CN103965120A

CN103965120A - Quinoline and quinazoline derivative, preparation method, intermediate, composition and application

Info

Publication number: CN103965120A
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: 2014-08-06
Anticipated expiration: 2034-01-26
Also published as: CN103965120B

Abstract

The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.

Description

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

Technical field

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

Background technology

Protein kinase has vital role in cell signaling.It can be transferred to phosphate group the particular amino acid residue of functional protein from ATP, causes a series of biochemical reactions.According in phosphorylation process as the amino acid classification of substrate, protein kinase can be divided into serine-threonine kinase (STKs) and Tyrosylprotein kinase (PTKs).Wherein PTKs can be divided three classes: 1. receptor tyrosine kinase (receptorprotein tyrosine kinases, RPTKs) is single transmembrane protein, has found that more than 50 plant in vertebrates; 2. cytoplasmic tyrosine kinase, RuSrc family, Tec family, JAK family etc.; 3. the interior Tyrosylprotein kinase of core is as Abl and Wee.

The extracellular region of RPTKs is binding partner structural domain, and part is solubility or membrane-bound polypeptide or protein hormone, comprises various kinds of cell somatomedin (as EGF).Born of the same parents' inner segment is the catalytic site of tyrosine protein kinase, and has autophosphorylation site.Part outside born of the same parents with receptors bind cause conformational change, cause receptor dimerizationization to form homology or heterodimer, phosphorylation born of the same parents inner segment tyrosine residues each other in dimer, the protein tyrosine kinase activity of activated receptor itself.The peptide chain-ordering that this receptoroid of most cells somatomedin contains Tyrosylprotein kinase mainly contains EGFR, PDGFR, FGFR, VEGFR etc., the overexpression of visible different tyrosine kinase receptors or excessive activation in many tumours.According to the similarity of peptide chain-ordering and some other structural feature, these acceptors are divided into some families: 1. Urogastron (EGFR) family; 2. Insulin Receptor Family; 3. platelet-derived growth factor receptors (PDGFR) family; 4. bfgf receptor (FGFR) family; 5. vascular endothelial growth factor receptor (VEGFR) family; 6. Fibronectin III receptor class; 7. hepatocyte growth factor receptor (HGFR) class etc.These acceptors are overexpression in different tumours respectively, causing abnormal signal in its cell activates, cause cell transformation, constantly breed, promote generation, the development of tumour, therefore use and can bring into play antitumor action for the inhibitor of above-mentioned protein kinase, particularly tyrosine kinase inhibitor.EGFR family for example, comprise EGFR, HER2, HER3, HER4 etc., are that a class is studied more Tyrosylprotein kinase, and they have high expression level in kinds of tumors, the phenomenons such as their expression and cancer cell multiplication, transfer are relevant, find that to take the inhibitor that EGFR is target spot be one of important directions of antitumor drug research and development in recent years.

EGFR tyrosine kinase inhibitor can be divided into reversible inhibitor and irreversible inhibitor two classes.The Gefitinib of wherein having gone on the market (Gefitinib), erlotinib (Erlotinib) are reversible inhibitor, and along with they are in clinical use, reversible inhibitor shows resistance problem gradually.Irreversible inhibitor can be with EGFR Tyrosylprotein kinase with covalent bonds, and many preclinical studies show, the irreversible inhibitor in exploitation can resist T790M sudden change at present, has overcome the resistance that T790M causes; Simultaneously, just at some irreversible inhibitors (such as BIBW2992 and PF00299804 etc.) in clinical development stage, a plurality of members that can suppress EGFR receptor family, particularly for the effect of EGFR and HER – 2, the synergistic signal path that may be activated by homodimer and heterodimer by blocking-up strengthens inhibition (Oncologist, 2009,14 (11): 1116-1130).

Summary of the invention

Technical problem to be solved by this invention is, a kind of quinoline and quinazoline derivant, its pharmacy acceptable salt and their enantiomer, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are provided, its preparation method, intermediate, composition and application.Quinoline of the present invention and quinazoline derivant, its pharmacy acceptable salt and their enantiomer, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug have preferably anti-tumor activity.

The invention provides a kind of suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug;

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

R ₁for the C replacing _6～10aryl, described in be substituted by selected from following a)～c) group in one or more replacements:

A) halogen, is preferably F, Cl or Br;

B) replacement or unsubstituted C _1～3alkoxyl group, the C of described replacement _1～3alkoxyl group can further be substituted or unsubstituted C _5～6aryl, replacement or unsubstituted C _5～6heteroaryl or 3～6 yuan of cycloalkyl substituted; Wherein, the C of described replacement _5～6the C of aryl or replacement _5～6heteroaryl also can be further by halogen (being preferably F) or C _1～3alkyl (being preferably methyl) replaces; Preferably, C _5～6aryl is phenyl, C _5～6heteroaryl is pyridyl, and 3～6 yuan of cycloalkyl are cyclopropyl;

C) replacement or unsubstituted C _5～8heteroaryloxy, the C of described replacement _5～8heteroaryloxy can be further by C _1～3alkyl (being preferably methyl) replaces; Described C _5～8heteroaryloxy is preferably the C that contains 1 nitrogen-atoms _5～8heteroaryloxy, more preferably pyridyl or indyl;

R ₂for replacing or unsubstituted C _1～3alkoxyl group 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 that contain Sauerstoffatom, more preferably tetrahydrofuran base oxygen base, more preferably 3S-tetrahydrofuran base oxygen base; The C of described replacement _1～3alkoxyl group is can be further selected from following d)～g) group replace:

D) replacement or unsubstituted 3～8 yuan of heterocyclic radicals, 3～8 yuan of heterocyclic radicals of described replacement can be further by C _1～5alkyl (is preferably C _1～3alkyl, more preferably methyl or ethyl) replace; Described 3～8 yuan of heterocyclic radicals are preferably pyrrolidyl, piperidyl, piperazinyl or morpholinyl, more preferably piperidyl or morpholinyl;

E) replacement or unsubstituted amino, the amino of described replacement can be further by C _1～5alkyl (is preferably C _1～3alkyl, more preferably methyl or ethyl) replace;

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

G) C _1～3alkoxyl group, is preferably methoxyl group;

R ₃and R ₄be hydrogen or replacement or unsubstituted C independently of one another _1～3alkyl, the C of described replacement _1～3alkyl is can be further selected from following h)～i) group replace:

H) replacement or unsubstituted amino, the amino of described replacement can be further by C _1～3alkyl (being 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, more preferably piperidyls that contain 1 nitrogen-atoms;

And, suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug do not comprise the compound with following structure:

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(Z)-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(E)-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(2-methoxyl group) oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(2-methoxyl group) oxyethyl group quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-((3R)-tetrahydrofuran (THF)-3-base oxygen base) quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-((tetrahydrochysene-2H-pyrans-4-yl) methoxyl group) quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(diethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(2-methoxyl group) oxyethyl group quinazoline-6-yl) the fluoro-4-of-2-(4-methylpiperazine-1-yl) but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-((2-methoxyethyl) (methyl) amino) but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-(4-methylpiperazine-1-yl) but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-((methyl) (tetrahydrofuran (THF)-3-yl) amino) but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(2-(dimethylamino) oxyethyl group)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-3-of-2-(1-methylpyrrolidin-2 (S) base) acrylamide;

N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenyl amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

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

4-(dimethylamino)-N-(4-(3-ethynyl phenyl is amino)-7-methoxyl group quinazoline-6-yl)-2-fluorine but-2-enamides;

N-(4-(the chloro-5-p-methoxy-phenyl of 2,4-bis-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(5-chlorobenzene also [d] [1,3] dioxolane-4-base is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-3-of 4-(trifluoromethyl) phenyl amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(3-bromophenyl is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-2-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the bromo-2-fluorophenyl of 4-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-2,4 difluorobenzene base of 3-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-2-fluorophenyl of 3,4-bis-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-2-fluorophenyl of the bromo-3-of 4-is amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(Z)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(E)-N-(4-(the chloro-4-of 3-(pyridine-2-ylmethoxy) phenyl amino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-2,4 difluorobenzene base of 3-is amino)-7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-(piperidin-1-yl) but-2-enamides;

(Z)-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-(piperidin-1-yl) but-2-enamides;

(E)-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-(piperidin-1-yl) but-2-enamides;

N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-((the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

N-(4-(3-bromobenzene is amino)-7-oxyethyl group quinazoline-6-yl) the fluoro-4-of-2-(piperidin-1-yl) but-2-enamides;

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

N-(the chloro-4-of 3-(2-pyridine benzyloxy) phenylamino)-7-oxyethyl group quinazoline-6-yl)-4-(piperidines is amino)-2-fluorine but-2-enamides;

N-(4-(3-bromobenzene is amino)-7-oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

N-(4-(3-bromobenzene is amino)-7-oxyethyl group quinazoline-6-yl) the fluoro-4-morpholinyl-but-2-enamides of-2-;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl) the fluoro-4-of-2-(pyrrolidin-1-yl) but-2-enamides;

(Z)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(E)-N-(4-((the chloro-4-of 3-(pyridine-2-methoxyl group) phenylamino)-7-oxyethyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(Z)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

(E)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

(Z)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(E)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-((3S)-tetrahydrochysene-3-furans oxygen base) quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides;

(Z)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

(E)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl) the fluoro-4-morpholinyl of-2-but-2-enamides;

N-(4-(the bromo-2-fluoroanilino of 4-)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the fluoro-3-chlorobenzene of 2,4-bis-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-3-ethynylphenylamino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the fluoro-3-chlorobenzene of 2-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-5-anisole of 2,4-bis-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-bromobenzene is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-3-of 2-(3-fluorine benzyloxy) phenylamino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(2-is fluoro-3, and 4-dichlorobenzene is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(2,4 difluorobenzene is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(2,3,4-trifluoro-benzene is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(2,4 dichloro benzene is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the fluoro-3-chlorobenzene of 2,4-bis-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(the chloro-3-anisole of 2,4-bis-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-3-anisole of 4-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-bromobenzene of the fluoro-3-of 2-is amino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-oxyethyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(3-(piperidin-1-yl) propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

The chloro-N-of 2-(4-(the chloro-4-fluoroanilino of 3-)-7-(3-morpholine propoxy-) quinazoline-6-yl) acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(3-(dimethylamino) propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-chlorine 4-fluoroanilino)-7-(3-(pyrrolidin-1-yl) propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(tetrahydrofuran (THF)-3-ylmethoxy) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(tetrahydrofuran (THF)-3-ylmethoxy) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(cyclobutyl methoxy base) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(cyclo propyl methoxy) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(1-methyl piperidine-4-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(N-methylpyrrole-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-2,4 difluorobenzene of 3-is amino)-7-(N-methylpyrrole-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-bromobenzene is amino)-7-methoxyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-bromobenzene is amino)-7-oxyethyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-trifluoromethyl phenylamino)-7-methoxyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-trifluoromethyl phenylamino)-7-oxyethyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-methoxyl group quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(3-trifluoromethyl phenylamino)-7-oxyethyl group quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(3-bromobenzene is amino)-7-oxyethyl group quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-oxyethyl group quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-of 3-(cyclopropyl benzyloxy) phenylamino)-7-(3-morpholine propoxy-) quinazoline-6-yl)-2-propenyl chloride acid amides;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(N-methylpyrrole-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(N-methylpyrrole-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-3-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-3-yl) methoxyl group) quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(piperidin-1-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(piperidin-1-yl) oxyethyl group) quinazoline-6-yl)-2-propenyl chloride acid amides;

N-(4-((the chloro-4-of 3-(pyridine-2-ylmethoxy phenylamino)-7-oxyethyl group quinazoline-6-yl)-2-propenyl chloride acid amides;

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

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

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-3-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((1-methyl piperidine-3-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((1-methyl piperidine-3-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-2-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-2-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methyl piperidine-4-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(4-methylpiperazine-1-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-morpholine oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methylpyrrolidin-2-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methylpyrrolidin-2-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methyl piperidine-2-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methyl piperidine-2-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(R)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methyl piperidine-3-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-(the chloro-4-fluoroanilino of 3-)-7-(2-(1-methyl piperidine-3-yl) oxyethyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(the chloro-4-fluoroanilino of 3-)-7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

N-(4-(3-bromobenzene is amino)-7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-6-yl)-2-fluorine acrylamide;

(S)-N-(4-((the chloro-4-fluoroanilino of 3-)-7-((4-methylmorpholine-3-yl) methoxyl group) quinazoline-6-yl)-2-propenyl chloride acid amides.

According to an embodiment of the invention, quinoline described in formula I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are as shown in the formula the quinazoline derivant shown in II:

Wherein,

X is halogen; R ₁for the C replacing _6～10aryl, described in be substituted by by halogen, replacement or unsubstituted C _1～3alkoxyl group and replacement or unsubstituted C _5～8one or more replacements in heteroaryloxy; R ₂for replacing or unsubstituted C _1～3alkoxyl group or 3～8 yuan of heterocyclic oxy groups; R ₃and R ₄be hydrogen or replacement or unsubstituted C independently of one another _1～3alkyl;

X is preferably F or Cl;

R ₁in, when described, while being substituted by halogen, described halogen is preferably F, Cl or Br;

R ₁in, as the described C that is substituted by replacement _1～3during alkoxyl group, the C of described replacement _1～3alkoxyl group is further substituted or unsubstituted C _5～6aryl, replacement or unsubstituted C _5～6heteroaryl or 3～6 yuan of cycloalkyl substituted; Wherein, the C of described replacement _5～6the C of aryl or replacement _5～6heteroaryl is also further replaced by halogen (being preferably F); Preferably, described C _5～6aryl is phenyl, described C _5～6heteroaryl is pyridyl, and described 3～6 yuan of cycloalkyl are cyclopropyl;

R ₁in, as the described C that is substituted by replacement _5～8during heteroaryloxy, the C of described replacement _5～8heteroaryloxy is further by C _1～3alkyl (being preferably methyl) replaces; Described C _5～8heteroaryloxy is preferably the C that contains 1 nitrogen-atoms _5～8heteroaryloxy, more preferably pyridyl or indyl, more preferably pyridyl;

R ₂in, the C of described replacement _1～3alkoxyl group is further substituted or unsubstituted 3～8 yuan of heterocyclic radicals, replacement or unsubstituted amino, halogen or C _1～3alkoxyl group replaces;

R ₂in, as the C of described replacement _1～3when alkoxyl group is further substituted or unsubstituted 3～8 yuan of heterocyclic radicals replace, 3～8 yuan of heterocyclic radicals of described replacement can be further by C _1～5alkyl (is preferably C _1～3alkyl, more preferably methyl or ethyl) replace; Described 3～8 yuan of heterocyclic radicals are preferably pyrrolidyl, piperidyl, piperazinyl or morpholinyl, more preferably piperidyl or morpholinyl;

R ₂in, as the C of described replacement _1～3when alkoxyl group is further substituted or unsubstituted amino replaces, the amino of described replacement can be further by 1～2 C _1～5alkyl (is preferably C _1～3alkyl, more preferably methyl or ethyl) replace;

R ₂in, as the C of described replacement _1～3when alkoxyl group is further replaced by halogen, described halogen is preferably F or Cl, more preferably F;

R ₂in, as the C of described replacement _1～3alkoxyl group is further by C _1～3when alkoxyl group replaces, described C _1～3alkoxyl group is preferably methoxyl group;

R ₂in, described 3～8 yuan of heterocyclic oxy groups are preferably 3～8 yuan of heterocyclic oxy groups that contain Sauerstoffatom, more preferably tetrahydrofuran base oxygen base, more preferably 3S-tetrahydrofuran base oxygen base;

R ₃and R ₄in, the C of described replacement _1～3alkyl can further be substituted or unsubstituted amino or 3～8 yuan of heterocyclic radicals replacements; Wherein, the amino of described replacement can be further by 1～2 C _1～3alkyl (being preferably methyl) replaces; Described 3～8 yuan of heterocyclic radicals are preferably 3～8 yuan of heterocyclic radicals, more preferably piperidyls that contain 1 nitrogen-atoms;

And, quinazoline derivant shown in formula II, its pharmacy acceptable salt, the enantiomer of quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug do not comprise the compound of following structure:

According to another implementation of the invention, quinoline described in formula I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are quinoline shown in following formula III:

Wherein,

X is preferably F or Cl;

R ₁in, as the described C that is substituted by replacement _5～8during heteroaryloxy, the C of described replacement _5～8heteroaryloxy is further by C _1～3alkyl (being preferably methyl) replaces; Described C _5～8heteroaryloxy is preferably the C that contains 1 nitrogen-atoms _5～8heteroaryloxy, more preferably pyridyl or indyl;

R ₂be preferably oxyethyl group;

R ₃and R ₄in, the C of described replacement _1～3alkyl can further be substituted or unsubstituted amino or 3～8 yuan of heterocyclic radicals replacements; Wherein, the amino of described replacement can be further by 1～2 C _1～3alkyl (being preferably methyl) replaces; Described 3～8 yuan of heterocyclic radicals are preferably 3～8 yuan of heterocyclic radicals, more preferably piperidyls that contain 1 nitrogen-atoms.

As of the present invention one preferred embodiment, R ₁for at least containing the C of 1 halogen _6～10aryl; Preferably, R ₁for at least containing the phenyl of 1 halogen; More preferably, with halogen at R ₁upper each other in a position replacement.

As of the present invention another preferred embodiment, R ₂for C _1～3alkoxyl group.

As of the present invention another preferred embodiment, R ₃and R ₄in have 1 at least for hydrogen; Preferably, work as R ₃and R ₄in only have 1 when the hydrogen, X is fluorine, works as R ₃and R ₄while being hydrogen, X is fluorine or chlorine.

Described suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are preferably as follows situation: R ₁for the C replacing _6～10aryl, described in be substituted by by halogen and/or replacement or unsubstituted C _1～3alkoxyl group replaces the (C of described replacement _1～3alkoxyl group can be further by C _5～6heteroaryl replaces, described C _5～6the preferred 2-pyridyl of heteroaryl); R ₂for C _1～3alkoxyl group (preferably oxyethyl group); R ₃and R ₄be hydrogen or replacement or unsubstituted C independently of one another _1～3alkyl (the C of described replacement _1～3alkyl can further be substituted or unsubstituted 3～8 yuan of heterocyclic radicals or replacement or unsubstituted amino replacement, and wherein, 3～8 yuan of heterocyclic radicals of described replacement or the amino of replacement also can be further by C _1～3alkyl replaces).

As an embodiment being more preferably of the present invention:

When Z=N, R ₁preferably

When Z=N, R ₂preferably methoxyl group, oxyethyl group, 3S-tetrahydrofuran base oxygen base, 2-(N-methyl-4-piperidyl) oxyethyl group, 3-(4-morpholinyl) propoxy-, 2-(N, N-diethylin)-oxyethyl group, 2,2,2-trifluoro ethoxy or 2-(methoxyl group)-oxyethyl group.

When Z=N, R ₃and R ₄independently of one another preferably hydrogen,

When Z=C-CN, R ₁be preferably

When Z=C-CN, R ₂be preferably oxyethyl group.

When Z=C-CN, R ₃and R ₄be preferably independently of one another hydrogen, N, N-dimethylamino methyl or piperidino methyl.

As a most preferred embodiment of the present invention:

Work as Z=N, R ₁during for the chloro-4-fluorophenyl of 3-, R ₂be preferably 3S-tetrahydrofuran base oxygen base, 2-(N-methyl-4-piperidyl) oxyethyl group, 2-(N, N-diethylamino)-oxyethyl group, 2,2,2-trifluoro ethoxy, 2-(methoxyl group)-oxyethyl group or oxyethyl group; R ₃and R ₄be preferably independently of one another hydrogen or piperidino methyl, more preferably R ₃and R ₄in one be hydrogen, another is hydrogen or piperidino methyl.

Work as Z=N, R ₁during for the bromo-phenyl of 3-or time, R ₂be preferably methoxyl group; R ₃and R ₄be preferably independently of one another hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R ₃and R ₄in one be hydrogen, another is piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R ₁for time, R ₂be preferably oxyethyl group; R ₃and R ₄be preferably independently of one another hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R ₃and R ₄in one be hydrogen, another is piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R ₁for time, R ₂be preferably oxyethyl group or 3-(4-morpholinyl) propoxy-; R ₃and R ₄be preferably independently of one another hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R ₃and R ₄in one be hydrogen, another is hydrogen, piperidino methyl or N, N-dimethylamino methyl.

Work as Z=N, R ₁for time, R ₂be preferably 3-(4-morpholinyl) propoxy-; R ₃and R ₄be preferably independently of one another hydrogen.

Work as Z=C-CN, R ₁during for the chloro-4-fluorophenyl of 3-, R ₂be preferably as oxyethyl group; R ₃and R ₄be preferably independently of one another hydrogen, piperidino methyl or N, N-dimethylamino methyl, more preferably R ₃and R ₄in one be hydrogen, another is hydrogen, N, N-dimethylamino methyl or piperidino methyl;

Work as Z=C-CN, R ₁for the bromo-phenyl of 3-, time, R ₂be preferably oxyethyl group; R ₃and R ₄be hydrogen.

Work as Z=C-CN, R ₁for time, R ₂be preferably oxyethyl group; R ₃and R ₄be preferably independently of one another hydrogen or N, N-dimethylamino methyl, more preferably R ₃and R ₄in one be hydrogen, another is hydrogen or N, N-dimethylamino methyl;

Work as Z=C-CN, R ₁for time, R ₂be preferably oxyethyl group; R ₃and R ₄be hydrogen.

Described suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are preferably as follows 1～41 arbitrary compound:

In above-claimed cpd 1～41, contain " key " compound refer to that this compound is cis and trans mixture.

It is a kind of as above suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt that the present invention also provides, the preparation method of the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, it is following either method:

1. method one comprises the steps:, in solvent, under the effect of alkali 1, compd A to be reacted with compd B, obtains Compound C; 2. in solvent, under the effect of alkali 2, the product C that 1. step is obtained is reacted with Compound D, obtains Compound I;

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

Wherein, R ₁, R ₂, R ₃, R ₄, R ₅, Z and X all as mentioned above, R and R ' are C independently of one another _1～6alkyl (preferred C _1～3alkyl).

1. method one step preferably includes following steps: compd A and alkali 1 mixed and be dissolved in solvent, react 15～60 minutes at-10 ℃～10 ℃, then mix with the solution of compd B, at 0 ℃～80 ℃, reacting.

Method one step 1. in, the solvent that the solvent in the solution of described compd B reacts with this is identical or different.The preferred DMF of solvent (DMF) in the solution of described compd B, DMSO, CH ₂cl ₂and CHCl ₃in one or more.

Method one step 1. in, the preferred DMF of described solvent (DMF), DMSO, CH ₂cl ₂and CHCl ₃in one or more.The consumption of described solvent generally do not affect reaction normally, preferred 10～100ml/g compd A.

Method one step 1. in, described alkali 1 can be organic bases or mineral alkali.The preferred triethylamine of described organic bases, DIPEA, pyridine or DMAP.The preferred sodium hydroxide of described mineral alkali, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, Quilonum Retard, cesium carbonate, saleratus or sodium bicarbonate.Described alkali 1 is preferably 1.0:1～3.0:1 with the mol ratio of compd A.

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

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

Method one step 1. in, the process of described reaction can be monitored by TLC or HPLC, when the compd A of generally usining disappears as the terminal of reaction.

Method one step 1. in, after described reaction finishes, also can be further purified product by last handling process.Described last handling process preferably includes following steps: cancellation reaction, and extractive reaction system, dry organic phase, concentrates and carries out column chromatography.Described cancellation reaction is preferably carried out with alkaline aqueous solution.The condition of described column chromatography and step all can be selected by the condition of the column chromatography of this area routine and step.

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

Method one step 2. in, one or more in described solvent preferred alcohol, methyl alcohol and Virahol.The consumption of described solvent be generally do not affect reaction normally.

Method one step 2. in, the preferred mineral alkali of described alkali 2.The preferred sodium hydride of described mineral alkali, potassium hydride KH, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide.Preferred 1:1～the 10:1 of mol ratio of described alkali 2 and Compound C.

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

Method one step 2. in, if contain amino in Compound D, described Compound D can the form by salt participate in reaction.Wherein, the salt preferably salt hydrochlorate of Compound D.

Method one step 2. in, the process of described reaction can be monitored by TLC or LC-MS, when the Compound C of generally usining disappears as the terminal of reaction.

Method one step 2. in, after described reaction finishes, also can be further purified product by last handling process.Described last handling process preferably includes following steps: below the pH regulator to 3.0 of reaction system, except mixing with water after desolventizing, then by more than the pH regulator to 10.0 of system, extraction, is dried organic phase, concentrates and carries out column chromatography purification.Conditioning agent below described pH regulator to 3.0 is preferably inorganic aqueous acid, as the aqueous hydrochloric acid of 4mol/L.The aqueous solution of the preferred mineral alkali of conditioning agent more than described pH regulator to 10.0, as the aqueous sodium hydroxide solution of 2mol/L.The organic solvent ethyl acetate of described extraction.The described siccative using when dry is preferably anhydrous sodium sulphate.Described column chromatography can be the column chromatography of this area routine, and its step and condition all can be selected according to conventional step and condition.

In method two, described reaction preferably includes following steps: by compd A and solvent, obtain solution, at-10 ℃～0 ℃, stir 5～10 minutes, then join in the solution of compd E, in system, add again alkali 1, react 30～40 minutes, be warming up to 10 ℃～50 ℃ and react.

In method two, one or more in the preferred methylene dichloride of described solvent, trichloromethane and ethylene dichloride.The consumption of described solvent does not generally affect the carrying out of reaction.

In method two, described alkali 1 can be organic bases or mineral alkali.The preferred triethylamine of described organic bases, DIPEA, pyridine or DMAP.The preferred sodium hydroxide of described mineral alkali, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, Quilonum Retard, cesium carbonate, saleratus or sodium bicarbonate.Preferred 2:1～the 4:1 of mol ratio of described alkali 1 and compd A.

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

In method two, the process of described reaction can be monitored by TLC or LC-MS, when the compd A of generally usining disappears as the terminal of reaction.

In method two, after described reaction finishes, also can be further purified product by last handling process.Described last handling process preferably includes following steps: after concentration response system, carry out column chromatography purification.Described column chromatography can be the column chromatography of this area routine, and 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 the product I obtaining is cis-trans-isomer can obtain pure cis or trans product I by the further separation of chiral column.The preferred AD-H chiral column of described chiral column.

It is a kind of suc as formula the compound shown in C that the present invention also provides,

Wherein, R ₁, R ₂, R, R ', X and Z all as mentioned above.

The present invention also provides and has contained above-mentioned formula I compound or its pharmacy acceptable salt, or the pharmaceutically useful composition of their solvate.

Wherein, described composition is by one or more formulas I compound, or its pharmacy acceptable salt, or their solvate and at least one pharmaceutical excipient composition.The selection of pharmaceutical excipient because of route of administration and effect feature different, conventionally can be weighting agent, thinner, tackiness agent, wetting agent, disintegrating agent, lubricant, emulsifying agent or suspending agent etc.

Pharmaceutical composition of the present invention can be by oral, injection (in vein, muscle, subcutaneous and coronary artery), hypogloeeis, through cheek, per rectum, per urethra, transvaginal, intranasal, suction or local approach, use, and optimization approach is oral.

The present invention also provides above-mentioned formula I compound or the application of aforementioned pharmaceutical compositions in the medicine of preparation EGFR tyrosine kinase inhibitor, A431 or H1975 inhibition of cell proliferation or prevention or treatment tumor disease.

On the basis of this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.

Agents useful for same of the present invention and raw material be commercially available obtaining all.

Positive progressive effect of the present invention is: the invention provides quinoline or quinazoline derivant that a class is new, its pharmacodynamics embodiment testing data shows: it is inhibited to EGFR Tyrosylprotein kinase, and A431 and H1975 cell are had to obvious inhibition proliferation activity.

some technical term of chemistry relating in the present invention are explained as follows:

" C _1～3" refer to that in its defined group (as alkyl, alkoxyl group, aryl, heteroaryl etc.), carbon atom number is 1,2 or 3.Can know the implication of other terms of describing in a similar manner by inference thus, as " C _1～5" " C _6～10" etc.

" 3～8 yuan " refer to that the atom number that surrounds this closed hoop skeleton itself in its defined closed ring system group (as heterocyclic radical, aryl, heteroaryl etc.) is 3,4,5,6,6,7 or 8, can get different numbers according to the number of rings of closed ring system group, saturation ratio and the atomic property that forms this ring etc.Can know the implication of other terms of describing in a similar manner by inference thus, as " 3～6 yuan ", " 4～6 yuan " etc.

" alkyl " only refer to by carbon atom form with hydrogen atom, containing unsaturated link(age), there is 1 to 12 carbon atom for example and the hydrocarbon chain group of the straight or branched that is connected with the rest part of molecule by singly-bound.Conventionally, the example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-methyl butyl, 2,2-dimethyl propyl, n-hexyl, heptyl, 2-methyl hexyl, 3-methyl hexyl, octyl group, nonyl and decyl etc.

" alkoxyl group " refers to formula-OR _agroup, wherein R _afor " alkyl " as hereinbefore defined.Conventionally, the example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy etc.

" cycloalkyl " refers to stable non-aromatic monocycle or the multi-ring alkyl being only comprised of carbon atom and hydrogen atom, can comprise fused rings system, bridged-ring system or volution system, conventionally has 3 to 15 carbon atoms.It can be connected with the rest part of molecule by singly-bound via the upper any suitable carbon atom of ring.Conventionally, the example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.With regard to object of the present invention, preferably there is the cycloalkyl of the monocycle system of 3 to 6 carbon atoms.

" heterocyclic radical " refers to by 2 to 14 carbon atoms and 1 to 6 common 3 yuan to 20 yuan stable non-aromatic cyclic group that form of heteroatoms that are selected from nitrogen, oxygen and sulphur, it can, for the member ring systems of monocycle, dicyclo, three rings or more rings, also can comprise fused rings system, bridged-ring system or volution system.It can be connected with the rest part of molecule by singly-bound via carbon atom or the heteroatoms of the upper any suitable of ring.Nitrogen-atoms wherein can optionally further be replaced to form tertiary amine or quaternary ammonium structure by other groups.Conventionally, the example of heterocyclic radical includes but not limited to that nitrogen heterocyclic propyl group, azelidinyl, oxa-cyclobutyl, pyrrolidyl, imidazolinyl, pyrazolidyl, imidazolidyl, thiazolidyl, isothiazole alkyl, isoxazole alkyl, tetrahydrofuran base, dioxolanyl, oxa-cyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazine base, N-replace homopiperazine base, piperidyl, N-substituted piperidine base, dioxane base, indolinyl, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base etc.With regard to object of the present invention, preferably 3 yuan to 8 yuan and at least contain 1 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen or oxygen, further preferably 4 yuan to 6 yuan and at least contain 1 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen or oxygen, more preferably 4 yuan to 6 yuan and contain 1～2 heterocyclic radical that is selected from the heteroatomic monocycle system of nitrogen or oxygen.

" heterocyclic oxy group " refers to formula-OR _bgroup, wherein R _bfor " heterocyclic radical " as hereinbefore defined.Conventionally, the example of heterocyclic oxy group includes but not limited to pyrrolidyl oxygen base, tetrahydrofuran base oxygen base, dioxolanyl oxygen base, morpholinyl oxygen base, piperazinyl oxygen base, piperidyl oxygen base etc.

" aryl " or " aromatic ring " refers to the conjugation aromaticity hydrocarbon member ring systems group with 6 to 18 carbon atoms, can be monocycle, dicyclo, three rings or polycyclic system more.It can be connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.Conventionally, the example of aryl includes but not limited to phenyl, naphthyl, anthryl, phenanthryl, fluorenyl etc.With regard to object of the present invention, preferably there is 6 to 10 monocycles of carbon atom or the aryl of bicyclic system or aromatic ring.

" heteroaryl " or " hetero-aromatic ring " refers to by 1 to 15 carbon atom and 1 to 6 common 5 yuan to 16 yuan conjugation aromaticity ring system group that form of heteroatoms that are selected from nitrogen, oxygen and sulphur, can be monocycle, dicyclo, three rings or polycyclic system more, it can be connected with the rest part of molecule by singly-bound via the atom on aromatic nucleus.Conventionally, the example of heteroaryl includes but not limited to pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazol radical, tetrazole base, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indazolyl, benzimidazolyl-, benzotriazole base, quinolyl, isoquinolyl, benzothiazolyl, benzo pyridazinyl, quinazolyl, quinoxalinyl etc.With regard to object of the present invention, 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 hereinbefore defined.Conventionally, the example of heteroaryloxy includes but not limited to furans oxygen base, thiophene oxy, pyridyloxy, 2-pyrimidinyl oxy, indoxyl, quinoline oxy etc.

Embodiment

Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.

Embodiment 1

The preparation of N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides

The preparation of step 1 4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-6-(the fluoro-2-diethoxy of 2-phosphate acetyl) amino-7-methoxyl group quinazoline

Raw material: ((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline is pressed document J.Med.Chem.2009 to 6-amino-4-, the preparation of 52,6880-6888 method.

The fluoro-2-diethoxy of raw material: 2-phosphoryl Acetyl Chloride 98Min. is pressed document Heterocycles, the preparation of 2004,63,699-706 method.

By 6-amino-4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline (1eq.) (876mg) and triethylamine (1.5eq.) (423 μ L) be dissolved in DMF (10ml), this solution stirs 30min at 0 ℃.DMF (5ml) solution of the fluoro-2-diethoxy of 2-phosphoryl Acetyl Chloride 98Min. (1.5eq.) (640 μ L) is slowly added drop-wise in above-mentioned solution, and then under room temperature, stirring reaction spends the night.After reaction finishes, use saturated NaHCO ₃cancellation, EtOAc extraction, organic phase is with anhydrous sodium sulfate drying, be evaporated to dry crude product, through column chromatography purification (moving phase 40:1DCM/MeOH) flaxen 4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-6-(the fluoro-2-diethoxy of 2-phosphate kharophen)-7-methoxyl group quinazoline 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(C ₂₈H ₂₈ClF ₂N ₄O ₆P+H) ⁺:621.1481;found:621.1475。

Step 2 N-4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline-6-yl) preparation of-4-(dimethylamino)-2-fluorine but-2-enamides

The sub-hydrochloride of raw material: 2-(dimethylamino)-acetaldehyde is pressed the preparation of document WO2007/85638 method.

By upper step product 4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-6-(the fluoro-2-diethoxy of 2-phosphate kharophen)-7-methoxyl group quinazoline (1eq.) (150mg) and 2-(dimethylamino)-acetaldehyde hydrochloride (2.0eq.) (71mg), be dissolved in EtOH (10ml), in 0 ℃, stir 30min, the solution that adds again NaOH (112mg) water-soluble (1mL), remove ice bath, naturally return to after room temperature, continue stirring reaction 0.5h.After reaction finishes, with 4N hydrochloric acid, adjust pH to 1.0, be spin-dried for solvent, add water, with 2NNaOH solution, regulate pH to 12.0, EtOAc extraction, organic phase is with anhydrous sodium sulfate drying, be evaporated to dry crude product, through column chromatography purification (moving phase 30:1DCM/MeOH) flaxen N-4-((the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides 0.1g.

HRMS(ESI):m/z calcd for(C ₂₈H ₂₆ClF ₂N ₅O ₃+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 isomer separately)

Embodiment 2

(Z)-N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides and (E)-N-(4-(the chloro-4-of 3-(3-fluorine benzyloxy) phenylamino)-7-methoxyl group quinazoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides and preparation

The mixture of the cis-trans-isomer that employing Thar SFC Pre80 Overcritical prepared chromatographic instrument obtains embodiment 1 carries out separation.

Chromatographic column: AD-H (20 * 250mm, 5 μ m, Tianjin Agela)

Monitoring wavelength: 254nm

Column temperature: 38 degree

Sample dissolution: dissolve with methanol, filters

Moving phase: ethanol (containing 0.1%DEA): carbonic acid gas=40:60

Collect retention time 5.09min component and obtain (Z)-type isomer (compound 2-1); Retention time 8.61min component obtains (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, adopt different raw materials, prepare following compound, the product obtaining is cis-trans-isomer mixture.

Embodiment 12～17

According to SFC equipment described in embodiment 2, the compound that embodiment 4,6 is obtained with 11 (cis-trans-isomer mixture) carries out respectively separated, is prepared as follows compound:

Embodiment 18

(S) preparation of-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(tetrahydrofuran (THF)-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide

The preparation of step 1 4-(the chloro-4-fluorophenyl of 3-is amino)-6-nitro-7-(tetrahydrofuran (THF)-3S-oxygen base) quinazoline

Raw material: 6-nitro-4-(the chloro-4-fluorophenyl of 3-is amino)-7-fluquinconazole quinoline is pressed document J.Med.Chem.2009, the preparation of 52,6880-6888 method.

6-nitro-4-(the chloro-4-fluorophenyl of 3-is amino)-7-fluquinconazole quinoline (1eq.) (3.03g) (1.2ml) is dissolved in DMSO (10ml) with S-tetrahydrofuran (THF)-3-alcohol (1.5eq.), and this solution stirs 5min under water bath condition.Potassium tert.-butoxide (3.0eq.) DMSO (5ml) solution (3.36g) is slowly added drop-wise in above-mentioned solution, then stirring reaction 30min under room temperature.After reaction finishes, add the dilution of 100ml water, with concentrated hydrochloric acid, regulate pH to neutral, stir 30min, separate out a large amount of yellow solids, filter, filter cake washes twice with water, dry yellow 4-(the chloro-4-fluorophenyl of 3-is amino)-6-nitro-7-(tetrahydrofuran (THF)-3S-oxygen base) the quinazoline solid 6.53g that obtains. 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(C ₁₈H ₁₄ClFN ₄O ₄+H) ⁺:405.0766;found:405.0775.

The preparation of step 2 4-(the chloro-4-fluorophenyl of 3-is amino)-6-amino-7-(tetrahydrofuran (THF)-3S-oxygen base) quinazoline

By upper step product 4-(3-chloro-4-fluorophenyl amino)-6-nitro-7-(tetrahydrofuran (THF)-3S-oxygen base) quinazoline (1eq.) (4.04g) and NiCl ₂6H ₂o (2.0eq.) (4.75g) is dissolved in DCM/MeOH (32ml:8ml), in 0 ℃ of stirring 5min, adds NaBH in batches ₄(4.0eq.) (1.51g), removes ice bath, naturally returns to after room temperature, continues stirring reaction 30min.After reaction finishes, be evaporated to dry crude product, through column chromatography purification (moving phase 10:1DCM/MeOH) flaxen 4-(the chloro-4-fluorophenyl of 3-is amino)-6-amino-7-(tetrahydrofuran (THF)-3-oxygen base) 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(C ₁₈H ₁₆ClFN ₄O ₂+H)+:375.1024;found:375.1012.

The preparation of step 3 (S)-N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(tetrahydrofuran (THF)-3-oxygen base) quinazoline-6-yl)-2-fluorine acrylamide

2-perfluoroalkyl acrylate (2.0eq.) (54mg) is dissolved in DCM (10ml), add 3 DMF, under condition of ice bath, be added dropwise to oxalyl chloride (1.7eq.) (44 μ L), under condition of ice bath, react 30min, remove ice bath, naturally return to room temperature, react 2 hours, upper step product 4-(the chloro-4-fluorophenyl of 3-is amino)-6-amino-7-(tetrahydrofuran (THF)-3-oxygen base) quinazoline (1eq.) (112mg) is dissolved in DCM (20ml), in 0 ℃ of stirring 5min, be added in above-mentioned solution of acid chloride, add Et ₃n(4.0eq.) (169 μ L) reacts 30min under condition of ice bath, removes ice bath, naturally returns to after room temperature, continues stirring reaction and spends the night.After reaction finishes, be evaporated to dry crude product, through column chromatography purification (moving phase 10:1DCM/MeOH) flaxen N-(4-(the chloro-4-fluorophenyl of 3-is amino)-7-(tetrahydrofuran (THF)-3-oxygen base) quinazoline-6-yl)-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(C ₂₁H ₁₇ClF ₂N ₄O ₃+H)+:447.1035;found:447.1035.

Embodiment 19～25

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

Embodiment 26

The preparation of N-(4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-fluorine acrylamide

The preparation of step 1 4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-6-amino-7-ethoxyquinoline

Raw material: N-(4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-7-ethoxyquinoline-6-yl) ethanamide is pressed document J.Med.Chem.2005, the preparation of 48,1107-1131 method.

N-(4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-7-ethoxyquinoline-6-yl) ethanamide (1eq.) (0.6g) is dissolved in concentrated hydrochloric acid 10ml, back flow reaction is spent the night, after reaction finishes, be evaporated to dry crude product, through column chromatography purification (moving phase 10:1DCM/MeOH) flaxen 4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-6-amino-7-ethoxyquinoline 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(C ₁₈H ₁₄ClFN ₄O+H)+:357.0918;found:357.0911.

The preparation of step 2N-(4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-fluorine acrylamide

2-perfluoroalkyl acrylate (2.0eq.) (40mg) is dissolved in DCM (10ml), add 3 DMF, under condition of ice bath, be added dropwise to oxalyl chloride (1.8eq.) (33 μ L), under condition of ice bath, react 30min, remove ice bath, naturally return to room temperature, react 2 hours, upper step product 4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-6-amino-7-oxyethyl group quinazoline (1eq.) (107mg) is dissolved in DCM (20ml), in 0 ℃ of stirring 5min, be added in above-mentioned solution of acid chloride, add Et ₃n(4.0eq.) (169 μ L) reacts 30min under condition of ice bath, removes ice bath, naturally returns to after room temperature, continues stirring reaction and spends the night.After reaction finishes, be evaporated to dry crude product, through column chromatography purification (moving phase 10:1DCM/MeOH) flaxen N-(4-(the chloro-4-fluorophenyl of 3-is amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-fluorine acrylamide, 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(C ₂₁H ₁₅ClF ₂N ₄O ₂+H)+:429.0930;found:429.0933.

Embodiment 27

The preparation of N-(4-(the chloro-4-fluoroanilino of 3-)-3-cyano group-7-ethoxyquinoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides

The step 1 4-(preparation of (the chloro-4-fluoroanilino of 3-)-3-cyano group-6-(the fluoro-2-diethoxy of 2-phosphate acetyl) amino-7-ethoxyquinoline

Raw material: ((the chloro-4-fluoroanilino of 3-)-7-ethoxyquinoline is pressed embodiment 26 method preparations to 3-cyano group-6-amino-4-.

By 3-cyano group-6-amino-4-((the chloro-4-fluoroanilino of 3-)-7-ethoxyquin azoles (1eq.) (308mg) and triethylamine (1.5eq.) (190 μ L) be dissolved in DMF (10ml), this solution stirs 30min at 0 ℃.The fluoro-2-diethoxy of 2-phosphoryl Acetyl Chloride 98Min. (1.5eq.) DMF (5ml) solution (313mg) is slowly added drop-wise in above-mentioned solution, and then under room temperature, stirring reaction spends the night.After reaction finishes, use saturated NaHCO ₃cancellation, EtOAc extraction, organic phase is with anhydrous sodium sulfate drying, be evaporated to dry crude product, through column chromatography purification (moving phase 40:1DCM/MeOH) flaxen 4-((the chloro-4-fluoroanilino of 3-)-3-cyano group-6-(the fluoro-2-diethoxy of 2-phosphate acetyl) amino-7-ethoxyquinoline 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(C ₂₄H ₂₄ClF ₂N ₄O ₅P+H) ⁺:553.1219;found:553.1205.

The preparation of step 2N-(4-(the chloro-4-fluoroanilino of 3-)-3-cyano group-7-ethoxyquinoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides

By upper step product 4-((the chloro-4-fluoroanilino of 3-)-3-cyano group-6-(the fluoro-2-diethoxy of 2-phosphate kharophen)-7-ethoxyquinoline (1eq.) (105mg) and 2-(dimethylamino)-acetaldehyde hydrochloride (2.0eq.) (57mg), be dissolved in EtOH (10ml), in 0 ℃, stir 30min, the aqueous solution that adds again NaOH (90mg), remove ice bath, naturally return to after room temperature, continue stirring reaction 0.5h.After reaction finishes, with 4N hydrochloric acid, adjust pH to 1.0, be spin-dried for solvent, add water, with 2NNaOH solution, regulate pH to 12.0, EtOAc extraction, organic phase is with anhydrous sodium sulfate drying, be evaporated to dry crude product, through column chromatography purification (moving phase 30:1DCM/MeOH) flaxen N-(4-(the chloro-4-fluoroanilino of 3-)-3-cyano group-7-ethoxyquinoline-6-yl)-4-(dimethylamino)-2-fluorine but-2-enamides, 100mg.

HRMS(ESI):m/z calcd for(C ₂₄H ₂₂ClF ₂N ₅O ₂+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 isomer separately)

Embodiment 28～29

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

Embodiment 30

The preparation of N-(4-(3-bromobenzene is amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-propenyl chloride acid amides

The preparation of step 1:N-(4-((3-bromophenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl) ethanamide

The chloro-3-cyano group-7-of raw material: N-(4-ethoxyquinoline-6-yl) ethanamide is pressed document J.Med.Chem.2009, the preparation of 52,6880-6888 method.N-(the chloro-3-cyano group-7-of 4-ethoxyquinoline-6-yl) ethanamide 0.61g, m-bromoaniline 0.21ml and pyridine hydrochloride 0.22g are joined in 10ml Virahol to return stirring 16 hours.After reaction finishes, naturally return to room temperature, suction filtration, washing, obtains yellow solid, dry, for next step, productive rate 83%.

The preparation of step 2:6-amino-4-(3-bromophenyl is amino)-7-ethoxyquinoline-3-formonitrile HCN

Upper step product N-(the chloro-3-cyano group-7-of 4-ethoxyquinoline-6-yl) ethanamide 0.7g is joined in 5ml concentrated hydrochloric acid to stirring and refluxing 3 hours, after reaction finishes, naturally return to room temperature, be spin-dried for solvent, with saturated sodium bicarbonate washing, then suction filtration, collect yellow solid, dry, productive rate 74.4%.

The preparation of step 3:N-(4-(3-bromophenyl is amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-propenyl chloride acid amides

2-chloracrylic acid (2.0eq.) (167mg) is dissolved in DCM (10ml), add 3 DMF, under condition of ice bath, be added dropwise to oxalyl chloride (1.7eq.) (138 μ L), under condition of ice bath, react 30min, remove ice bath, naturally return to room temperature, react 2 hours, upper step product 3-itrile group-6-amino-4-((3-bromophenyl) amino)-7-ethoxyquinoline (1eq.) (300mg) is dissolved in DCM (20ml), in 0 ℃ of stirring 5min, be added in above-mentioned solution of acid chloride, add Et ₃n(4.0eq.) (474 μ L) reacts 30min under condition of ice bath, removes ice bath, naturally returns to after room temperature, continues stirring reaction and spends the night.After reaction finishes, be evaporated to dry crude product, through column chromatography purification (moving phase 10:1DCM/MeOH), obtain flaxen N-(4-((3-bromophenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-propenyl chloride acid amides 80mg, productive rate 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

Fluoro-benzyloxy-the phenyl amino of the chloro-4-(3-of step 1:N-{4-[3-]-3-cyano group-7-ethoxyquinoline-6-yl } preparation of-ethanamide

By N-(the chloro-3-cyano group-7-of 4-ethoxyquinoline-6-yl) the chloro-4-of ethanamide 0.658g, 3-(the fluoro-benzyloxy of 3-)-aniline (according to Journal of Medicinal Chemistry, 53 (24), 8546-8555; Method preparation described in 2010) 0.567g and pyridine hydrochloride 0.262g join in 20ml Virahol, return stirring 16 hours.After reaction finishes, naturally return to room temperature, suction filtration, washing, obtains brown solid, productive rate 77.8%.

Fluoro-benzyloxy-the phenyl amino of the chloro-4-(3-of step 2:6-amino-4-[3-] preparation of-7-ethoxyquinoline-3-formonitrile HCN

In a 100ml round-bottomed flask, add the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of step 1 product N-{4-[3-]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide 0.3g, then add methyl alcohol 10ml, add 30% potassium hydroxide 10ml, be warming up to backflow.After TLC detection reaction finishes, use saturated NH ₄cl10ml cancellation reaction, vacuum is revolved methyl alcohol, and suction filtration first washes with water for 3 times 3 times with saturated sodium bicarbonate solution washing later.Dry.Product is crossed column purification.Obtain yellow solid, productive rate 82.8%.

The chloro-4-((3-luorobenzyl of the chloro-N-(4-((3-of step 3:2-) oxygen base) phenyl) the amino)-3-cyano group-7-ethoxyquinoline-6-yl) preparation of acrylamide

In dry 100ml round-bottomed flask, add 2-chloracrylic acid 0.213g, add 20ml anhydrous methylene chloride, stir, then add after 3 DMF, transfer in ice bath.Add oxalyl chloride 148 μ l, continue to stir.Deicing is bathed, and continues to stir after two hours under normal temperature, and system is transferred in 50 ℃ of water-baths, stirs 10 minutes, then transfers in ice bath.

By the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of step 2 product 6-amino-4-[3-of 0.445g] the use 10ml anhydrous methylene chloride dissolving in 50ml round-bottomed flask of-7-ethoxyquinoline-3-formonitrile HCN, then pour in above-mentioned solution of acid chloride.Add triethylamine 760.5 μ l.After reaction is spent the night, cross post and process.Obtain yellow solid, productive rate 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 step 1 and the step 2 of embodiment 31.

The chloro-4-((3-luorobenzyl of the fluoro-N-(4-((3-of step 3:2-) oxygen base) phenyl) the amino)-3-cyano group-7-ethoxyquinoline-6-yl) preparation of acrylamide

Wherein, except 2-perfluoroalkyl acrylate replaces 2-chloracrylic acid, adopt method and the condition identical with step 3 in embodiment 31, obtain yellow solid, productive rate 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

The chloro-4-of step 1:N-{4-[3-(pyridine-2-ylmethoxy)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl } preparation of-ethanamide

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

The chloro-4-of step 2:6-amino-4-[3-(pyridine-2-ylmethoxy)-phenyl amino] preparation of-7-ethoxyquinoline-3-formonitrile HCN

Except with the chloro-4-of step 1 product N-{4-[3-(pyridine-2-ylmethoxy)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material N-{4-[3-of embodiment 31 steps 2]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide, adopt the method identical with step 2 in embodiment 31, obtain yellow solid, productive rate 97%.

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

Except with the chloro-4-of step 2 product 6-amino-4-[3-(pyridine-2-ylmethoxy)-phenyl amino]-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 31 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 31, obtain yellow solid.Productive rate 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 step 1 and the step 2 of embodiment 33.

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

Except with the chloro-4-of step 2 product 6-amino-4-[3-(pyridine-2-ylmethoxy)-phenyl amino]-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 32 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 32, obtain yellow solid.Productive rate 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 step 1 and the step 2 of embodiment 30.

Step 3:N-[4-(the bromo-phenyl amino of 3-)-3-cyano group-7-ethoxyquinoline-6-yl] the preparation of-fluoro-acrylamide of 2-

Except replace the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 30 steps 3 with step 2 product 6-amino-4-(the bromo-phenyl amino of 3-)-7-ethoxyquinoline-3-formonitrile HCN]-7-ethoxyquinoline-3-formonitrile HCN, with 2-perfluoroalkyl acrylate, replace 2-chloracrylic acid, adopt the method identical with step 3 in embodiment 30, obtain yellow solid.Productive rate 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

The chloro-4-of step 1:N-{4-[3-(1H-indoles-4-base oxygen base)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl } preparation of-ethanamide

Except replace the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine with the chloro-4-of 3-(1H-indoles-4-base oxygen base)-aniline, adopt the method identical with step 1 in embodiment 31, obtain brown solid, productive rate 78%.

The chloro-4-of step 2:6-amino-4-[3-(1H-indoles-4-base oxygen base)-phenyl amino] preparation of-7-ethoxyquinoline-3-formonitrile HCN

Except with the chloro-4-of step 1 product N-{4-[3-(1H-indoles-4-base oxygen base)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material N-{4-[3-of embodiment 31 steps 2]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide, adopt the method identical with step 2 in embodiment 31, obtain brown solid, productive rate 93.8%.

The chloro-4-of the chloro-N-{4-[3-of step 3:2-(1H-indoles-4-base oxygen base)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl } preparation of-acrylamide

Except with the chloro-4-of step 2 product 6-amino-4-[3-(1H-indoles-4-base oxygen base)-phenyl amino]-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 31 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 31, obtain yellow solid.Productive rate 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 step 1 and the step 2 of embodiment 36.

The chloro-4-of the fluoro-N-{4-[3-of step 3:2-(1H-indoles-4-base oxygen base)-phenyl amino]-3-cyano group-7-ethoxyquinoline-6-yl } preparation of-acrylamide

Except with the chloro-4-of step 2 product 6-amino-4-[3-(1H-indoles-4-base oxygen base)-phenyl amino]-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 32 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 32, obtain yellow solid.Productive rate 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

The chloro-4-((6-picoline-3-of step 1:N-(4-((3-yl) oxygen base) phenyl) the amino)-3-cyano group-7-ethoxyquinoline-6-yl) preparation of ethanamide

Except with the chloro-4-(of 3-p-tolyloxy) aniline replaces, the chloro-4-of 3-(the fluoro-benzyloxy of 3-)-phenyl amine, adopting the method identical with step 1 in embodiment 31, obtains brown solid, productive rate 79%.

The chloro-4-((6-picoline-3-of step 2:6-amino-4-((3-yl) the oxygen base) phenyl) amino) preparation of-7-ethoxyquinoline-3-formonitrile HCN

In a 50ml round-bottomed flask, add the chloro-4-((6-picoline-3-of 0.6g step 1 product N-(4-((3-yl) oxygen base) phenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl) ethanamide and 10ml concentrated hydrochloric acid, reflux stirs 3 hours, and TLC detection reaction finishes, stopped reaction, naturally cool to room temperature, be spin-dried for solvent, with saturated sodium bicarbonate washing, filter, collect solid, dry, obtain tawny solid, yield 93%.

The preparation of step 3:N-(4-((the chloro-4-of 3-((6-picoline-3-yl) oxygen base) phenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-propenyl chloride acid amides

Except with step 2 product 6-amino-4-((3-chloro-4-((6-picoline-3-yl) oxygen base) phenyl) amino)-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 31 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 31, obtain yellow solid.Productive rate 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 step 1 and the step 2 of embodiment 38.

The preparation of step 3:N-(4-((the chloro-4-of 3-((6-picoline-3-yl) oxygen base) phenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-fluorine acrylamide

Except with step 2 product 6-amino-4-((3-chloro-4-((6-picoline-3-yl) oxygen base) phenyl) amino)-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 31 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, with 2-perfluoroalkyl acrylate, replace 2-chloracrylic acid, adopt the method identical with step 3 in embodiment 32, obtain yellow solid.Productive rate 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

The chloro-4-(cyclo propyl methoxy of step 1:N-(4-((3-) phenyl) Amino 3 cyano-7-ethoxyquinoline-6-yl) preparation of ethanamide

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

The chloro-4-(cyclo propyl methoxy of step 2:6-amino-4-((3-) phenyl) amino) preparation of-7-ethoxyquinoline-3-formonitrile HCN

Except with step 2 product N-(4-((3-chloro-4-(cyclo propyl methoxy) phenyl) Amino 3 cyano-7-ethoxyquinoline-6-yl) ethanamide replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material N-{4-[3-of embodiment 31 steps 2]-3-cyano group-7-ethoxyquinoline-6-yl }-ethanamide, adopt the method identical with step 2 in embodiment 31, obtain yellow solid, productive rate 57%.

The preparation of step 3:N-(4-((the chloro-4-of 3-(cyclo propyl methoxy) phenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-propenyl chloride acid amides

Except with step 2 product 6-amino-4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino) preparation of-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 31 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 31, obtain yellow solid.Productive rate 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 step 1 and the step 2 of embodiment 40.

The preparation of step 3:N-(4-((the chloro-4-of 3-(cyclo propyl methoxy) phenyl) amino)-3-cyano group-7-ethoxyquinoline-6-yl)-2-fluorine acrylamide

Except with step 2 product 6-amino-4-((3-chloro-4-(cyclo propyl methoxy) phenyl) amino)-7-ethoxyquinoline-3-formonitrile HCN replaces the fluoro-benzyloxy-phenyl amino of the chloro-4-(3-of raw material 6-amino-4-[3-of embodiment 32 steps 3]-7-ethoxyquinoline-3-formonitrile HCN, adopt the method identical with step 3 in embodiment 32, obtain yellow solid.Productive rate 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)。

The restraining effect of effect embodiment 1 the compounds of this invention to EGFR tyrosine kinase activity

Test-compound is to the active 503nhibiting concentration IC that uses of kinase whose inhibition ₅₀value represents.Such test adopts homogeneous phase time discrimination fluorescence (HTRF) technology to measure, method is as follows: by the compound of a series of gradient concentrations, jointly hatch 5 minutes with the enzyme solution of certain concentration at ambient temperature, add afterwards appropriate enzyme reaction substrate, ATP, start enzyme reaction process, after 30 minutes, in enzyme reaction system, add appropriate reaction terminating liquid and detect liquid, hatch after 1 hour, on the EnVision2104 of PerkinElmer company multiple labeling micropore detector, under 665nm and 620nm wavelength, measure the enzyme activity under specific compound concentration, and the compound that calculates different concns is active to the inhibition of enzyme activity, afterwards according to four parametric equations, inhibition activity to enzyme activity under different concns compound is carried out matching, calculate IC ₅₀value.The kinases EGFR that the present embodiment adopts is purchased from Sigma Aldrich, and detection kit HTRFKinEASE-TK is purchased from Cisbio Bioassays company, and ATP is purchased from Sigma Aldrich company.The IC of test-compound of the present invention ₅₀data are as follows:

Effect embodiment 2 compounds are to A431, the determination of activity of H1975 cell inhibitory effect

This example is used for measuring the compounds of this invention for the proliferation inhibition activity of EGFR wild-type overexpression cell line A431 and T790M point mutation cell strain H1975, the active half-inhibition concentration IC that uses of the inhibition of compound on cell proliferation ₅₀represent.Testing program 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 concn (A431:20000 cell/ml substratum, H1975:15000 cell/ml substratum) cell is inoculated on 384 well culture plates of White-opalescent, cell is positioned over to 37 ℃ afterwards, 5%CO ₂environment in cultivate, after 24 hours, to the medicine that adds a series of concentration gradients in cultured cells substratum, 10 concentration of general selection, afterwards cell is put back in former culture environment and continued to cultivate 48 hours, afterwards according to the method for CellTiter-Glo Luminescent Cell Viability Assay, at the EnVision2104 of PerkinElmer company multiple labeling micropore detector, measure the impact of test-compound on A431 and H1975 cell proliferation, and the inhibition of compound on cell proliferation of calculating different concns is active, CellTiter-Glo Luminescent Cell Viability Assay detection reagent is purchased from Promega.Afterwards A431 under the compound of different concns and H1975 cell inhibitory effect activity are carried out to four parameter fittings, the IC of test-compound of the present invention ₅₀data are as follows:

Embodiment numbering	IC ₅₀(A431)(μM)	IC ₅₀(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 inhibition proliferation activity to A431 and H1975.

Claims

1. suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug;

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

R ₁for the C replacing _6～10aryl, described in be substituted by by one or more and be selected from following substituting group and replace: halogen, replacement or unsubstituted C _1～3alkoxyl group, and replacement or unsubstituted C _5～8heteroaryloxy;

R ₂for replacing or unsubstituted C _1～3alkoxyl group or 3～8 yuan of heterocyclic oxy groups;

R ₃and R ₄be hydrogen independently of one another, or replacement or unsubstituted C _1～3alkyl;

And, suc as formula the quinoline shown in I or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug are not following arbitrary compound:

2. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₁for the C at least being replaced by a halogen _6～10aryl.

3. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₃and R ₄in at least one is hydrogen.

4. quinoline as claimed in claim 3 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: work as R ₃and R ₄in have one when the hydrogen, X is fluorine; Work as R ₃and R ₄while being hydrogen, X is fluorine or chlorine.

5. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₁in, as the described C that is substituted by replacement _1～3during alkoxyl group, the C of described replacement _1～3alkoxyl group is further substituted or unsubstituted C _5～6aryl, replacement or unsubstituted C _5～6heteroaryl or 3～6 yuan of cycloalkyl substituted.

6. quinoline as claimed in claim 5 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₁in, as the described C that is substituted by replacement _1～3during alkoxyl group, the C of described replacement _1～3the C that alkoxyl group is further replaced by halogen _5～6the C that aryl or halogen replace _5～6heteroaryl replaces.

7. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₁in, when described being substituted by replaces or unsubstituted C _5～8during heteroaryloxy, described replacement or unsubstituted C _5～8heteroaryloxy is replacement or the unsubstituted C that contains 1 nitrogen-atoms _5～8heteroaryloxy.

8. quinoline as claimed in claim 7 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: R ₁in, as the described C that is substituted by the replacement that contains 1 nitrogen-atoms _5～8during heteroaryloxy, described in contain 1 nitrogen-atoms the C of replacement _5～8heteroaryloxy is further by C _1～3alkyl replaces; The described replacement that contains 1 nitrogen-atoms or unsubstituted C _5～8heteroaryloxy is pyridyl or indyl.

9. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that:

Work as R ₂for replacing or unsubstituted C _1～3during alkoxyl group, the C of described replacement _1～3alkoxyl group is further substituted or unsubstituted 3～8 yuan of heterocyclic radicals, replacement or unsubstituted amino, halogen or C _1～3alkoxyl group replaces;

Work as R ₂while being 3～8 yuan of heterocyclic oxy groups, described 3～8 yuan of heterocyclic oxy groups are 3～8 yuan of heterocyclic oxy groups that contain Sauerstoffatom.

10. quinoline as claimed in claim 9 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that:

Work as R ₂for replacing or unsubstituted C _1～3alkoxyl group, the C of described replacement _1～3when alkoxyl group is further replaced by halogen, described halogen is fluorine;

Work as R ₂for replacing or unsubstituted C _1～3alkoxyl group, the C of described replacement _1～3alkoxyl group is when further the amino of substituted 3～8 yuan of heterocyclic radicals or replacement replaces, and 3～8 yuan of heterocyclic radicals of described replacement or the amino of replacement are further by C _1～5alkyl replaces;

Described 3～8 yuan of heterocyclic oxy groups that contain Sauerstoffatom are tetrahydrofuran base oxygen base.

11. quinoline as claimed in claim 9 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: work as R ₂for replacing or unsubstituted C _1～3alkoxyl group, the C of described replacement _1～3when alkoxyl group is further substituted or unsubstituted 3～8 yuan of heterocyclic radicals replace, described 3～8 yuan of heterocyclic radicals are pyrrolidyl, piperidyl, piperazinyl or morpholinyl.

12. quinoline as claimed in claim 10 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: the absolute configuration of described tetrahydrofuran base oxygen base is 3S.

13. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: work as R ₃and R ₄independently of one another for replacing or unsubstituted C _1～3during alkyl, the C of described replacement _1～3alkyl is further substituted or unsubstituted amino or 3～8 yuan of heterocyclic radicals replacements, and described 3～8 yuan of heterocyclic radicals are 3～8 yuan of heterocyclic radicals that contain 1 nitrogen-atoms.

14. quinoline as claimed in claim 13 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that:

Work as R ₃and R ₄independently of one another for replacing or unsubstituted C _1～3during alkyl, the C of described replacement _1～3in alkyl, described in contain 1 nitrogen-atoms 3～8 yuan of heterocyclic radicals be piperidyl;

Work as R ₃and R ₄independently of one another for replacing or unsubstituted C _1～3alkyl, the C of described replacement _1～3alkyl is during further substituted amino replacement, and the amino of described replacement is further by C _1～3alkyl replaces.

15. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that:

When Z=N, R ₁for

Or, when Z=N, R ₂for methoxyl group, oxyethyl group, 3S-tetrahydrofuran base oxygen base, 2-(N-methyl-4-piperidyl) oxyethyl group, 3-(4-morpholinyl) propoxy-, 2-(N, N-diethylin)-oxyethyl group, 2,2,2-trifluoro ethoxy or 2-(methoxyl group)-oxyethyl group;

Or, when Z=N, R ₃and R ₄be independently of one another hydrogen,

Or, when Z=C-CN, R ₁for

Or, when Z=C-CN, R ₂for oxyethyl group;

Or, when Z=C-CN, R ₃and R ₄be hydrogen, N independently of one another, N-dimethylamino methyl or piperidino methyl.

16. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that:

Work as Z=N, R ₁during for the chloro-4-fluorophenyl of 3-, R ₂for 3S-tetrahydrofuran base oxygen base, 2-(N-methyl-4-piperidyl) oxyethyl group, 2-(N, N-diethylamino)-oxyethyl group, 2,2,2-trifluoro ethoxy, 2-(methoxyl group)-oxyethyl group or oxyethyl group; R ₃and R ₄in one be hydrogen, another is hydrogen or piperidino methyl;

Or, work as Z=N, R ₁for the bromo-phenyl of 3-or time, R ₂for methoxyl group; R ₃and R ₄in one be hydrogen, another is piperidino methyl or N, N-dimethylamino methyl;

Or, work as Z=N, R ₁for time, R ₂for oxyethyl group; R ₃and R ₄in one be hydrogen, another is piperidino methyl or N, N-dimethylamino methyl;

Or, work as Z=N, R ₁for time, R ₂for oxyethyl group or 3-(4-morpholinyl) propoxy-; R ₃and R ₄in one be hydrogen, another is hydrogen, piperidino methyl or N, N-dimethylamino methyl;

Or, work as Z=N, R ₁for time, R ₂for 3-(4-morpholinyl) propoxy-; R ₃and R ₄be hydrogen;

Work as Z=C-CN, R ₁during for the chloro-4-fluorophenyl of 3-, R ₂for oxyethyl group; R ₃and R ₄in one be hydrogen, another is hydrogen, N, N-dimethylamino methyl or piperidino methyl;

Or, work as Z=C-CN, R ₁for the bromo-phenyl of 3-, time, R ₂for oxyethyl group; R ₃and R ₄be hydrogen.

Or, work as Z=C-CN, R ₁for time, R ₂for oxyethyl group; R ₃and R ₄in one be hydrogen, another is hydrogen or N, N-dimethylamino methyl;

Or, work as Z=C-CN, R ₁for time, R ₂for oxyethyl group; R ₃and R ₄be hydrogen.

17. quinoline as claimed in claim 1 or quinazoline derivant, its pharmacy acceptable salt, the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, is characterized in that: it is for being numbered as follows the arbitrary compound in 1～41:

18. 1 kinds as described in claim 1～17 any one suc as formula the quinoline as shown in I or quinazoline derivant, its pharmacy acceptable salt, the preparation method of the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug, it is following either method:

Wherein, R ₁, R ₂, R ₃, R ₄, R ₅, Z and X all as described in claim 1～17 any one, R and R ' are C independently of one another _1～6alkyl.

19. preparation methods as claimed in claim 18, is characterized in that: in described method one and method two, if the mixture that the product I obtaining is cis-trans-isomer obtains pure cis or trans product I by the further separation of chiral column; Described chiral column is AD-H chiral column.

20. 1 kinds suc as formula the compound shown in C,

Wherein, R ₁, R ₂, R, R ', X and Z all as claimed in claim 18.

21. 1 kinds containing just like the quinoline described in claim 1～17 any one or quinazoline derivant, its pharmacy acceptable salt, the pharmaceutically useful composition of the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug.

22. quinoline as described in claim 1～17 any one or quinazoline derivant, its pharmacy acceptable salt, the application in the medicine of preparation EGFR tyrosine kinase inhibitor, A431 or H1975 inhibition of cell proliferation or prevention or treatment tumor disease of the enantiomer of quinoline or quinazoline derivant or its salt, diastereomer, tautomer, raceme, solvate, metabolic precursor thereof or prodrug;

Or, the application of pharmaceutically useful composition as claimed in claim 21 in the medicine of preparation EGFR tyrosine kinase inhibitor, A431 or H1975 inhibition of cell proliferation or prevention or treatment tumor disease.