount of yellow solid, mistake Filter, filter cake is washed twice with water, be dried to obtain yellow 4-(3-chloro-4-Fluorophenylamino)-6-nitro-7-(oxolane- 3S-epoxide) quinazoline solid 6.53g.¹H NMR(500MHz,DMSO)δ10.18(s,1H),9.23(s,1H),8.69(s, 1H),8.17(dd,J=6.5,2.5Hz,1H),7.82-7.79(m,1H),7.50-7.46(m,2H),5.46(t,J=5.5Hz, 1H),3.98(dd,J=10.5,4.5Hz,1H),3.92-3.84(m,2H),3.83-3.78(m,1H),2.39-2.32(m,1H), 2.10-2.05(m,1H).HRMS(ESI):m/z calcd for(C₁₈H₁₄ClFN₄O₄+H)⁺:405.0766;found: 405.0775.

The preparation of step 2 4-(3-chloro-4-Fluorophenylamino)-6-amino-7-(oxolane-3S-epoxide) quinazoline

By upper step product 4-(3-chloro-4-Fluorophenylamino)-6-nitro-7-(oxolane-3S-epoxide) quinazoline (1eq.) (4.04g) and NiCl₂6H₂O (2.0eq.) (4.75g) is dissolved in DCM/MeOH (32ml:8ml), stirs 5min in 0 DEG C, It is dividedly in some parts NaBH₄(4.0eq.) (1.51g), removes ice bath, after clear-cutting forestland to room temperature, continues stirring reaction 30min.Reaction After end, being evaporated to do to obtain crude product, through column chromatography purification (flowing phase 10:1DCM/MeOH), (3-is chloro-to obtain flaxen 4- 4-Fluorophenylamino)-6-amino-7-(oxolane-3-epoxide) quinazoline 3.6g.¹H NMR(500MHz,DMSO)δ10.26 (s,1H),8.56(s,1H),8.11(s,1H),7.76(s,1H),7.57(s,1H),7.46(t,J=9.0Hz,1H),7.24(s, 1H),5.70(s,2H),5.22(s,1H),4.02-3.99(m,2H),3.95-3.91(m,1H),3.81-3.80(m,1H), 2.36-2.32(m,1H),2.15-2.13(m,1H).HRMS(ESI):m/z calcd for(C₁₈H₁₆ClFN₄O₂+H)+: 375.1024;found:375.1012.

Step 3 (S)-N-(4-(3-chloro-4-Fluorophenylamino)-7-(oxolane-3-epoxide) quinazoline-6-base)-2- The preparation of fluoropropene amide

2-perfluoroalkyl acrylate (2.0eq.) (54mg) is dissolved in DCM (10ml), adds 3 DMF, under condition of ice bath, drip Add oxalyl chloride (1.7eq.) (44 μ L), under condition of ice bath, react 30min, remove ice bath, clear-cutting forestland to room temperature, reacts 2 Individual hour, by upper step product 4-(3-chloro-4-Fluorophenylamino)-6-amino-7-(oxolane-3-epoxide) quinazoline (1eq.) (112mg) it is dissolved in DCM (20ml), stirs 5min in 0 DEG C, add to above-mentioned solution of acid chloride, add Et₃N(4.0eq.) (169 μ L), reacts 30min under condition of ice bath, removes ice bath, after clear-cutting forestland to room temperature, continues stirring reaction overnight.Reaction After end, it is evaporated to do to obtain crude product, obtains flaxen N-(4-(3-through column chromatography purification (flowing phase 10:1DCM/MeOH) Chloro-4-Fluorophenylamino)-7-(oxolane-3-epoxide) quinazoline-6-base)-2-fluorine but-2-enamides 80mg.¹H NMR (500MHz,DMSO)δ9.86(s,1H),9.79(s,1H),8.73(s,1H),8.58(s,1H),8.17-8.16(m,1H), 7.82-7.80(m,1H),7.45(t,J=9.0Hz,1H),7.32(s,1H),5.77(dd,J=48.5,3.5Hz,1H),5.52 (dd,J=16.0,4.0Hz,1H),5.33(brs,1H),4.01-3.98(m,1H),3.88-3.85(m,2H),3.82-3.78 (m,1H),2.34-2.30(m,1H),2.07-2.04(m,1H).HRMS(ESI):m/z calcd for(C₂₁H₁₇ClF₂N₄O₃+ H)+:447.1035;found:447.1035.

Embodiment 19～25

According to embodiment 18 same procedure, use different raw materials, prepare following compound.

Embodiment 26

The preparation of N-(4-(3-chloro-4-Fluorophenylamino)-3-cyano group-7-ethoxy quinoline-6-base)-2-fluoropropene amide

The preparation of step 1 4-(3-chloro-4-Fluorophenylamino)-3-cyano group-6-amino-7-ethoxy quinoline

Raw material: N-(4-(3-chloro-4-Fluorophenylamino)-3-cyano group-7-ethoxy quinoline-6-base) acetamide presses document Prepared by J.Med.Chem.2005,48,1107-1131 method.

By N-(4-(3-chloro-4-Fluorophenylamino)-3-cyano group-7-ethoxy quinoline-6-base) acetamide (1eq.) (0.6g) being dissolved in concentrated hydrochloric acid 10ml, back flow reaction overnight, after reaction terminates, is evaporated to do to obtain crude product, pure through column chromatography Change (flowing phase 10:1DCM/MeOH) and obtain flaxen 4-(3-chloro-4-Fluorophenylamino)-3-cyano group-6-amino-7-ethyoxyl Quinoline 0.5g.¹H NMR(500MHz,DMSO)δ9.28(s,1H),8.38(s,1H),7.34(t,J=9.0Hz,1H),7.26 (dd,J=6.5,2.5Hz,1H),7.21(s,1H),7.17(s,1H),7.07-7.04(m,1H),5.55(brs,2H),4.22 (q,J=7.0Hz,2H),1.43(t,J=7.0Hz,3H).HRMS(ESI):m/z calcd for(C₁₈H₁₄ClFN₄O+H)+: 357.0918;found:357.0911.

Step 2N-(4-(3-chloro-4-Fluorophenylamino)-3-cyano group-7-ethoxy quinoline-6-base)-2-fluoropropene amide Preparation

2-perfluoroalkyl acrylate (2.0eq.) (40mg) is dissolved in DCM (10ml), adds 3 DMF, under condition of ice bath, drip Add oxalyl chloride (1.8eq.) (33 μ L), under condition of ice bath, react 30min, remove ice bath, clear-cutting forestland to room temperature, reacts 2 Individual hour, by upper step product 4-(3-chloro-4-Fluorophenylamino)-3-cyano group-6-amino-7-ethoxyquin oxazoline (1eq.) (107mg) it is dissolved in DCM (20ml), stirs 5min in 0 DEG C, add to above-mentioned solution of acid chloride, add Et₃N(4.0eq.) (169 μ L), reacts 30min under condition of ice bath, removes ice bath, after clear-cutting forestland to room temperature, continues stirring reaction overnight.Reaction After end, it is evaporated to do to obtain crude product, obtains flaxen N-(4-(3-through column chromatography purification (flowing phase 10:1DCM/MeOH) Chloro-4-Fluorophenylamino)-3-cyano group-7-ethoxy quinoline-6-base)-2-fluoropropene amide, 60mg.¹H NMR(500MHz, DMSO)δ9.82(s,1H),9.68(s,1H),8.75(s,1H),8.59(s,1H),7.53-7.51(m,1H),7.47-7.44 (m,2H),7.30-7.28(m,1H),5.76(dd,J=48.0,3.5Hz,1H),5.52(dd,J=15.5,3.5Hz,1H),4.31 (dd,J=14.5,7.5Hz,2H),1.44(t,J=6.5Hz,3H).HRMS(ESI):m/z calcd for(C₂₁H₁₅ClF₂N₄O₂+ H)+:429.0930;found:429.0933.

Embodiment 27

N-(4-(3-chloro-4-fluoroanilino)-3-cyano group-7-ethoxy quinoline-6-base)-4-(dimethylamino)-2-fluorine butyl- The preparation of 2-acrylamide

Step 1 4-((3-chloro-4-fluoroanilino)-3-cyano group-6-(2-fluoro-2-diethoxy phosphate acetyl) amino- The preparation of 7-ethoxy quinoline

Raw material: ((3-chloro-4-fluoroanilino)-7-ethoxy quinoline presses embodiment 26 method system to 3-cyano group-6-amino-4- Standby.

Raw material: 2-fluoro-2-diethoxy phosphoryl chloroacetic chloride presses document Heterocycles, and 2004,63,699-706 side Prepared by method.

By 3-cyano group-6-amino-4-((3-chloro-4-fluoroanilino)-7-ethoxyquin azoles (1eq.) (308mg) and three second Amine (1.5eq.) (190 μ L) is dissolved in DMF (10ml), and this solution stirs 30min at 0 DEG C.By fluoro-for 2-2-diethoxy phosphinylidyne DMF (5ml) solution of base chloroacetic chloride (1.5eq.) (313mg) is slowly dropped in above-mentioned solution, and stirring is anti-the most at room temperature Should be overnight.After reaction terminates, use saturated NaHCO₃Cancellation, EtOAc extracts, and organic facies is dried with anhydrous sodium sulfate, concentrating under reduced pressure To obtain crude product to doing, to obtain flaxen 4-((3-chloro-4-fluoroanilino)-3-through column chromatography purification (flowing phase 40:1DCM/MeOH) Cyano group-6-(2-fluoro-2-diethoxy phosphate acetyl) amino-7-ethoxy quinoline solid 150mg.¹H NMR(500MHz, DMSO)δ9.85(s,1H),9.47(s,1H),8.92(s,1H),8.59(s,1H),7.49-7.47(m,2H),7.43(t,J= 9.0Hz,1H),7.27-7.24(m,1H),6.06(dd,J=44.5,11.0Hz,1H),4.34(q,J=7.0Hz,2H),4.23- 4.14(m,4H),1.46(t,J=7.0Hz,4H),1.30-1.24(m,6H).

HRMS(ESI):m/z calcd for(C₂₄H₂₄ClF₂N₄O₅P+H)⁺:553.1219;found:553.1205.

Step 2N-(4-(3-chloro-4-fluoroanilino)-3-cyano group-7-ethoxy quinoline-6-base)-4-(dimethylamino)-2- The preparation of fluorine but-2-enamides

By upper step product 4-((3-chloro-4-fluoroanilino)-3-cyano group-6-(2-fluoro-2-diethoxy phosphate acetyl ammonia Base)-7-ethoxy quinoline (1eq.) (105mg) and 2-(dimethylamino)-acetaldehyde hydrochlorate (2.0eq.) (57mg), it is dissolved in EtOH (10ml), in, stir 30min in 0 DEG C, add the aqueous solution of NaOH (90mg), remove ice bath, after clear-cutting forestland to room temperature, continue Continuous stirring reaction 0.5h.After reaction terminates, adjust pH to 1.0 with 4N hydrochloric acid, be spin-dried for solvent, add water, regulate pH with 2NNaOH solution To 12.0, EtOAc extracts, and organic facies is dried with anhydrous sodium sulfate, is evaporated to do to obtain crude product, through (the flowing of column chromatography purification Phase 30:1DCM/MeOH) obtain flaxen N-(4-(3-chloro-4-fluoroanilino)-3-cyano group-7-ethoxy quinoline-6-base)-4- (dimethylamino)-2-fluorine but-2-enamides, 100mg.

HRMS(ESI):m/z calcd for(C₂₄H₂₂ClF₂N₅O₂+H)⁺:486.1508;

LC/MS:

Peak 1 RT=4.98min,[M+H]+=486.1511

Peak 2 RT=5.10min,[M+H]+=486.1503

Rf value: 0.53,0.60(silica gel, methylene chloride/methanol=10:1；Two isomers are separately)

Embodiment 28～29

According to embodiment 27 same procedure, using different raw materials, prepare following compound, following each compound is Cis-trans-isomer mixture.

Embodiment 30

The preparation of N-(4-(3-bromoanilino)-3-cyano group-7-ethoxy quinoline-6-base)-2-chloroacrylamide

The preparation of step 1:N-(4-((3-bromophenyl) amino)-3-cyano group-7-ethoxy quinoline-6-base) acetamide

Raw material: N-(4-chloro-3-cyano group-7-ethoxy quinoline-6-base) acetamide presses document J.Med.Chem.2009,52, Prepared by 6880-6888 method.By N-(4-chloro-3-cyano group-7-ethoxy quinoline-6-base) acetamide 0.61g, m-bromoaniline 0.21ml and pyridine hydrochloride 0.22g joins in 10ml isopropanol, return stirring 16 hours.After reaction terminates, natural Recover to room temperature, sucking filtration, washing, obtain yellow solid, be dried, for next step, productivity 83%.

The preparation of step 2:6-amino-4-(3-bromophenylamino)-7-ethoxy quinoline-3-formonitrile HCN

Upper step product N-(4-chloro-3-cyano group-7-ethoxy quinoline-6-base) acetamide 0.7g is joined 5ml concentrated hydrochloric acid In be stirred at reflux 3 hours, after reaction terminates, clear-cutting forestland, to room temperature, is spin-dried for solvent, washs with saturated sodium bicarbonate, then sucking filtration, Collect yellow solid, be dried, productivity 74.4%.

The system of step 3:N-(4-(3-bromophenylamino)-3-cyano group-7-ethoxy quinoline-6-base)-2-chloroacrylamide Standby

2-chloracrylic acid (2.0eq.) (167mg) is dissolved in DCM (10ml), adds 3 DMF, under condition of ice bath, drip Add oxalyl chloride (1.7eq.) (138 μ L), under condition of ice bath, react 30min, remove ice bath, clear-cutting forestland to room temperature, reacts 2 Individual hour, by molten for upper step product 3-itrile group-6-amino-4-((3-bromophenyl) amino)-7-ethoxy quinoline (1eq.) (300mg) In DCM (20ml), stir 5min in 0 DEG C, add to above-mentioned solution of acid chloride, add Et₃N(4.0eq.) (474 μ L), at ice React 30min under the conditions of bath, remove ice bath, after clear-cutting forestland to room temperature, continue stirring reaction overnight.After reaction terminates, decompression It is concentrated to dryness to obtain crude product, obtains flaxen N-(4-((3-bromophenyl) ammonia through column chromatography purification (flowing phase 10:1DCM/MeOH) Base)-3-cyano group-7-ethoxy quinoline-6-base)-2-chloroacrylamide 80mg, productivity 14%.¹H NMR(500MHz,DMSO-d6) δ9.81(s,1H),9.68(s,1H),8.86(s,1H),8.64(s,1H),7.49(s,1H),7.40(s,1H),7.31(d,J= 5.1Hz,2H),7.22-7.15(m,1H),6.59(d,J=2.3Hz,1H),6.19(d,J=2.3Hz,1H),4.33(q,J= 6.9Hz,2H),1.46(t,J=6.9Hz,3H)。

Embodiment 31

Step 1:N-{4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of 3-]-3-cyano group-7-ethoxy quinoline-6-base }- The preparation of acetamide

By N-(4-chloro-3-cyano group-7-ethoxy quinoline-6-base) the chloro-4-of acetamide 0.658g, 3-(the fluoro-benzyloxy of 3-)- Aniline is (according to Journal of Medicinal Chemistry, 53 (24), 8546-8555;Described in 2010 prepared by method) 0.567g and pyridine hydrochloride 0.262g joins in 20ml isopropanol, return stirring 16 hours.After reaction terminates, natural Recover to room temperature, sucking filtration, washing, obtain brown solid, productivity 77.8%.

The system of step 2:6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of 3-]-7-ethoxy quinoline-3-formonitrile HCN Standby

The step 1 product N-{4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3-is added in a 100ml round-bottomed flask Base]-3-cyano group-7-ethoxy quinoline-6-base }-acetamide 0.3g, it is subsequently adding methanol 10ml, adds 30% potassium hydroxide 10ml, is warming up to backflow.After TLC detection reaction terminates, use saturated NH₄Cl10ml cancellation is reacted, and vacuum is revolved and removed methanol, sucking filtration, 3 times are washed with water after first washing 3 times with saturated sodium bicarbonate solution.It is dried.Product crosses column purification.Obtain yellow solid, productivity 82.8%。

The chloro-N-(4-((3-of step 3:2-chloro-4-((3-luorobenzyl) epoxide) phenyl) amino)-3-cyano group-7-ethoxyquin Quinoline-6-base) preparation of acrylamide

In dry 100ml round-bottomed flask, add 2-chloracrylic acid 0.213g, add 20ml anhydrous methylene chloride, stir Mix, after being subsequently adding 3 DMF, transfer in ice bath.Add oxalyl chloride 148 μ l, continue stirring.Go to continue to stir under ice bath, room temperature After mixing two hours, system is transferred in 50 DEG C of water-baths, stirs 10 minutes, is then transferred in ice bath.

By step 2 product 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-ethoxyquin of 0.445g Quinoline-3-formonitrile HCN dissolves with 10ml anhydrous methylene chloride in 50ml round-bottomed flask, is subsequently poured in above-mentioned solution of acid chloride.Add three Ethamine 760.5 μ l.After reaction overnight, cross post and process.Obtain yellow solid, productivity 25.9%.¹H NMR(500MHz,DMSO-d6) δ9.69(d,J=9.4Hz,2H),8.83(s,1H),8.51(s,1H),7.47(td,J=8.1,6.1Hz,1H),7.44–7.37 (m,2H),7.36–7.29(m,2H),7.24(d,J=2.3Hz,2H),7.18(ddd,J=10.3,8.1,2.6Hz,1H),6.58 (d,J=2.4Hz,1H),6.18(d,J=2.4Hz,1H),5.26(s,2H),4.31(q,J=6.9Hz,2H),1.45(t,J= 6.9Hz,3H)。

Embodiment 32

Step 1 and step 2 are with the step 1 of embodiment 31 and step 2.

The fluoro-N-(4-((3-of step 3:2-chloro-4-((3-luorobenzyl) epoxide) phenyl) amino)-3-cyano group-7-ethoxyquin Quinoline-6-base) preparation of acrylamide

Wherein, in addition to 2-perfluoroalkyl acrylate replaces 2-chloracrylic acid, the method identical with step 3 in embodiment 31 is used And condition, obtain yellow solid, productivity 69.3%.¹H NMR(500MHz,DMSO-d6)δ9.76–9.55(m,2H),8.74(s, 1H),8.51(s,1H),7.52–7.45(m,1H),7.45–7.38(m,2H),7.37–7.30(m,2H),7.25(d,J= 1.6Hz,2H),7.18(ddd,J=10.3,8.1,2.6Hz,1H),5.75(dd,J=48.1,3.8Hz,1H),5.50(dd,J= 15.7,3.8Hz,1H),5.26(s,2H),4.29(q,J=6.9Hz,2H),1.42(s,3H)。

Embodiment 33

Step 1:N-{4-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino]-3-cyano group-7-ethoxy quinoline-6- Base } preparation of-acetamide

Except with the chloro-4-of 3-(pyridine-2-ylmethoxy)-aniline replace the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine with Outward, use the method identical with step 1 in embodiment 31, obtain yellow solid, productivity 81.5%.

Step 2:6-amino-4-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino]-7-ethoxy quinoline-3-first The preparation of nitrile

Except with step 1 product N-{4-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino]-3-cyano group-7-ethoxy Base quinoline-6-base }-acetamide replace embodiment 31 step 2 the raw material N-{4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3- Base]-3-cyano group-7-ethoxy quinoline-6-base } beyond-acetamide, use the method identical with step 2 in embodiment 31, obtain Yellow solid, productivity 97%.

The chloro-N-{4-of step 3:2-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino)-3-cyano group-7-ethoxyquin Quinoline-6-base)] } preparation of acrylamide

Except with step 2 product 6-amino-4-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino]-7-ethyoxyl Quinoline-3-formonitrile HCN replaces raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-of embodiment 31 step 3 Beyond ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 31, obtain yellow solid.Productivity 15.1% 。¹H NMR(500MHz,DMSO-d6)δ9.70(d,J=12.4Hz,2H),8.83(s,1H),8.60(dt,J=4.9,1.2Hz, 1H),8.51(s,1H),7.88(td,J=7.7,1.8Hz,1H),7.59(d,J=7.8Hz,1H),7.50–7.39(m,2H), 7.37(ddd,J=7.6,4.8,1.2Hz,1H),7.27(d,J=8.9Hz,1H),7.22(dd,J=8.8,2.5Hz,1H),6.58 (d,J=2.3Hz,1H),6.18(d,J=2.3Hz,1H),5.29(s,2H),4.31(q,J=6.9Hz,2H),1.45(t,J= 6.9Hz,3H)。

Embodiment 34

Step 1 and step 2 are with the step 1 of embodiment 33 and step 2.

The fluoro-N-{4-of step 3:2-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino)-3-cyano group-7-ethoxyquin Quinoline-6-base)] } preparation of acrylamide

Except with step 2 product 6-amino-4-[the chloro-4-of 3-(pyridine-2-ylmethoxy)-phenyl amino]-7-ethyoxyl Quinoline-3-formonitrile HCN replaces raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-of embodiment 32 step 3 Beyond ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 32, obtain yellow solid.Productivity 43.7% 。¹H NMR(500MHz,DMSO-d6)δ9.67(d,J=20.3Hz,2H),8.74(s,1H),8.60(dt,J=4.9,1.2Hz, 1H),8.50(s,1H),7.88(td,J=7.7,1.8Hz,1H),7.59(d,J=7.8Hz,1H),7.42(d,J=2.2Hz,2H), 7.37(ddd,J=7.6,4.9,1.2Hz,1H),7.29–7.18(m,2H),5.75(dd,J=48.2,3.8Hz,1H),5.50 (dd,J=15.8,3.8Hz,1H),5.29(s,2H),4.29(q,J=7.0Hz,2H),1.43(t,J=6.9Hz,3H)。

Embodiment 35

Step 1 and step 2 are with the step 1 of embodiment 30 and step 2.

Step 3:N-[4-(the bromo-phenyl amino of 3-)-3-cyano group-7-ethoxy quinoline-6-base] the fluoro-acrylamide of-2- Preparation

Except replacing embodiment with step 2 product 6-amino-4-(the bromo-phenyl amino of 3-)-7-ethoxy quinoline-3-formonitrile HCN Raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-ethoxy quinoline-3-formonitrile HCN of 30 steps 3, use 2- Perfluoroalkyl acrylate replaces, beyond 2-chloracrylic acid, using the method identical with step 3 in embodiment 30, obtaining yellow solid.Productivity 53%。¹H NMR(500MHz,DMSO-d6)δ9.79(s,1H),9.61(d,J=2.8Hz,1H),8.78(s,1H),8.64(s, 1H),7.49(s,1H),7.40(d,J=2.2Hz,1H),7.37–7.27(m,2H),7.25–7.15(m,1H),5.76(dd,J= 48.1,3.8Hz,1H),5.51(dd,J=15.7,3.8Hz,1H),4.32(q,J=6.9Hz,2H),1.44(t,J=6.9Hz, 3H)。

Embodiment 36

Step 1:N-{4-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-3-cyano group-7-ethoxy quinoline- 6-yl } preparation of-acetamide

Except with the chloro-4-of 3-(1H-indole-4-base epoxide)-aniline replace the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine with Outward, use the method identical with step 1 in embodiment 31, obtain brown solid, productivity 78%.

Step 2:6-amino-4-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-7-ethoxy quinoline-3-first The preparation of nitrile

Except by step 1 product N-{4-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-3-cyano group-7-second Phenoxyl quinoline-6-base }-acetamide replace embodiment 31 step 2 the raw material N-{4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3- Base]-3-cyano group-7-ethoxy quinoline-6-base } beyond-acetamide, use the method identical with step 2 in embodiment 31, obtain Brown solid, productivity 93.8%.

The chloro-N-{4-of step 3:2-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-3-cyano group-7-ethyoxyl Quinoline-6-base } preparation of-acrylamide

Except with step 2 product 6-amino-4-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-7-ethyoxyl Quinoline-3-formonitrile HCN replaces raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-of embodiment 31 step 3 Beyond ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 31, obtain yellow solid.Productivity 15%.¹H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.87(s,1H),9.69(s,1H),8.88(s,1H),8.59(s,1H), 7.66–7.40(m,2H),7.30(t,J=2.8Hz,1H),7.25–7.06(m,2H),7.01(dt,J=7.9,3.6Hz,2H), 6.60(d,J=2.4Hz,1H),6.49(d,J=7.7Hz,1H),6.32(t,J=2.4Hz,1H),6.19(d,J=2.4Hz,1H), 4.32(q,J=7.0Hz,2H),1.46(t,J=6.9Hz,3H)。

Embodiment 37

Step 1 and step 2 are with the step 1 of embodiment 36 and step 2.

The fluoro-N-{4-of step 3:2-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-3-cyano group-7-ethyoxyl Quinoline-6-base } preparation of-acrylamide

Except with step 2 product 6-amino-4-[the chloro-4-of 3-(1H-indole-4-base epoxide)-phenyl amino]-7-ethyoxyl Quinoline-3-formonitrile HCN replaces raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-of embodiment 32 step 3 Beyond ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 32, obtain yellow solid.Productivity 50.3% 。¹H NMR(400MHz,DMSO-d6)δ11.30(d,J=2.7Hz,1H),9.82(s,1H),9.63(d,J=2.8Hz,1H), 8.79(s,1H),8.57(s,1H),7.52(d,J=2.6Hz,1H),7.45(s,1H),7.34–7.27(m,1H),7.21(dd,J =8.3,4.0Hz,2H),7.09–6.96(m,2H),6.49(d,J=7.7Hz,1H),6.32(t,J=2.5Hz,1H),5.99– 5.65(m,1H),5.52(dd,J=15.7,3.8Hz,1H),4.31(q,J=6.9Hz,2H),1.44(t,J=6.9Hz,3H)。

Embodiment 38

Step 1:N-(4-((3-chloro-4-((6-picoline-3-base) epoxide) phenyl) amino)-3-cyano group-7-ethyoxyl Quinoline-6-base) preparation of acetamide

Except with the 3-p-toloxyl of chloro-4-() aniline replaces, in addition to the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine, adopting By the method identical with step 1 in embodiment 31, obtain brown solid, productivity 79%.

Step 2:6-amino-4-((3-chloro-4-((6-picoline-3-base) epoxide) phenyl) amino)-7-ethoxyquin The preparation of quinoline-3-formonitrile HCN

0.6g step 1 product N-(4-((3-chloro-4-((6-picoline-3-base is added in a 50ml round-bottomed flask) oxygen Base) phenyl) amino)-3-cyano group-7-ethoxy quinoline-6-base) acetamide and 10ml concentrated hydrochloric acid, it is heated to reflux stirring 3 little Time, TLC detection reaction terminates, and stopped reaction naturally cools to room temperature, is spin-dried for solvent, wash with saturated sodium bicarbonate, filters, Collect solid, be dried, obtain Tan solid, yield 93%.

Step 3:N-(4-((the chloro-4-of 3-((6-picoline-3-base) epoxide) phenyl) amino)-3-cyano group-7-ethyoxyl Quinoline-6-base) preparation of-2-chloroacrylamide

Except with step 2 product 6-amino-4-((3-chloro-4-((6-picoline-3-base) epoxide) phenyl) amino)-7- Ethoxy quinoline-3-formonitrile HCN replaces the raw material 6-amino-4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3-of embodiment 31 step 3 Base] beyond-7-ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 31, obtain yellow solid.Productivity 17%。¹H NMR(500MHz,DMSO-d6)δ10.06-9.79(m,1H),9.67(s,1H),8.87(s,1H),8.60(s,1H), 8.21(d,J=2.4Hz,1H),7.51(s,1H),7.47(s,1H),7.25(qd,J=8.6,2.7Hz,4H),6.61(d,J= 2.3Hz,1H),6.19(d,J=2.3Hz,1H),4.33(q,J=6.9Hz,2H),2.44(s,3H),1.46(t,J=6.9Hz, 3H)。

Embodiment 39

Step 1 and step 2 are with the step 1 of embodiment 38 and step 2.

Step 3:N-(4-((the chloro-4-of 3-((6-picoline-3-base) epoxide) phenyl) amino)-3-cyano group-7-ethyoxyl Quinoline-6-base) preparation of-2-fluoropropene amide

Except with step 2 product 6-amino-4-((3-chloro-4-((6-picoline-3-base) epoxide) phenyl) amino)-7- Ethoxy quinoline-3-formonitrile HCN replaces the raw material 6-amino-4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3-of embodiment 31 step 3 Base]-7-ethoxy quinoline-3-formonitrile HCN, replace beyond 2-chloracrylic acid with 2-perfluoroalkyl acrylate, use and step 3 in embodiment 32 Identical method, obtains yellow solid.Productivity 30%.¹H NMR(500MHz,DMSO-d6)δ9.85(s,1H),9.60(s,1H), 8.79(s,1H),8.59(s,1H),8.21(d,J=2.4Hz,1H),7.56-7.50(m,1H),7.47(s,1H),7.33-7.20 (m,4H),5.79(dd,J=48.3,3.8Hz,1H),5.52(dd,J=15.7,3.8Hz,1H),4.32(q,J=6.9Hz,2H), 2.44(s,3H),1.44(t,J=6.9Hz,3H)。

Embodiment 40

Step 1:N-(4-((3-chloro-4-(cyclo propyl methoxy) phenyl) Amino 3 cyano-7-ethoxy quinoline-6-base) The preparation of acetamide

Except with 3-chloro-4-(cyclo propyl methoxy) aniline replaces, in addition to the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine, adopting By the method identical with step 1 in embodiment 1, obtain brown solid, productivity 77%.

Step 2:6-amino-4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-7-ethoxy quinoline-3-formonitrile HCN Preparation

Except with step 2 product N-(4-((3-chloro-4-(cyclo propyl methoxy) phenyl) Amino 3 cyano-7-ethyoxyl Quinoline-6-base) acetamide replace embodiment 31 step 2 raw material N-{4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of 3-]-3- Cyano group-7-ethoxy quinoline-6-base } beyond-acetamide, use the method identical with step 2 in embodiment 31, obtain yellow solid Body, productivity 57%.

Step 3:N-(4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-3-cyano group-7-ethoxy quinoline-6- Base) preparation of-2-chloroacrylamide

Except with step 2 product 6-amino-4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-7-ethoxyquin The preparation of quinoline-3-formonitrile HCN replaces the raw material 6-amino-4-[fluoro-benzyloxy-phenylamino of the chloro-4-(3-of 3-of embodiment 31 step 3 Base] beyond-7-ethoxy quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 31, obtain yellow solid.Productivity 35%。¹H NMR(500MHz,DMSO-d6)δ9.68(s,2H),8.83(s,1H),8.49(s,1H),7.43(s,1H),7.37 (d,J=2.4Hz,1H),7.20(dd,J=8.8,2.4Hz,1H),7.13(d,J=8.8Hz,1H),6.58(d,J=2.2Hz,1H), 6.17(d,J=2.2Hz,1H),4.31(q,J=6.9Hz,2H),3.93(d,J=6.9Hz,2H),1.45(t,J=6.9Hz,3H), 1.31–1.22(m,1H),0.64–0.56(m,2H),0.41–0.33(m,2H)。

Embodiment 41

Step 1 and step 2 are with the step 1 of embodiment 40 and step 2.

Step 3:N-(4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-3-cyano group-7-ethoxy quinoline-6- Base) preparation of-2-fluoropropene amide

Except with step 2 product 6-amino-4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-7-ethoxyquin Quinoline-3-formonitrile HCN replaces raw material 6-amino-4-[the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of the 3-]-7-second of embodiment 32 step 3 Beyond phenoxyl quinoline-3-formonitrile HCN, use the method identical with step 3 in embodiment 32, obtain yellow solid.Productivity 60%.¹H NMR(500MHz,DMSO-d6)δ9.67(s,2H),8.74(s,1H),8.49(s,1H),7.42(s,1H),7.38(d,J= 2.1Hz,1H),7.21(dd,J=8.7,2.0Hz,1H),7.13(d,J=8.8Hz,1H),5.75(dd,J=48.1,3.6Hz, 1H),5.50(dd,J=15.7,3.6Hz,1H),4.29(q,J=6.8Hz,2H),3.93(d,J=6.8Hz,2H),1.43(t,J= 6.9Hz,3H),1.26(s,1H),0.60(d,J=7.4Hz,2H),0.37(d,J=4.7Hz,2H)。

Effect example 1 the compounds of this invention inhibitory action to EGFR tyrosine kinase activity

Test-compound is to kinase whose inhibitory activity 503nhibiting concentration IC₅₀Value represents.Such test uses equal phase time Between resolved fluorometric (HTRF) technology be measured, method is as follows: by the compound of a series of gradient concentrations, at ambient temperature with The enzymatic solution of certain concentration is hatched 5 minutes jointly, adds appropriate enzyme reaction substrate, ATP afterwards, starts enzyme reaction process, and 30 After minute, in enzyme reaction system, add appropriate reaction terminating liquid and detection liquid, after hatching 1 hour, public at PerkinElmer On the EnVision2104 multiple labeling micropore detector of department, measure under specific compound concentration under 665nm and 620nm wavelength Enzyme activity, and calculate the inhibitory activity of the compounds on enzyme activities of variable concentrations, afterwards according to quadruplex parameters, to variable concentrations Under compound, the inhibitory activity of enzyme activity is fitted, and calculates IC₅₀Value.The kinases EGFR that the present embodiment is used is purchased from Sigma Aldrich, detection kit HTRFKinEASE-TK is purchased from Sigma purchased from Cisbio Bioassays company, ATP Aldrich.The IC of test-compound of the present invention₅₀Data are as follows:

Effect example 2 compound is to A431, H1975 cell inhibitory effect determination of activity

It is thin for EGFR wild type overexpression cell line A431 and T790M point mutation that this example is used for measuring the compounds of this invention The proliferation inhibition activity of born of the same parents strain H1975, the inhibitory activity half-inhibition concentration IC of compound on intracellular propagation₅₀Represent.Examination Proved recipe case is as follows: EGFR wild type overexpression cell line A431 and T790M point mutation cell strain H1975 cell are all purchased from ATCC, With suitable cell concentration (A431:20000 cell/ml culture medium；H1975:15000 cell/ml culture medium) by cell It is inoculated on 384 well culture plates of White-opalescent；Afterwards cell is positioned over 37 DEG C, 5%CO₂Environment in cultivate, 24 After hour, in the cell culture medium cultivated, add the medicine of a series of Concentraton gradient, be typically chosen 10 concentration, afterwards will be thin Born of the same parents put back to and continue in former culture environment to cultivate 48 hours, afterwards according to CellTiter-Glo Luminescent Cell The method of Viability Assay, the EnVision2104 multiple labeling micropore detector in PerkinElmer company measures tested The compound impact on A431 and H1975 cell proliferation, and calculate the inhibitory activity of the compound on intracellular propagation of variable concentrations, CellTiter-Glo Luminescent Cell Viability Assay detectable is purchased from Promega.Afterwards to difference Under the compound of concentration, A431 and H1975 cell inhibitory effect activity carries out four parameter fittings, the IC of test-compound of the present invention₅₀ Data are as follows:

Embodiment is numbered	IC₅₀(A431)(μM)	IC₅₀(H1975)(μM)
			12	3.5	3.6
13	25	6.4
			14	5.3	2.4
15	5.5	2.4
			16	1.8	4.4
17	1.3	2.4
			18	5.9	7.7
20	11	7.5
			21	10	8.2
23	2.5	9.4
			24	11	9.2
26	3.5	22
			32	9.6	11
37	6.8	17

Conclusion: the compounds of this invention has obvious Inhibit proliferaton activity to A431 and H1975.

Claims

1. a quinoline shown in formula I or quinazoline derivant, its pharmaceutically acceptable salt；

Wherein, Z is N or C-CN；

R₃And R₄In at least one is hydrogen, work as R₃And R₄In have one for hydrogen time, X is fluorine；Work as R₃And R₄When being hydrogen, X be fluorine or Chlorine；

As Z=N, R₁For R₂For methoxyl group, ethyoxyl, 3S-tetrahydrofuran base Epoxide, 2-(N-methyl-4-piperidyl) ethyoxyl, 3-(4-morpholinyl) propoxyl group, 2-(N, N-lignocaine)-ethyoxyl, 2, 2,2-trifluoro ethoxy or 2-(methoxyl group)-ethyoxyl；R₃And R₄Be each independently hydrogen,

As Z=C-CN, R₁For R₂For ethyoxyl；R₃And R₄It is each independently Hydrogen, N, N-dimethylamino methyl or piperidino methyl；

Further, quinoline or quinazoline derivant, its pharmaceutically acceptable salt shown in formula I is not following arbitrary compound:

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine but-2-ene Amide；

(Z)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

(E)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base)-4-(dimethylamino)-2- Fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-ethoxyquin oxazoline-6-base)-4-(dimethylamino)-2-fluorine but-2-ene Amide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base)-2-fluoro-4-morpholinyl butyl- 2-acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-((3R)-oxolane-3-base epoxide) quinazoline-6-base)-4-(dimethyl Amino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-((tetrahydrochysene-2H-pyrans-4-base) methoxyl group) quinazoline-6-base)-4-(two Methylamino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diethylamino)-2-fluorine but-2-ene Amide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-(2-methoxyl group) ethoxyquin oxazoline-6-base) the fluoro-4-of-2-(4-methyl piperazine Piperazine-1-base) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-((2-methoxyethyl) (methyl) Amino) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-(4-methylpiperazine-1-yl) butyl- 2-acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-4-of-2-((methyl) (oxolane-3- Base) amino) but-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(2-(dimethylamino) ethyoxyl)-2-fluorine But-2-enamides；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base) the fluoro-3-of-2-(1-methylpyrrolidin-2 (S) Base) acrylamide；

N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino Base)-2-fluorine but-2-enamides；

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2- Fluorine but-2-enamides；

The fluoro-N-of 4-(dimethylamino)-2-(4-(1-(3-luorobenzyl)-1H-indazole-5-base amino)-7-methoxyquinazoline hydrochloride- 6-yl) but-2-enamides；

4-(dimethylamino)-N-(4-(3-ethynyl phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluorine but-2-ene acyl Amine；

N-(4-(2,4-bis-chloro-5-Methoxyphenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

N-(4-(5-chlorobenzene also [d] [1,3] dioxolanes-4-base amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino Base)-2-fluorine but-2-enamides；

N-(4-(4-chloro-3-(trifluoromethyl) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine But-2-enamides；

N-(4-(3-bromophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine but-2-ene Amide；

N-(4-(4-bromo-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine but-2-ene Amide；

N-(4-(3-chloro-2,4 difluorobenzene base amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3,4-bis-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

N-(4-(the bromo-3-of 4-chloro-2-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-4-(dimethylamino)-2-fluorine butyl- 2-acrylamide；

(Z)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan Base amino)-2-fluorine but-2-enamides；

(E)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyquinazoline hydrochloride-6-base)-4-(diformazan Base amino)-2-fluorine but-2-enamides；

N-(4-(3-chloro-2,4 difluorobenzene base amino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(piperidin-1-yl) but-2-ene acyl Amine；

(Z)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(piperidin-1-yl) butyl-2- Acrylamide；

(E)-N-(4-(3-chloro-4-Fluorophenylamino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(piperidin-1-yl) butyl-2- Acrylamide；

N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(dimethylamino)-2- Fluorine but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-2-fluoro-4-morpholine Base but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4-(diformazan ammonia Base)-2-fluorine but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-enamides；

N-(4-((3-chloro-4-fluoroanilino)-7-(2-methoxyethyl) quinazoline-6-base)-2-fluoro-4-(piperidin-1-yl) butyl- 2-acrylamide；

N-(the chloro-4-of 3-(2-pyridine benzyloxy) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(piperidines amino)-2-fluorine butyl- 2-acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-(pyrrolidin-1-yl) but-2-ene acyl Amine；

(Z)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(diformazan ammonia Base)-2-fluorine but-2-enamides；

(E)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-ethoxyquin oxazoline-6-base)-4-(diformazan ammonia Base)-2-fluorine but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base) the fluoro-4-of-2- Morpholinyl but-2-enamides；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base) the fluoro-4-of-2- Morpholinyl but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4-(diformazan Amino)-2-fluorine but-2-enamides；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-((3S)-tetrahydrochysene-3-furan epoxide) quinazoline-6-base)-4-(diformazan Amino)-2-fluorine but-2-enamides；

(Z)-N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-ene acyl Amine；

(E)-N-(4-((3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride-6-base)-2-fluoro-4-morpholinyl but-2-ene acyl Amine；

N-(4-(the chloro-3-of 2-(3-fluorine benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

N-(4-(the fluoro-3-of 2-chloro-4-bromoanilino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(piperidin-1-yl) propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(dimethylamino) propoxyl group) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(3-(4-methylpiperazine-1-yl) propoxyl group) quinazoline-6-base)-2-fluoropropene Amide；

(R)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(oxolane-3-ylmethoxy) quinazoline-6-base)-2-fluorine third Acrylamide；

(S)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(oxolane-3-ylmethoxy) quinazoline-6-base)-2-fluorine third Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(1-methyl piperidine-4-epoxide) quinazoline-6-base)-2-fluoropropene amide；

(R)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene Amide；

(S)-N-(4-(3-chloro-2,4 difluorobenzene amino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-fluoropropene amide；

N-(4-(3-bromoanilino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxyl group) quinazoline-6-base)-2-chloropropene Amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene acyl Amine；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(N-methylpyrrole-3-epoxide) quinazoline-6-base)-2-fluoropropene acyl Amine；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2-chlorine third Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(piperidin-1-yl) ethyoxyl) quinazoline-6-base)-2-fluoropropene amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(piperidin-1-yl) ethyoxyl) quinazoline-6-base)-2-chloroacrylamide；

N-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy phenylamino)-7-ethoxyquin oxazoline-6-base)-2-chloroacrylamide；

N-(4-((the chloro-4-of 3-(cyclo propyl methoxy phenylamino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6- Base)-2-chloroacrylamide；

N-(4-((the chloro-4-of 3-(cyclo propyl methoxy phenylamino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6- Base)-2-fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-3-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-3-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-2-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-2-base) methoxyl group) quinazoline-6-base)-2-fluorine third Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-4-base) ethyoxyl) quinazoline-6-base)-2-fluoropropene Amide；

N-(4-(3-chloro-4-fluoroanilino)-7-(2-(4-methylpiperazine-1-yl) ethyoxyl) quinazoline-6-base)-2-fluoropropene Amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methylpyrrolidin-2-yl) ethyoxyl) quinazoline-6-base)-2- Fluoropropene amide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methylpyrrolidin-2-yl) ethyoxyl) quinazoline-6-base)-2- Fluoropropene amide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-2-base) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-2-base) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

(R)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-3-base) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

(S)-N-(4-(3-chloro-4-fluoroanilino)-7-(2-(1-methyl piperidine-3-base) ethyoxyl) quinazoline-6-base)-2-fluorine Acrylamide；

N-(4-(3-chloro-4-fluoroanilino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)-2-fluoropropene acyl Amine；

N-(4-(3-bromoanilino)-7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-6-base)-2-fluoropropene amide；

(S)-N-(4-((3-chloro-4-fluoroanilino)-7-((4-methyl morpholine-3-base) methoxyl group) quinazoline-6-base)-2-chlorine Acrylamide.

2. quinoline as claimed in claim 1 or quinazoline derivant, its pharmaceutically acceptable salt, it is characterised in that:

Work as Z=N, R₁During for 3-chloro-4-fluorophenyl, R₂For 3S-tetrahydrofuran base epoxide, 2-(N-methyl-4-piperidyl) ethoxy Base, 2-(N, N-diethylamino)-ethyoxyl, 2,2,2-trifluoro ethoxy, 2-(methoxyl group)-ethyoxyl or ethyoxyl；R₃And R₄ In one be hydrogen, another is hydrogen or piperidino methyl；

Or, work as Z=N, R₁For the bromo-phenyl of 3-orTime, R₂For methoxyl group；R₃And R₄In one be Hydrogen, another is piperidino methyl or N, N-dimethylamino methyl；

Or, work as Z=N, R₁ForTime, R₂For ethyoxyl；R₃And R₄In one be Hydrogen, another is piperidino methyl or N, N-dimethylamino methyl；

Or, work as Z=N, R₁ForTime, R₂For ethyoxyl or 3-(4-morpholinyl) propoxyl group；R₃And R₄In One is hydrogen, and another is hydrogen, piperidino methyl or N, N-dimethylamino methyl；

Or, work as Z=N, R₁ForTime, R₂For 3-(4-morpholinyl) propoxyl group；R₃And R₄It is hydrogen；

Work as Z=C-CN, R₁During for 3-chloro-4-fluorophenyl, R₂For ethyoxyl；R₃And R₄In one be hydrogen, another is hydrogen, N, N- Dimethylamino methyl or piperidino methyl；

Or, work as Z=C-CN, R₁For the bromo-phenyl of 3-, Time, R₂For ethyoxyl；R₃And R₄It is hydrogen；

Or, work as Z=C-CN, R₁ForTime, R₂For ethyoxyl；R₃And R₄In one be hydrogen, another is Hydrogen or N, N-dimethylamino methyl；

Or, work as Z=C-CN, R₁ForTime, R₂For ethyoxyl；R₃And R₄It is hydrogen.

3. quinoline as claimed in claim 1 or quinazoline derivant, its pharmaceutically acceptable salt, it is characterised in that: it is Arbitrary compound in the most numbered 1～41:

4. the quinoline shown in formula I as described in any one of claims 1 to 3 or quinazoline derivant, it pharmaceutically may be used The preparation method of the salt accepted, it is following either method:

Method one comprises the steps:, 1. in solvent, under the effect of alkali 1, to be reacted with compound B by compound A, obtain Compound C,；2., in solvent, under the effect of alkali 2, product C step 1. obtained reacts with compound D, obtains Compound I；

Method two comprises the steps: in solvent, under the effect of alkali 1, is reacted with compound E by compound A, is changed Compound I；

Wherein, R₁、R₂、R₃、R₄, Z and X all as described in any one of claims 1 to 3, R and R ' is each independently C_1～6Alkyl.

5. preparation method as claimed in claim 4, it is characterised in that: in described method one and method two, if the product I obtained For the mixture of cis-trans-isomer, by the cis or trans product I that the further isolated of chiral column is pure；Described chiral column is AD-H chiral column.

6. the compound as shown in formula C,

Wherein, R₁、R₂, R, R ', X and Z the most as claimed in claim 4.

7. one kind contains just like the quinoline described in any one of claims 1 to 3 or quinazoline derivant, its pharmaceutically acceptable salt Pharmaceutically useful compositions.

8. quinoline as described in any one of claims 1 to 3 or quinazoline derivant, its pharmaceutically acceptable salt are in preparation Application in the medicine of EGFR tyrosine kinase inhibitor；

Or, pharmaceutically useful compositions as claimed in claim 7 answering in the medicine preparing EGFR tyrosine kinase inhibitor With.

9. quinoline as described in any one of claims 1 to 3 or quinazoline derivant, its pharmaceutically acceptable salt are in preparation Application in A431 or H1975 inhibition of cell proliferation medicine；Or, pharmaceutically useful compositions as claimed in claim 7 is in system Application in standby A431 or H1975 inhibition of cell proliferation medicine.

10. quinoline as described in any one of claims 1 to 3 or quinazoline derivant, its pharmaceutically acceptable salt are in preparation Application in the medicine of prevention or treatment tumor disease；Or, pharmaceutically useful compositions as claimed in claim 7 is in preparation prevention Or the application in the medicine for the treatment of tumor disease.