CN104774184A

CN104774184A - Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof

Info

Publication number: CN104774184A
Application number: CN201510184302.3A
Authority: CN
Inventors: 赖宜生; 庞俊霞; 罗明昊; 陈�峰; 王佩倍; 张奕华
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2015-04-17
Filing date: 2015-04-17
Publication date: 2015-07-15

Abstract

The invention belongs to the field of medicines, and particularly relates to an alpha-cyano-alpha, beta-unsaturated amide compound with a structure in a formula (I), and a stereisomer or a pharmaceutically acceptable salt thereof, and an application of the alpha-cyano-alpha, beta-unsaturated amide compound in anti-tumor. A pharmacological experiment result proves that the compound has an excellent inhibiting effect on an epidermal growth factor receptor (EGFR) and a mutant of the epidermal growth factor receptor, and is capable of inhibiting multiplication of a plurality of tumor cells, so that the alpha-cyano-alpha, beta-unsaturated amide compound can be applied to preparation of anti-tumor medicines as an EGFR kinase inhibitor. The formula is shown in the description.

Description

Alpha-cyano-α, beta-unsaturated acyl aminated compounds and medicinal use thereof

Technical field

The invention belongs to pharmaceutical field, be specifically related to a kind of alpha-cyano-α, beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt and medicinal compositions thereof and they are in the application of field of medicaments, particularly preparing the application in antitumor drug.

Background technology

Protein kinase is that a class can transfer to enzyme family on gal4 amino acid residue by catalysis Triphosaden (ATP) γ-phosphate.By the phosphorylation to self or substrate protein, protein kinase mediated nearly all eukaryotic signal transduction pathway, the physiological process (Science, 2002,298 (5600): 1912-1934) such as metabolism, motion, differentiation, proliferation and apoptosis of regulating cell.

EGF-R ELISA (EGFR) is a kind of Receptor type tyrosine protein kinase, hold the C in ligand binding domain, cross-film district and born of the same parents to hold kinase activity district to form by the N outside born of the same parents, four kinds of hypotypes such as erbB1 (EGFR/HER1), erbB2 (HER2), erbB3 (HER3), erbB4 (HER4) can be divided into.When the signaling molecule outside born of the same parents is as after the N of cytokine outside EGFR born of the same parents hold binding domain to be combined, specific region in EGFR born of the same parents is by homology or Heterodimerization, form dimer, this dimer phosphorylation each other in born of the same parents, then raise downstream albumen, thus activate the signal path in downstream, the process (Oncogene such as propagation, differentiation, migration, apoptosis of regulating cell, 2000,19 (56): 6550-6565).The generation of the kinds cancers such as the kinase whose dysfunction of EGFR and lung cancer, intestinal cancer, bladder cancer, mammary cancer and developing closely related (Clin Cancer Res, 2006,12 (18): 5268-5272).

Gefitinib (Gefitinib) and Tarceva (erlotinib) obtain good effect as first-generation EGFR inhibitor in the treatment of tumour such as treatment non-small cell type lung cancer and carcinoma of the pancreas etc., but along with the prolongation in medication cycle, patient shows resistance gradually.T790M sudden change in EGFR 20 exon is considered to the major cause that acquired resistance occurs patient.Crystallography shows, and T790 is positioned at the catalysis region of ATP-binding site, is the critical sites that the medicine such as Gefitinib and Tarceva is combined with EGFR kinases.At present mainly contain two kinds of explanations about the T790M resistance caused of suddenling change: one, T790M sudden change makes the kinase whose active pocket of EGFR diminish, thus hinder combination (the N Engl J Med of the inhibitor such as Gefitinib and active pocket, 2005,352 (8): 786-792); Its two, T790M sudden change adds the bonding force (Proc Natl Acad ScL USA, 2008,105 (6): 2070-2075) of ATP and active pocket.In order to overcome the resistance problems of first-generation EGFR kinase inhibitor, people are devoted to the exploitation s-generation irreversible EGFR covalency inhibitor, such inhibitor by there is Michael addition reaction with the ATP binding pocket place Cys797 sulfydryl of EGFR kinase region, thus strengthens compound to kinase whose inhibit activities.So far, multiple irreversible EGFR inhibitor such as existing dacomitinib, neratinib and CO-1686 are in III phase clinical study, and wherein afatinib is used for the treatment of transitivity non-small cell type lung cancer in July, 2013 by FDA approval.

Although the halfcystine generation covalent attachment of irreversible inhibitor and target protein usually can strengthen pharmacologically active and extend action time, if but its Electron Affinities is crossed good general it can be caused to be easy to, with the nucleophilic group of non-target protein in body, non-specific covalent attachment occurs, thus the generation of the phenomenon that causes missing the target, and then produce toxic side effect.In addition, when irreversible covalent attachment occurs for medicine and substrate protein, the haptenization of protein can be caused, thus cause autoimmune response (Chem Res Toxicol, 2008,21 (1): 84-92; Expert Opin Drug Discov, 2012,7 (7): 561-581).

It is worth mentioning that, Taunton group confirms containing alpha-cyano-α, reversibility covalent attachment can be there is in the compound of beta-unsaturated carbonyl with p90 ribosome S 6 protein kinase (RSK), therefore untoward reaction (the Nat Chem Biol overcoming or reduce the initiation of irreversible covalent drug is contributed to, 2012,8 (5): 471-476).

Summary of the invention

The invention discloses one and there is alpha-cyano-α, beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt and medicinal use.The pharmacological results shows, this compounds his-and-hers watches skin growth factor acceptor (EGFR) and mutant have excellent restraining effect, and can suppress the propagation of kinds of tumor cells.Therefore can be used as EGFR kinase inhibitor for the preparation of antitumor drug.

Open alpha-cyano-the α shown in formula (I) of the present invention, beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt:

Wherein:

A represents N or CR ₄;

R ₁represent hydrogen, C ₁-C ₈alkyl, C ₃-C ₆cycloalkyl, C ₅-C ₁₀aryl or C ₅-C ₁₀aromatic heterocyclic, wherein said alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, C ₂-C ₅alkynyl, phenyl, phenoxy group, benzyl, benzyloxy, pyridyloxy or pyridine time methoxyl group;

R ₂represent hydrogen, halogen, NR ₅r ₆or OR ₇;

R ₃represent C ₁-C ₈alkyl, C ₃-C ₆cycloalkyl, NR ₅r ₆, C ₅-C ₁₀aryl or C ₅-C ₁₀aromatic heterocyclic, wherein said alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, trifluoromethyl, cyano group, nitro, hydroxyl, C ₁-C ₈alkyl, C (O) NR ₅r ₆, C (O) OR ₇or NHR ₇;

R ₄represent CN;

R ₅and R ₆can be identical or not identical, represent hydrogen, C ₁-C ₈alkyl, or R ₅and R ₆5-7 unit heterocyclic group is formed together with the nitrogen connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from: halogen, hydroxyl, nitro, cyano group, amino, C ₁-C ₆alkyl or C ₁-C ₆alkoxyl group;

R ₇represent hydrogen, C ₁-C ₈alkyl, C ₃-C ₆cycloalkyl, C ₃-C ₆heterocyclylalkyl, C ₅-C ₁₀aryl or C ₅-C ₁₀aromatic heterocyclic, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, trifluoromethyl, cyano group, nitro, hydroxyl or amino.

Further, the alpha-cyano-α shown in general formula (I), beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt, is characterized in that:

A represents N or CR ₄;

R ₁represent C ₁-C ₈alkyl, C ₅-C ₁₀aryl or C ₅-C ₁₀aromatic heterocyclic, wherein said alkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, hydroxyl or pyridine time methoxyl group;

R ₂represent NR ₅r ₆or OR ₇;

R ₃represent C ₁-C ₈alkyl, C ₃-C ₆cycloalkyl, NR ₅r ₆, C ₅-C ₁₀aryl or C ₅-C ₁₀aromatic heterocyclic, wherein said alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: trifluoromethyl, C ₁-C ₈alkyl, C (O) NR ₅r ₆or C (O) OR ₇;

R ₄represent CN;

R ₅and R ₆can be identical or not identical, represent hydrogen, C ₁-C ₈alkyl, or R ₅and R ₆5-7 unit heterocyclic group is formed together with the nitrogen connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from: hydrogen or C ₁-C ₆alkyl;

R ₇represent C ₁-C ₈alkyl or C ₃-C ₆heterocyclylalkyl.

Again further, the alpha-cyano-α shown in general formula (I), beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt, is characterized in that:

A represents N or CR ₄;

R ₁represent 3-chloro-4-fluorophenyl, S-2-phenylethyl alcohol-2-base, hydroxyethyl or the chloro-4-of 3-(pyridine-2-methoxyl group) phenyl;

R ₂representation methoxy, oxyethyl group, S-tetrahydrofuran (THF)-3-oxygen base, dimethylin, N methyl piperazine-1-base, pyrrolidin-1-yl or N, N-dimethylated propyl diethylenetriamine-1-base;

R ₃represent phenyl, pyridine-2-base, 4-trifluoromethyl, 3-trifluoromethyl, furans-2-base, imidazoles-2-base, pyrroles-2-base, pyrazole-3-yl, imidazol-4 yl, cyclopropyl, the tertiary butyl, dimethylin,

R ₄represent CN.

Specifically, the alpha-cyano-α shown in general formula (I), beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt are preferably from following compounds:

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-1);

N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrroles-3-carboxylic acid amides (LP-2);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-3);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide (LP-4);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-dimethylin acrylamide (LP-5);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-6);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-7);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-8);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-9);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-10);

5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-2,4-Dimethyl-pyrrol-3-carboxylic acid, ethyl esters (LP-11);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-12);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LP-13);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide (LP-14);

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-15);

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide (LP-16);

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LP-17);

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-18);

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-19);

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-20);

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-21);

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-22);

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-23);

N-[4-[(2-hydroxyethyl) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-24);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-25);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-26);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-27);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-28);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-29);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-30);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-31);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-32);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-33);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-34);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-35);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-36);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-37);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-38);

N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrroles-3-carboxylic acid amides (LP-39);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-40);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide (LP-41);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-42);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-43);

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-44);

N-[4-[(the chloro-4-of 3-(pyridine-2-methoxyl group) phenyl) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-45).

The compound numbers related in pharmacological evaluation is below equal to the compound herein corresponding to code name.

Described compound comprises all conformers of compound shown in general formula (I), optically active isomer and racemic modification, diastereomer and tautomer and steric isomer, and the mixture of any above-mentioned form.

Another object of the present invention is to provide the application at anti-tumor aspect of compound, its steric isomer or its pharmacy acceptable salt with (I) formula and the composition be made up of them, especially in the application of non-small cell type lung cancer, mammary cancer, cancer of the stomach, colorectal carcinoma, cervical cancer, bladder cancer or carcinoma of the pancreas.

Embodiment

For setting forth the present invention further, will specifically introduce some embodiments below, but being not limited in of the present invention.

Embodiment 1

The synthesis of 4-hydroxyl-7-chloro-quinazoline (2a)

Added in 30mL methane amide by 1a (5.00g, 29.20mmol), be heated to 150 DEG C, be cooled to room temperature after 5h, pour in frozen water, a large amount of solid is separated out, suction filtration, dry, obtains brown solid 3.70g, yield 70%, mp 254-257 DEG C.

The synthesis of 4-hydroxyl-6-nitro-7-chloro-quinazoline (3a)

Under ice bath, by solid 2a (3.00g, 16.60mmmol) slowly add in the nitration mixture be made up of the vitriol oil (9mL) and nitrosonitric acid (9mL), react 1h at 90 DEG C, be cooled to room temperature, down in frozen water, suction filtration, acetic acid recrystallization, obtains yellow crystals 2.43g, yield 65%, mp 295-298 DEG C.

The synthesis of the chloro-6-nitro of 4--7-chloro-quinazoline (4a)

3a (2.00g, 8.90mmol) is added to SOCl ₂(15mL) in, add 3 DMF, backflow reaction overnight, is spin-dried for excessive SOCl ₂obtain crude product, be directly used in next step reaction.

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-chloro-quinazoline (5a)

Gained 4a crude product (1.00g, 4.10mmol) is dissolved in the anhydrous CH of 20mL ₂cl ₂in, add 30mL Virahol and the chloro-4-fluoroaniline (0.60g, 4.10mmol) of 3-, room temperature reaction 1h, drip triethylamine to neutral, suction filtration, dry, obtain orange solid 1.38g, yield 95%, mp 255-257 DEG C.

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-methoxychlor quinazoline (6a)

By sodium (1.31g under ice bath, 57.00mmol) add in 30mL anhydrous methanol, add 5a (2.00g, 5.70mmol), tube sealing back flow reaction 12h, be cooled to room temperature, drip Glacial acetic acid to neutral, add 20mL water, stir suction filtration, dry yellow solid 1.92g, yield 98%, mp 221-223 DEG C.

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-methoxyquinazoline hydrochloride (7a)

Get 6a (1.00g, 2.90mmol) to add in ethanol/water (15mL/15mL) mixed solvent, be heated to 53 DEG C, take a policy powder (2.00g, 11.40mmol) in batches, and TLC monitoring reacts completely, be warming up to 70 DEG C, drip concentrated hydrochloric acid 2.4mL, reaction 30min, be cooled to room temperature, 2%NaOH solution regulates pH to be about 9, suction filtration, dry solid 0.64mg, yield 70%, mp 253-255 DEG C.

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-methoxyquinazoline hydrochloride (8a)

Get itrile group acetic acid (0.50g, 6.20mmol) add in the DMF of 20mL, add EDCHCl (2.40g, 12.50mmol), DIPEA (3.30mL successively, 18.80mmol) with 7a (1.00g, 3.10mmol), room temperature reaction 4h, pours in 50mL water by reaction solution, stir, suction filtration obtains brown solid 0.65g, yield 54%, mp 257-259 DEG C.ESI-MS：354.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.02(s，3H)，4.10(s，2H)，7.31(s，1H)，7.43(t，1H，J＝4.71Hz)，7.76～7.80(m，1H)，8.10(t，1H，J＝6.18Hz)，8.54(s，1H)，8.86(s，1H)，9.87(s，1H)，10.02(br s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-1)

Added to by 8a (40.00mg, 0.10mmol) in 5mL acetonitrile, drip the Piperidineacetic acid that then 3 phenyl aldehydes add catalytic amount, after room temperature reaction 4h, suction filtration, obtains yellow solid 35mg, yield 74%, mp 276-278 DEG C.ESI-MS：472.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)：4.04(s，3H)，7.36(s，1H)，7.44(t，1H，J＝4.51Hz)，7.62～7.64(m，3H)，7.78～7.85(m，1H)，8.02～8.05(m，2H)，8.15～8.18(m，1H)，8.40(s，1H)，8.59(s，1H)，8.79(s，1H)，9.87(s，1H)，9.96(s，1H).

Embodiment 2

The synthesis of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrroles-3-carboxylic acid amides (LP-2)

With reference to LP-1 synthetic method, be that raw material obtains with 8a and N-[2-(diethylin) ethyl]-2,4 dimethyl-5-acyl methylpyrrole-3-carboxylic acid amides, yield 89%, mp 230-232 DEG C.ESI-MS：633.2[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：0.97(s，6H)，1.23(m，2H)，2.33(s，3H)，2.45(s，3H)，3.27～3.33(m，4H)，4.04(s，3H)，7.35(s，1H)，7.44(s，1H)，7.57(t，1H，J＝5.4Hz)，7.81(s，1H)，8.06(s，1H)，8.15～8.17(m，1H)，8.57(s，1H)，8.80(s，1H)，9.49(s，1H)，9.84(s，1H)，11.10(s，1H).

Embodiment 3

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-3)

Added to by 8a (40.00mg, 0.10mmol) in 5mL acetonitrile, drip 3 furfurals and 1 triethylamine, stirring at room temperature 4h, suction filtration, obtains yellow solid, yield 85%, mp 280-283 DEG C.ESI-MS：462.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.03(s，3H)，6.88～6.90(m，1H)，7.35(s，1H)，7.44(t，1H，J＝4.54Hz)，7.50(d，1H，J＝3.51Hz)，7.78～7.82(m，1H)，8.14～8.17(dd，1H，J＝6.76Hz，2.60Hz)，8.19(s，1H)，8.22(d，1H，J＝1.20Hz)，8.58(s，1H)，8.81(s，1H)，9.74(s，1H)，9.87(s，1H).

Embodiment 4

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide (LP-4)

With reference to LP-1 synthetic method, with 8a and 3-trifluoromethylated benzaldehyde for raw material obtains, yield 78%, mp 236-238 DEG C.

ESI-MS：530.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.03(s，3H)，7.35(s，1H)，7.42(t，1H，J＝8.74Hz)，7.86(t，1H，J＝7.4Hz)，7.79～7.83(m，1H)，7.98(s，1H)，8.14(d，1H，J＝5.31Hz)，8.30(d，1H，J＝7.47Hz)，8.35(s，1H)，8.50(s，1H)，8.57(s，1H)，8.78(s，1H)，9.86(s，1H)，10.00(s，1H).

Embodiment 5

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-dimethylin acrylamide (LP-5)

Be dissolved in the toluene of 5mL by 8a (40.00mg, 0.10mmol), add 5 DMF-DMA, back flow reaction 4h, revolves partial solvent, suction filtration, methanol rinses, obtains light tan solid 30mg, yield 68%, mp 278-280 DEG C.ESI-MS：439.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.27(s，6H)，4.04(s，3H)，7.31(s，1H)，7.42(t，1H，J＝9.5Hz)，7.77～7.80(m，1H)，7.90(s，1H)，8.12(d，1H，J＝2.34Hz)，8.53(s，1H)，8.57(s，1H)，8.94(s，1H)，9.83(s，1H).

Embodiment 6

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-6)

With reference to LP-1 synthetic method, with 8a and pyridine-2-formaldehyde for raw material obtains, yield 89%, mp 257-259 DEG C.ESI-MS：473.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.03(s，3H)，7.35(s，1H)，7.42(t，1H，J＝9.78Hz)，7.59(t，1H，J＝3.48Hz)，7.78～7.81(m，1H)，7.92(d，1H，J＝7.71Hz)，8.08(t，1H，J＝7.20Hz)，8.14(d，1H，J＝5.10Hz)，8.34(s，1H)，8.57(s，1H)，8.80～8.83(m，2H)，9.83(s，1H)，9.93(s，1H).

Embodiment 7

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-7)

With reference to LP-1 synthetic method, with 8a and 4-trifluoromethylated benzaldehyde for raw material obtains, yield 80%, mp 245-248 DEG C.ESI-MS：540.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.04(s，3H)，7.37(s，1H)，7.43(t，1H，J＝8.49Hz)，7.80～7.84(m，1H)，7.99(s，1H)，8.02(s，1H)，8.15～8.21(m，3H)，8.43(s，1H)，8.59(s，1H)，8.79(s，1H)，9.87(s，1H)，10.08(s，1H).

Embodiment 8

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-8)

8a (40.00mg, 0.10mmol) is added in 5mL ethanol, adds imidazoles-2-formaldehyde (19.20mg, 0.20mmol), room temperature reaction 4h, 2% sodium hydroxide solution regulates pH to be about 9, suction filtration, obtain orange solid 33mg, yield 72%, mp 233-235 DEG C.ESI-MS：462.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.05(s，3H)，7.36(s，1H)，7.44～7.47(m，2H)，7.64(s，1H)，7.77～7.82(m，1H)，8.08(s，1H)，8.13～8.15(m，1H)，8.58(s，1H)，8.90(s，1H)，9.64(s，1H)，9.92(s，1H).

Embodiment 9

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-9)

With reference to LP-1 synthetic method, with 8a and ring third formaldehyde for raw material obtains, yield 88%, mp 225-227 DEG C.ESI-MS：436.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.06(s，2H)，1.32(s，2H)，1.95～2.05(m，1H)，4.00(s，3H)，7.21(d，1H，J＝10.86Hz)，7.30(s，1H)，7.38～7.46(m，1H)，7.80(d，1H，J＝4.26Hz)，8.15(d，1H，J＝3.72Hz)，8.57(s，1H)，8.68(s，1H)，9.63(s，1H)，9.82(s，1H).

Embodiment 10

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-10)

With reference to LP-1 synthetic method, with 8a and special valeral for raw material obtains, yield 87%, mp 117-119 DEG C.ESI-MS：452.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.31(s，9H)，4.01(s，3H)，7.33(s，1H)，7.45(t，1H，J＝4.89Hz)，7.60(s，1H)，7.80～7.82(m，1H)，8.14(s，1H)，8.58(s，1H)，8.68(s，1H)，9.80(s，1H)，9.85(s，1H).

Embodiment 11

The synthesis of 5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-2,4-Dimethyl-pyrrol-3-ethyl formates (LP-11)

With reference to LP-1 synthetic method, be that raw material obtains with 8a and 2,4-dimethyl-5-acyl methylpyrrole-3-carboxylic acyl ethyl ester, yield 82%, mp 280-283 DEG C.ESI-MS：561.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.29(t，3H，J＝7.26Hz)，2.39(s，3H)，2.56(s，3H)，4.03(s，3H)，4.22(q，2H，J＝7.32Hz)，7.32(d，H，J＝10.53Hz)，7.44(t，1H，J＝8.94Hz)， 7.75～7.83(m，1H)，8.12(s，1H)，8.14～8.16(m，1H)，8.55(d，1H，J＝10.62Hz)，8.78(s，1H)，9.61(s，1H)，9.84(s，1H)，10.04(s，1H).

Embodiment 12

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-12) synthesizes

With reference to LP-1 synthetic method, with 8a and pyrrole-2-aldehyde for raw material obtains, yield 82%, mp 297-300 DEG C.ESI-MS：461.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.04(s，3H)，6.50(s，1H)，7.34(s，1H)，7.42～7.49(m，3H)，7.79～7.89(m，1H)，8.14(d，1H，J＝7.05Hz)，8.22(s，1H)，8.56(s，1H)，8.86(s，1H)，9.35(s，1H)，9.86(s，1H)，12.09(br s，1H).

Embodiment 13

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LP-13) synthesizes

With reference to LP-8 synthetic method, with 8a and 3-pyrazoles formaldehyde for raw material obtains, yield 88%, mp 290-293 DEG C.ESI-MS：462.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.07(s，1H)，6.35(d，1H，J＝3.13Hz)，7.12(s，1H)，7.32(s，1H)，7.43(t，1H，J＝9.39Hz)，7.60(d，1H，J＝8.12Hz)，7.79～7.82(m，1H)，7.97(s，1H)，8.19(d，1H，J＝10.17Hz)，8.33(s，1H)，8.56(s，1H)，8.74(s，1H)，9.91(br s，2H).

Embodiment 14

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide (LP-14) synthesizes

With reference to LP-8 synthetic method, with 8a and 4-imidazole formaldehyde for raw material obtains, yield is 87%, mp 295-298 DEG C.ESI-MS：462.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：4.04(s，1H)，7.26(s，1H)，7.34(s，1H)，7.40～7.46(m，1H)，7.65(d，1H，J＝11.3Hz)，7.78～7.83(m，1H)，7.91(s，1H)，8.05(s，1H)，8.15(s，1H)，8.22(s，1H)，8.56(s，1H)，8.86(s，1H)，9.90(s，1H).

Embodiment 15

The synthesis of N-[4-(the chloro-4-fluoroanilino of 3-)] 7-benzenesulfinyl-6-nitro-quinazoline (1b)

By 5a (1.00g, 2.83mmol) add in DMF (25mL), add benzene sulfinic acid sodium salt (0.93g, 5.66mmol), 90 DEG C of reaction 10h, be cooled to room temperature, pour in frozen water, stir, suction filtration is dry obtains yellow solid 1.23g, yield 95%, mp 283-286 DEG C.

(S) synthesis of-N-[4-(the chloro-4-fluoroanilino of 3-)]-7-(tetrahydrofuran base-3-oxygen base)-6-nitro-quinazoline (2b)

1b (0.70g, 1.52mmol) is added in the 30mL trimethyl carbinol, adds S-3-dihydroxy-tetrahydro furans (0.18mL, 2.28mmol), the tetrahydrofuran (THF) drop of potassium tert.-butoxide (0.43g, 3.81mmol) is entered in reaction solution, backflow is spent the night, be cooled to room temperature, suction filtration abandons insolubles, filtrate is poured in the water of 500mL, stir, suction filtration is dry obtains yellow solid 0.44g, yield 71%, mp 237-240 DEG C.

(S) synthesis of-N-[4-(the chloro-4-fluoroanilino of 3-)]-7-(tetrahydrofuran base-3-oxygen base)-6-amido quinazoline (3b)

With reference to the synthetic method of 7a, be that raw material obtains with 2b, yield 78%, mp 120-123 DEG C.

(S) synthesis of-4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-(tetrahydrofuran base-3-oxygen base) quinazoline (4b)

With reference to the synthetic method of 8a, be that raw material obtains with 3b, yield 56%.ESI-MS：440.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.14～2.49(m，2H)，3.79～3.87(m，1H)，3.91～3.98(m，2H)，4.08(m，1H)，5.29～5.35(m，1H)，7.25(s，1H)，7.43(t，1H，J＝9.51Hz)，7.76～7.80(m，1H)，8.11(s，1H)，8.53(s，1H)，8.85(s，1H)，9.74(s，1H)，9.85(s，1H).

(S) synthesis of-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-15)

With reference to the synthetic method of LP-3, with 4b and furfural for raw material obtains, yield 87%, mp 269-271 DEG C.ESI-MS：518.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.10～2.15(m，1H)，2.27～2.38(m，1H)，3.78～3.85(m，1H)，3.87～3.92(m，2H)，4.00～4.06(m，1H)，5.38(m，1H)，6.89(d，1H，J＝1.71Hz)，7.33(s，1H)，7.44(t，1H，J＝9.12Hz)，7.52(d，1H，J＝3.33Hz)，7.78～7.80(m，1H)，8.14(dd，1H，J＝6.96Hz，2.25Hz)，8.17(s，1H)，8.23(d，1H，J＝7.02Hz)，8.57(s，1H)，8.90(s，1H)，9.56(s，1H)，9.93(s，1H).

Embodiment 16

(S) synthesis of-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide (LP-16)

With reference to the synthetic method of LP-8, with 4b and 4-imidazole formaldehyde for raw material obtains, yield 74%, mp 268-270 DEG C.ESI-MS：518.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.12～2.15(m，1H)，2.31～2.39(m，1H)，3.80～3.86(m，1H)，3.92～3.94(m，2H)，4.01～4.07(m，1H)，5.40(m，1H)，7.37(s，1H)，7.48(t，1H，J＝7.12Hz)，7.62～7.68(m，1H)，7.76～7.80(m，1H)，7.90(s，1H)，8.06(s，1H)，8.15(d，1H，J＝4.66Hz)，8.25(s，1H)，8.57(s，1H)，9.00(s，1H)，9.39(br s，1H)，9.91(s，1H).

Embodiment 17

(S) synthesis of-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LP-17)

With reference to LP-8 synthetic method, with 4b and 3-pyrazoles formaldehyde for raw material obtains, yield 89%, mp 227-230 DEG C.ESI-MS：518.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)： ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.82～3.85(m，2H)，3.87(t，2H，J＝5.19Hz)，4.01(d，2H，J＝3.24Hz)，5.34～5.37(m，1H)，6.35(s，1H)，7.11(s，1H)，7.30(s，1H)，7.35～7.45(m，1H)，7.80(s，1H)，7.93(s，1H)，8.12(s，1H)，8.29(s，1H)，8.55(s，1H)，8.85(s，1H).

Embodiment 18

(S) synthesis of-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-18)

With reference to the synthetic method of LP-8, with 4b and 2-imidazole formaldehyde for raw material obtains, yield 86%, mp 217-220 DEG C.ESI-MS：518.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.33～2.41(m，2H)，3.79(m，1H)，3.82～3.93(m，2H)，3.97～4.03(m，1H)，5.38(m，1H)，7.34(s，1H)，7.46(t，1H，J＝7.32Hz)，7.58～7.66(m，1H)，7.76～7.80(m，1H)，7.94(s，1H)，8.08(s，1H)，8.13(d，1H，J＝4.68Hz)，8.23(s，1H)，8.55(s，1H)，8.99(s，1H)，9.37(br s，1H)，9.95(s，1H).

Embodiment 19

The synthesis of 4-hydroxyl-6-nitro-7-methoxyquinazoline hydrochloride (1c)

Under ice bath, sodium block (1.01mg, 44.00mmol) is dissolved in 20mL methyl alcohol, add 3a (1.00g, 4.40mmol), tube sealing back flow reaction 12h, to be cooled to room temperature, drip Glacial acetic acid to neutral, add 20mL water, stir, suction filtration is dry obtains orange solid 0.79g, yield 81%, mp 243-247 DEG C.

The synthesis of the chloro-6-nitro of 4--7-methoxyquinazoline hydrochloride (2c)

1c (1.00g, 4.50mmol) is added to 20mL SOCl ₂in, drip 3 DMF, back flow reaction 5h, be spin-dried for excessive solvent, be directly used in next step reaction.

(S) synthesis of-4-(N-2-hydroxyl-1-phenylethyl)-6-nitro-7-methoxyquinazoline hydrochloride (3c)

Gained 2c (1g, 4.20mmol) is added in 30mL Virahol, adds S-benzene glycinol (0.58g, 4.20mmol), back flow reaction 1h, column chromatography (P: E=1: 3), obtain yellow solid 0.88g, yield 62%, mp 116-118 DEG C.ESI-MS：339.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.70～3.87(m，2H)，4.07(s，3H)，5.08(t，1H，J＝5.83Hz)，5.51(q，1H，J＝7.38Hz，8.16Hz)，7.23(t，1H，J＝7.04Hz)，7.32(t，2H，J＝9.78Hz，7.32Hz)，7.35(s，1H)，7.44(d，2H，J＝7.26Hz)，8.44(s，1H)，8.80(d，1H，J＝16.86Hz)，9.25(s，1H).

(S) synthesis of-4-(N-2-hydroxyl-1-phenylethyl)-6-amino-7-methoxyquinazoline hydrochloride (4c)

By 3c (1.00g, 2.90mmol) add in ethanol/water (15mL/15mL) mixing solutions, be heated to 53 DEG C, take a policy powder (2.01g, 11.60mmol) in batches, concentrated hydrochloric acid 2.5mL is added after 30min, react 1h at 70 DEG C, be cooled to room temperature, column chromatography (E: M=45: 1), obtain yellow-brown solid 0.57g, yield 51%. ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.72～3.84(m，2H)，3.92(s，3H)，4.97(t，1H，J＝2.82Hz)，5.16(s，2H)，5.42(q，1H，J＝7.53Hz)，6.98(s，1H)，7.19(t，1H，J＝7.21Hz)，7.29(t，2H，J＝7.32Hz)，7.34(s，1H)，7.42(d，2H，J＝7.17Hz)，7.58(d，1H，J＝7.89Hz)，8.12(s，1H).

(S) synthesis of-4-(N-2-hydroxyl-1-phenylethyl)-6-cyano-acetamide amido-7-methoxyquinazoline hydrochloride (5c)

With reference to the synthetic method of 8a, be that raw material obtains with 4c, yield 52%, mp 221-225 DEG C.ESI-MS：378.3[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.69～3.75(m，1H)，3.81～3.85(m，1H)，3.96(s，3H)，4.06(s，2H)，5.02(t，1H，J＝5.58Hz)，5.48～5.57(m，1H)，7.17(s，1H)，7.21(t，1H，J＝6.99Hz)，7.29(t，2H，J＝7.32Hz)，7.43(d，2H，J＝7.35Hz)，8.27(d，1H，J＝10.11Hz)，8.29(s，1H)，8.73(s，1H)，9.94(s，1H).

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-the methoxyquinazoline hydrochloride]-6-base] synthesis of-2-cyano group-3-(pyridine-2-base) acrylamide (LP-19)

With reference to the synthetic method of LP-1, with 5c and pyridine-2-formaldehyde for raw material obtains, yield 85%, mp 227-229 DEG C.ESI-MS：465.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.73～3.88(m，2H)，5.04(t，1H，J＝5.56Hz)， 5.48～5.55(m，1H)，7.22(t，2H，J＝5.97Hz)，7.30(t，2H，J＝7.18Hz)，7.43(d，2H，J＝7.29Hz)，7.60(t，1H，J＝5.82Hz)，7.92(d，1H，J＝7.68Hz)，8.02(t，1H，J＝8.85Hz)，8.34(d，3H，J＝6.63Hz)，8.71(s，1H)，8.82(d，1H，J＝3.43Hz)，9.97(s，1H).

Embodiment 20

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-the methoxyquinazoline hydrochloride]-6-base] synthesis of-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-20)

With reference to the synthetic method of LP-1, with 5c and pyrrole-2-aldehyde for raw material obtains, yield 84%, mp 218-221 DEG C.ESI-MS：453.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.71～3.88(m，2H)，3.98(s，3H)，5.02(br s，1H)，5.49(q，1H，J＝5.94Hz)，6.48(br s，1H)，7.20(s，1H)，7.21(t，1H，J＝6.73Hz)，7.32(t，2H，J＝6.99Hz)，7.41(s，1H)，7.44(d，2H，J＝7.11Hz)，8.22(s，1H)，8.27(d，2H，J＝7.56Hz)，8.32(s，1H)，8.71(s，1H)，9.39(br s，1H).

Embodiment 21

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-the methoxyquinazoline hydrochloride]-6-base] synthesis of-2-cyano group-3-(furans-2-base) acrylamide (LP-21)

With reference to the synthetic method of LP-3, with 5c and furans-2-formaldehyde for raw material obtains, yield 88%, mp 232-234 DEG C.ESI-MS：454.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.73～3.88(m，2H)，3.97(s，3H)，5.03(t，1H，J＝5.58Hz)，5.48～5.55(m，1H)，6.89(s，1H)，7.21(d，2H，J＝6.33Hz)，7.30(t，2H，J＝6.58Hz)，7.43(d，2H，J＝6.93Hz)，7.48(s，1H)，8.20(d，2H，J＝7.65Hz)，8.31(d，2H，J＝5.58Hz)，8.67(s，1H)，9.75(s，1H).

Embodiment 22

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-the methoxyquinazoline hydrochloride]-6-base] synthesis of-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-22)

With reference to the synthetic method of LP-8, with 5c and imidazoles-2-formaldehyde for raw material obtains, yield 78%, mp 193-195 DEG C.ESI-MS：454.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.71～3.89(m，2H)，3.99(s，3H)，5.01(t，1H，J＝6.50Hz)，5.50(q，1H，J＝5.7Hz，7.14Hz)，7.21(s，1H)，7.25(t，1H，J＝5.67Hz)，7.30(t，2H，J＝7.29Hz)，7.44(d，2H，J＝7.32Hz)，7.53(br s，2H)，8.06(s，1H)，8.29(d，1H，J＝6.69Hz)，8.33(s，1H)，8.75(s，1H)，9.62(s， 1H).

Embodiment 23

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-the methoxyquinazoline hydrochloride]-6-base] synthesis of-2-cyano group-3-cyclopropyl acrylamide (LP-23)

With reference to the synthetic method of LP-1, with 5c and ring third formaldehyde for raw material obtains, yield 89%, mp 184-187 DEG C.ESI-MS：428.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.05(q，2H，J＝2.5Hz，4.1Hz)，1.32(q，2H，J＝3.06Hz，4.41Hz)，1.98～2.04(m，1H)，3.70～3.88(m，1H)，3.94(s，3H)，5.01(t，1H，J＝6.57Hz)，5.48(t，1H，J＝5.16Hz)，7.17(s，2H)，7.20(t，1H，J＝6.72Hz)，7.29(t，2H，J＝6.81Hz)，7.42(d，2H，J＝7.11Hz)，8.25(d，1H，J＝7.44Hz)，8.31(s，1H)，8.55(s，1H)，9.60(s，1H).

Embodiment 24

The synthesis of 4-hydroxyethylamine-6-nitro-7-methoxyquinazoline hydrochloride (1d)

2c (1.00g, 4.20mmol) is added to the anhydrous CH of 50mL ₂cl ₂in, add thanomin (1.00mL, 16.80mmol), room temperature reaction 1.5h, is spin-dried for solvent, adds ethanol/water (10mL/10mL), stirs, suction filtration, dry light yellow solid 0.96g, yield 87%.ESI-MS：265.2[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：3.60(br s，4H)，4.01(s，3H)，4.84(br s，1H)，7.34(s，1H)，8.48(s，1H)，8.69(s，1H)，9.02(s，1H).

The synthesis of 4-hydroxyethylamine-6-amido-7-methoxyquinazoline hydrochloride (2d)

Get 1d (0.55g, 2.10mmol) to add in 45mL THF, add 5%Pd-C (0.22g, 0.11mmol), hydrogen reducing, room temperature reaction 5h, suction filtration removing Pd-C, is spin-dried for solvent, obtain yellow solid 0.48g, yield 98%, ESI-MS:235.2 [M+H] ⁺.

The synthesis of 4-hydroxyethylamine-6-cyano-acetamide amido-7-methoxyquinazoline hydrochloride (3d)

Get cyanoacetic acid (0.35g, 4.10mmol) be dissolved in 20mLDMF, add EDCHCl (1.58g, 8.22mmol), DIPEA (2.20mL, 12.30mmol) with 2d (0.50g, 2.05mmol), room temperature reaction 4h, adds 100mL water, extraction into ethyl acetate, be spin-dried for obtain yellow solid 0.31g, yield 50%, ESI-MS:302.2 [M+H] ⁺.

The synthesis of N-[4-[(2-hydroxyethyl) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide (LP-24)

Get 3d (40.00mg, 0.13mmol) to add in 5mL acetonitrile, add 2-pyrrole aldehyde (25.20mg, 0.26mmol) and the Piperidineacetic acid of catalytic amount, after room temperature reaction 4h, suction filtration, obtain yellow solid 34mg, yield 70%, mp 277-280 DEG C.ESI-MS：379.2 [M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.15～1.21(m，4H)，3.97(s，3H)，4.84(m，1H)，6.54(s，1H)，7.14(s，1H)，7.39(m，2H)，8.09(s，1H)，8.19(s，1H)，8.36(s，1H)，8.57(s，1H)，9.30(br s，1H).

Embodiment 25

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-dimethylamino quinazoline (1e)

5a (3.10g, 8.90mmol) is joined in 30mL dioxane, adds the dimethylamine agueous solution (9mL, 44.50mmol) of 33%, back flow reaction 12h, to be cooled to room temperature, suction filtration, dry red solid 2.09g, yield 65%, mp 263-266 DEG C.ESI-MS：360.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.92(s，6H)，7.18(s，1H)，7.46(t，1H，J＝8.96Hz)，7.79～7.82(m，1H)，8.17(d，1H，J＝6.87Hz)，8.56(s，1H)，9.10(s，1H)，10.07(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-dimethylamino quinazoline (2e)

With reference to the synthetic method of 7a, be that raw material obtains with 1e, yield 73%, mp 196-198 DEG C.ESI-MS：332.2[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.78(s，6H)，5.60(br s，2H)，7.12(t，1H，J＝7.62Hz)，7.40～7.47(m，2H)，7.69(d，1H，J＝6.03Hz)，8.05(s，1H)，8.57(s，1H)，10.20(br s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-dimethylamino quinazoline (3e)

With reference to the synthetic method of 8a, be that raw material obtains with 2e, yield 56%, mp 264-267 DEG C.ESI-MS：397.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.80(s，6H)，4.08(s，2H)，7.26(s，1H)，7.42(t，1H，J＝9.00Hz)，7.77～7.80(m，1H)，8.13(d，1H，J＝6.51Hz)，8.51(s，1H)，8.60(s，1H)，9.82(s，1H)，10.00(s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-25)

With reference to the synthetic method of LP-1, with 3e and pyridine-2-formaldehyde for raw material obtains, yield 88%, mp 243-246 DEG C.ESI-MS：486.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.87(s，6H)，7.36(s，1H)，7.43(t，1H，J＝9.09Hz)，7.60(t，1H，J＝6.36Hz)，7.79～7.83(m，1H)，7.94(d，1H，J＝7.56Hz)，8.04(t，1H，J＝7.89Hz)，8.14～8.17(m，1H)，8.38(s，1H)，8.55(s，1H)，8.75(s，1H)，8.83(d，1H，J＝3.12Hz)，9.85(s，1H)，10.05(s，1H).

Embodiment 26

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-26)

With reference to the synthetic method of LP-3, with 3e and furans-2-formaldehyde for raw material obtains, yield 90%, mp 243-246 DEG C.ESI-MS：475.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.86(s，6H)，6.89(d，1H，J＝1.41Hz)，7.34(s，1H)，7.43(t，1H，J＝9.16Hz)，7.51(d，1H，J＝3.3Hz)，7.79～7.84(m，1H)，8.14～8.17(m，1H)，8.21(s，1H)，8.22(s，1H)，8.54(s，1H)，8.72(s，1H)，9.79(s，1H)，9.87(s，1H).

Embodiment 27

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-27)

With reference to the synthetic method of LP-8, with 3e and imidazoles-2-formaldehyde for raw material obtains, yield 78%, mp 184-187 DEG C.ESI-MS：475.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.86(s，6H)，7.39(s，1H)，7.45(d，1H，J＝9.36Hz)，7.54(s，2H)，7.80～7.83(m，1H)，8.10(s，1H)，8.14(dd，1H，J＝2.16Hz，6.85Hz)，8.55(s，1H)，8.82(s，1H)，9.77(br s，1H)，9.87(s，1H).

Embodiment 28

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-28)

With reference to the synthetic method of LP-1, with 3e and phenyl aldehyde for raw material obtains, yield 91%, mp 241-243 DEG C.ESI-MS：485.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.88(s，6H)，7.32(s，1H)，7.43(t，1H，J＝8.52Hz)，7.64(br s，3H)，7.90(br s，1H)，8.04(br s，2H)，8.16～8.18(m，1H)，8.42(s，1H)，8.55(s，1H)，8.68(s，1H)，9.83(s，1H)，10.07(s，1H).

Embodiment 29

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-(N methyl piperazine-1-base) quinazoline (1f)

With reference to the synthetic method of 1e, with 5a and N methyl piperazine for raw material obtains, yield 78%, mp 198-200 DEG C.ESI-MS：415.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.22(t，4H，J＝9.1Hz)，3.08(t，4H，J＝11.0Hz)，7.30(s，1H)，7.45(t，1H，J＝9.2Hz)，7.79～7.81(m，1H)，8.16(d，1H，J＝4.53Hz)，8.62(s，1H)，9.11(s，1H)，10.11(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-(N methyl piperazine-1-base) quinazoline (2f)

With reference to the synthetic method of 7a, be that raw material obtains with 1f, yield 78%, mp 231-234 DEG C.ESI-MS：385.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.27(s，3H)，2.56(br s，4H)，2.99(br s，4H)，5.16(s，2H)，7.19(s，1H)，7.40(t，1H，J＝9.3Hz)，7.45(s，1H)，7.80～7.83(m，1H)，8.21(d，1H，J＝4.98Hz)，8.38(s，1H)，9.43(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-(N methyl piperazine-1-base) quinazoline (3f)

With reference to the synthetic method of 8a, be that raw material obtains with 2f, yield 60%, mp 150-152 DEG C.ESI-MS：415.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.30(s，3H)，2.57(m，4H)，3.06(m，4H)，4.09(s，2H)，7.32(s，1H)，7.43(t，1H，J＝6.8Hz)，7.78～7.81(m，1H)，8.12～8.14(m，1H)，8.54(s，1H)，8.64(s，1H)，9.70(s，1H)，9.87(s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-29)

With reference to the synthetic method of LP-1, with 3f and ring third formaldehyde for raw material obtains, yield 85%, mp 237-240 DEG C.ESI-MS：504.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.07～1.11(m，2H)，1.34～1.40(m，2H)，1.99～2.07(m，1H)，2.5]～2.57(m，4H)，2.92～3.09(m，4H)，7.25(d，1H，J＝11.4Hz)，7.40～7.7.46(m，2H)，7.72～7.82(m，1H)，8.12(d，1H，J＝6.93Hz)，8.55(s，1H)，8.84(s，1H)，9.50(s，1H)，9.88(s，1H).

Embodiment 30

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-30)

With reference to the synthetic method of LP-1, with 3f and special valeral for raw material obtains, yield 87%, mp 142-144 DEG C.ESI-MS：520.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.32(s，9H)，2.25(s，3H)，2.58(m，4H)，3.02(m，4H)，7.40～7.47(m，2H)，7.63(d，1H，J＝6.87Hz)，7.79～7.83(m，1H)，8.13(d，IH，J＝4.71Hz)，8.56(s，1H)，8.86(s，1H)，9.76(s，1H)，9.90(s，1H).

Embodiment 31

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide (LP-31)

With reference to the synthetic method of LP-8, with 3f and imidazoles-2-formaldehyde for raw material obtains, yield 77%, mp 202-204 DEG C.ESI-MS：530.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.28(s，3H)，2.64(m，4H)，3.07(m，4H)，7.46(t，1H，J＝8.82Hz)，7.51～7.54(m，3H)，7.79～7.85(m，1H)，8.11～8.21(m，2H)，8.56(s，1H)，9.05(s，1H)，9.71(s，1H)，9.97(s，1H).

Embodiment 32

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-32)

With reference to the synthetic method of LP-3, with 3f and furans-2-formaldehyde for raw material obtains, yield 86%, mp 239-242 DEG C.ESI-MS：530.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.26(s，3H)，2.56(m，4H)，3.03(m，4H)，6.90(d，1H，J＝1.89Hz)，7.44(t，1H，J＝0.91Hz)，7.52(s，1H)，7.54(d，1H，J＝3.69Hz)，7.78～7.84(m，1H)，8.11～8.14(dd，1H，J＝2.49Hz，6.8Hz)，8.22(s，1H)，8.24(s，1H)，8.56(s，1H)，8.99(s，1H)，9.72(s，1H)，9.98(s，1H).

Embodiment 33

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-33)

With reference to the synthetic method of LP-1, with 3f and 4-trifluoromethylated benzaldehyde for raw material obtains, yield 87%, mp 215-217 DEG C.ESI-MS：632.1[M+Na] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.26(s，3H)，2.64(br s，4H)，3.07(br s，4H)，7.44(t，2H，J＝9.21Hz)，7.53(s，1H)，7.79～7.82(m，1H)，7.88(t，1H，J＝7.80Hz)，8.02(d，1H，J＝7.68Hz)，8.14(d，1H，J＝4.65Hz)，8.34(d，1H，J＝4.38Hz)，8.41(s，1H)，8.56(s，1H)，8.57(s，1H)，8.98(s，1H)，9.89(s，1H)，9.98(s，1H).

Embodiment 34

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-(pyrrolidin-1-yl) quinazoline (1g)

With reference to the synthetic method of 1e, with 5a and tetramethyleneimine for raw material obtains, yield 80%, mp 255-257 DEG C.ESI-MS：386.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：2.01(s，4H)，3.24(s，4H)，7.04(s，1H)，7.44(t，1H，J＝7.65Hz)，7.80(s，1H)，8.14(d，1H，J＝7.58Hz)，8.52(s，1H)，9.03(s，1H)，9.98(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-(pyrrolidin-1-yl) quinazoline (2g)

With reference to the synthetic method of 7a, be that raw material obtains with 1g, yield 76%, mp 196-199 DEG C.ESI-MS：358.2[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.94(s，4H)，2.49(s，4H)，5.32～5.47(br s，2H)，6.89(s，1H)，7.40～7.46(m，2H)，7.71(t，1H，J＝5.88Hz)，8.05(s，1H)，8.56(s，1H)，10.24(br s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-(pyrrolidin-1-yl) quinazoline (3g)

With reference to the synthetic method of 8a, be that raw material obtains with 2g, yield 57%, mp 172-174 DEG C.ESI-MS：423.1[M-H] ^-； ¹H-NMR(300 MHz，DMSO-d ₆)，δ(ppm)：1.92(s，4H)，2.58(s，4H)，4.01(s，2H)，6.85(s，1H)，7.40(t，1H，J＝5.97Hz)，7.78～7.80(m，1H)，8.18(s，1H)，8.20(s，1H)，8.47(s，1H)，9.66(s，1H)，10.09(s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-34)

With reference to the synthetic method of LP-1, with 3g and pyridine-2-formaldehyde for raw material obtains, yield 85%, mp 235-237 DEG C.ESI-MS：512.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.93(s，4H)，3.61(s，4H)，6.89(s，1H)，7.41(t，1H，J＝8.85Hz)，7.59～7.61(m，1H)，7.82(s，1H)，7.92(d，1H，J＝4.86Hz)，8.02(d，1H，J＝6.87Hz)，8.20(s，1H)，8.29(s，1H)，8.34(s，1H)，8.48(s，1H)，8.81(s，1H)，9.63(s，1H)，10.39(br s，1H).

Embodiment 35

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N-pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-35)

With reference to the synthetic method of LP-3, with 3g and furans-2-formaldehyde for raw material obtains, yield 88%, mp 285-287 DEG C.ESI-MS：503.3[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.92(s，4H)，3.44(s，4H)，6.88(s，2H)，7.41(t，1H，J＝6.52Hz)，7.48(d，1H，J＝3.63Hz)，7.82～7.87(m，1H)，8.18(s，1H)，8.20～8.23(m，2H)，8.26(s，1H)，8.48(s，1H)，9.60(s，1H)，10.21(s，1H).

Embodiment 36

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-nitro-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline (1h)

With reference to the synthetic method of 1e, be that raw material obtains with 5a and N, N-dimethylated propyl diethylenetriamine, yield 84%. ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.81(t，2H，J＝6.5Hz)，2.20(s，6H)，2.39(t，2H，J＝6.2Hz)，3.40～3.44(m，2H)，6.96(s，1H)，7.45(t，1H，J＝4.6Hz)，7.79～7.88(m，1H)，8.47(d，1H，J＝8.1Hz)，9.47(s，1H)，10.24(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline (2h)

With reference to the synthetic method of 7a, be that raw material obtains with 1h, yield 76%, mp 214-216 DEG C.ESI-MS：387.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.91～1.97(m，2H)，2.54(t，2H，J＝6.03Hz)，3.36(t，2H，J＝6.12Hz)，3.72(br s，2H)，6.87(s，1H)，6.94(s，1H)，6.98(s，1H)，7.15(t，1H，J＝8.7Hz)，7.91(dd，1H，J＝2.49Hz，6.55Hz)，8.56(s，1H).

The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline (3h)

With reference to the synthetic method of 8a, be that raw material obtains with 2h, yield 58%, mp 146-149 DEG C.ESI-MS：454.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.73～1.79(m，2H)，2.26(s，6H)，2.38(t，2H，J＝6.75Hz)，3.32(t，2H，J＝6.21Hz)，3.94(s，2H)，6.71(s，1H)，7.40(t，1H，J＝9.12Hz)，7.77～7.82(m，1H)，8.16～8.19(m，2H)，8.43(s，1H)，9.56(s，1H)，9.75(s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-36)

With reference to the synthetic method of LP-1, with 3h and furans-2-formaldehyde for raw material obtains, yield 70%, mp 228-230 DEG C.ESI-MS：532.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.71～1.78(m，2H)，2.15(s，6H)，2.35(t，2H，J＝6.03Hz)，3.24(t，2H，J＝5.33Hz)，5.31～5.35(br s，1H)，6.60(s，1H)，6.71(s，1H)，6.89(s，1H)，7.40(t，1H，J＝6.56Hz)，7.48(s，1H)，7.82(d，1H，J＝2.34Hz)，8.20～8.22(m，3H)，8.45(s，1H)，9.50(s，1H)，9.85(br s，1H).

Embodiment 37

The synthesis of 3-nitro-4-hydroxy-benzoic acid methyl esters (2m)

By ANN aluminium nitrate nonahydrate (20.00g, 53.00mmol) be placed in the mixed solution of acetic acid and acetic anhydride (V/V=1/1,80mL), under ice bath, add 1m (20.00g, 0.13mol), stir 1h, pour in frozen water (500mL), separate out solid, suction filtration, dry faint yellow solid 24.00g, yield 93%, mp 73 ~ 75 DEG C.

The synthesis of 3-amino-4-hydroxy-methyl benzoate (3m)

2m (10.00g, 51.00mmol) is dissolved in 60% ethanolic soln (100mL), is warming up to 60 DEG C, add V-Brite B (17.80g, 0.10mol), reaction 1h in batches, cooling, recycling design, residual solution is poured in frozen water (100mL), suction filtration, washing, dry white solid 6.80g, yield 80%, mp 141 ~ 143 DEG C.

The synthesis of 3-acetylaminohydroxyphenylarsonic acid 4-hydroxy-benzoic acid methyl esters (4m)

By 3m (5.00g, 30.00mmol) be suspended in acetic acid (50mL), drip diacetyl oxide (4.40mL, 47.00mmol) at being warming up to 60 DEG C, drip Bi Jixu and react 50min, cooling, pour frozen water (100mL) into, suction filtration, dry white solid 5.80g, yield 93%, mp 180 ~ 182 DEG C.

The synthesis of 3-acetylaminohydroxyphenylarsonic acid 4-oxyethyl group-methyl benzoate (5m)

By 4m (4.85g, 23.00mmol) and K ₂cO ₃(4.85g, 35.00mmol) adds in DMF (30mL), at 60 DEG C, add C ₂h ₅br (2.10mL, 28.00mmol), reaction 3.5h, cooling, pours in frozen water, suction filtration, dry white solid 5.30g, yield 96%, mp 150 ~ 152 DEG C.

The synthesis of 2-nitro-4-oxyethyl group-5-acetyl-amino-benzoic acid methyl ester (6m)

5m (4.51g, 19.00mmol) is dissolved in CH ₃nO ₂(50mL) in, under room temperature, drip 95% nitrosonitric acid (3.00mL, 69.00mmol), drip Bi Fanying 5h, pour in frozen water (125mL), separate organic layer, concentrate to obtain crude product, water recrystallization obtains yellow solid 5.00g, yield 93%, mp 148 ~ 150 DEG C. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.42(t，3H，J＝7.0Hz)，2.18(s，3H)，3.81(s，3H)，4.28(q，2H，J＝6.9Hz)，7.67(s，1H)，8.56(s，1H)，9.50(s，1H).

The synthesis of 2-amino-4-oxyethyl group-5-acetyl-amino-benzoic acid methyl ester (7m)

By 6m (4.00g, 14.00mmol) add in 50% aqueous ethanolic solution (30mL), be warming up to 60 DEG C, under stirring, add V-Brite B (4.90g in batches, 28.00mmol), reaction 1h, decompression recycling ethanol, in resistates impouring frozen water (200mL), stir suction filtration, dry white solid 3.20g, yield 90%, mp 170 ~ 172 DEG C. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.36(t，3H，J＝6.9Hz)，1.99(s，3H)，3.73(s，3H)，4.02(q，2H，J＝6.9Hz)，6.34(s，1H)，6.58(s，2H)，8.01(s，1H)，8.75(s，1H).

The synthesis of 2-[(2-vinyl) is amino]-4-oxyethyl group-5-acetyl-amino-benzoic acid methyl ester (8m)

By 7m (9.00g, 36.00mmol) be dissolved in acetic acid (65mL), drip trans-3-(dimethylamino) vinyl cyanide (6.50g, 68.00mmol) under room temperature, under dripping complete room temperature, continue reaction 1.5h, by reaction solution impouring frozen water (in (150mL), suction filtration, washing, dries to obtain faint yellow solid 10.40g, yield 96%, mp 243 ~ 245 DEG C. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.38(t，3H，J＝7.1Hz)，2.05(s，3H)，3.82(s，3H)，4.23(q，2H，J＝7.1Hz)，5.14(d，1H，J＝13.2Hz)，7.02(s，1H)，8.18(t，1H，J＝13.2Hz)，8.44(s，1H)，9.03(s，1H)，10.84(d，1H，J＝12.8Hz).

The synthesis of 3-cyano group-4-oxo-6-acetylaminohydroxyphenylarsonic acid 7-oxyethyl group-Isosorbide-5-Nitrae-dihydroquinoline (9m)

By 8m (5.00g, 16.00mmol) be placed in dehydrated alcohol (20mL), back flow reaction 1h with potassium tert.-butoxide (4.26g, 38.00mmol), cooling, concentrated, in resistates, add frozen water (30mL), 10%HCl adjusts pH to 3, leave standstill suction filtration, dry pale solid 3.78g, yield 85%, mp > 300 DEG C. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.45(t，3H，J＝6.9Hz)，2.14(s，3H)，4.20(q，2H，J＝6.9Hz)，7.05(s，1H)，8.59(s，1H)，8.70(s，1H)，9.19(s，1H).

The synthesis of 3-cyano group-4-chloro-6-acetylaminohydroxyphenylarsonic acid 7-ethoxyquinoline (10m)

9m (4.32g, 16.00mmol) is dissolved in POCl ₃in (45mL, 0.49mol), back flow reaction 3h, slowly pours reaction solution into Na under ice-water bath ₂cO ₃solution (2mol/L, 450mL), stirs, suction filtration, and warm water washs, dry pale yellow solid 4.10g, yield 89%, mp 253 ~ 255 DEG C. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.50(t，3H，J＝6.8Hz)，2.25(s，3H)，4.41(q，2H，J＝6.8Hz)，7.59(s，1H)，9.00(s，1H)，9.11(s，1H)，9.50(s，1H).

The synthesis of 3-cyano group-4-(the chloro-4-fluoroanilino of 3-)-6-amino-7-ethoxyquinoline (11m)

By 10m (3.80g, 13.00mmol) with the chloro-4-fluoroaniline of 3-(1.90g, 13.00mmol) add in dehydrated alcohol (100mL), add methylsulfonic acid (2), return stirring 2h, directly reaction solution is cooled to room temperature, adds 0.6mol/L hydrochloric acid (170mL), back flow reaction 3h.Cooling, suction filtration, is dissolved in methyl alcohol (100mL) by gained crude product, add 1mol/L wet chemical (70mL), stirs suction filtration, washing, dry white-yellowish solid 3.92g, yield 85%, mp 250 ~ 253 DEG C.

The synthesis of 3-cyano group-4-(the chloro-4-fluoroanilino of 3-)-6-cyano-acetamide amido-7-ethoxyquinoline (12m)

11m (0.20g, 0.56mmol) is dissolved in DMF (10ml), adds methyl-cyanacetate (0.50ml, 5.60mmol), heating reflux reaction 5h, cooling, is poured into water, separate out solid, suction filtration, washing, dry greenish yellow solid 0.18g, yield 76%, mp 248 DEG C decomposition. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.47(t，3H，J＝6.96Hz)，4.12(s，2H)，4.23(q，2H，J＝5.28Hz)，7.28～7.30(m，1H)，7.44～7.46(m，2H)，7.53～7.55(m，1H)，8.63(s，1H)，8.90(s，1H)，9.95(s，1H).

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-37)

With reference to the synthetic method of LP-1, with 12m and phenyl aldehyde for raw material, be that catalyzer obtains with piperidines, yield 81%, mp 279 ~ 282 DEG C.ESI-MS：510.2[M-H] ^-； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.48(t，3H，J＝6.87Hz)，4.35(q，2H，J＝6.93 Hz)，7.26(s，1H)，7.40(t，1H，J＝8.97Hz)，7.46～7.48(m，2H)，7.61～7.63(m，3H)，8.00～8.02(m，2H)，8.36(s，1H)，8.58(s，1H)，8.89(s，1H)，9.64(s，1H)，9.72(br s，1H).

Embodiment 38

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide (LP-38)

With reference to the synthetic method of LP-37, with 12m and pyridine-2-formaldehyde for raw material obtains, yield 89%.243 DEG C of decomposition.ESI-MS：511.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.48(t，3H，J＝7.14Hz)，4.35(q，2H，J＝6.90Hz)，7.27～7.29(m，1H)，7.44(t，1H，J＝8.97Hz)，7.50～7.52(m，2H)，7.60～7.62(m，1H)，7.93(d，1H，J＝7.74Hz)，8.01～8.03(m，1H)，8.35(s，1H)，8.60(s，1H)，8.82～8.84(m，1H)，8.96(s，1H)，9.78(s，1H)，9.85(br s，1H).

Embodiment 39

The synthesis of N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrrole-3-carboxamide (LP-39)

By 12m (50.00mg, 0.12mmol) be suspended in acetonitrile (6mL), add N-[2-(diethylin) ethyl]-2,4 dimethyl-5-acyl methylpyrrole-3-carboxylic acid amides (63.70mg, 0.24mmol) He 1 piperidines, heating reflux reaction 20h, cooling, suction filtration, the a small amount of acetonitrile wash of filter cake, dry yellow solid 66mg, yield 82%, mp 212 ~ 215 DEG C.ESI-MS：671.2[M+H] ⁺； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：0.96(t，6H，J＝6.03Hz)，1.23(s，2H)，1.48(s，3H)，2.08(s，6H)，2.43～2.45(m，4H)，3.27～3.29(m，2H)，4.32～4.34(m，2H)，7.43(s，1H)，7.44～7.46(m，3H)，7.47(s，1H)，8.00(s，1H)，8.57(s，1H)，8.96(s，1H)，9.30(s，1H).

Embodiment 40

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LP-40)

With reference to the synthetic method of LP-37, with 12m and 4-trifluoromethylated benzaldehyde for raw material obtains, yield 83.3%, mp 272 ~ 275 DEG C.ESI-MS：578.1[M-H] ^-； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.48(t，J＝6.84Hz，3H)，4.35(q，2H，J＝6.99Hz)，7.28 (s，1H)，7.42(t，1H，J＝8.91Hz)，7.46～7.48(m，2H)，7.97(d，2H，J＝8.16Hz)，8.12(d，2H，J＝8.19Hz)，8.44(s，1H)，8.60(s，1H)，8.87(s，1H)，9.76(s，2H).

Embodiment 41

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide (LP-41)

With reference to the synthetic method of LP-37, with 12m and 3-trifluoromethylated benzaldehyde for raw material obtains, yield is 75%, mp 270 ~ 274 DEG C.ESI-MS：602.1[M+Na] ⁺； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.48(t，J＝7.08Hz，3H)，4.35(q，J＝6.75Hz，2H)，7.27～7.29(m，1H)，7.44(t，J＝9.33Hz，1H)，7.48～7.50(m，2H)，7.87(t，J＝8.82Hz，1H)，8.00(d，J＝6.72Hz，1H)，8.31～8.33(m，1H)，8.38(br s，1H)，8.50(s，1H)，8.60(s，1H)，8.88(s，1H)，9.79(s，1H)，9.85(s，1H).

Embodiment 42

The synthesis of N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide (LP-42)

With reference to the synthetic method of LP-3, with 12m and furans-2-formaldehyde for raw material obtains, yield 80%, mp 275 DEG C decomposition.ESI-MS：524.1[M+Na] ⁺； ¹H-NMR(300MHz，DMSO-d6)δ(ppm)：1.47(t，3H，J＝6.87Hz)，4.36(q，2H，J＝5.31Hz)，6.87～6.89(m，1H)，7.42～7.44(m，1H)，7.49(t，1H，J＝5.4Hz)，7.51～7.53(m，3H)，8.15(s，1H)，8.23(s，1H)，8.59(s，1H)，8.92(s，1H)，9.52(s，1H)，9.82(s，1H).

Embodiment 43

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-cyclopropyl acrylamide (LP-43) synthesizes

With reference to the synthetic method of LP-37, with 12m and ring third formaldehyde for raw material obtains, yield 85%, mp 237-240 DEG C.ESI-MS：474.0[M-H] ^-； ¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：1.05(br s，2H)，1.33(br s，2H)，1.46(t，3H，J＝4.83Hz)，4.31(q，2H，J＝4.95Hz)，7.17～7.25(m，2H)，7.39～7.45(m，3H)，8.57(s，1H)，8.77(s，1H)，9.38(s，1H)，9.82(br s，1H).

Embodiment 44

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide (LP-44) synthesizes

With reference to the synthetic method of LP-37, with 12m and special valeral for raw material obtains, yield 87%, mp 133-136 DEG C of ESI-MS:490.0 [M-H] ^-; ¹h-NMR (300MHz, DMSO-d ₆), δ (ppm): 1.29 (s, 9H), 1.45 (t, 3H, J=6.84Hz), 4.32 (q, 2H, J=7.14Hz), 7.23 ~ 7.28 (m, 1H), 7.39 ~ 7.48 (m, 3H), 7.57 (s, 1H), 8.56 (s, 1H), 8.78 (s, 1H), 9.65 (br s, 2H).

Embodiment 45

The synthesis of 2-(2-chlorine 4-nitro Phenoxymethyl)-pyridine (2n)

2-chloromethyl pyridine hydrochloride (4.10g, 25.00mmol) and salt of wormwood (6.90g, 50.00mmol) are added in DMF (20mL), 1n (4.35g is added successively after stirring at room temperature 10min, 25mmol) with potassiumiodide (0.21g, 1.30mmol), be warming up to 60 DEG C of reactions and spend the night, reaction solution is poured into water (100mL), separate out solid, suction filtration, dry off-white color solid 6.50g, yield 98%, mp 148 ~ 150 DEG C.

The synthesis of the chloro-4-of 3-(pyridine-2-methoxyl group) aniline (3n)

By 2n (5.00g, 19.00mmol), iron powder (4.20g, 75.00mmol) and ammonium chloride (6.00g, 112.00mol) be placed in 90% ethanolic soln (130mL), back flow reaction 1.5h, cooling, suction filtration, filtrate is concentrated into dry, and residual solid is dissolved in ethyl acetate, washing, anhydrous magnesium sulfate drying organic layer, concentrate to obtain brown solid 4.30g, yield 97%, mp 88 ~ 91 DEG C.

The synthesis of 3-cyano group-4-[3-chloro-(pyridine-2-methoxyl group) anilino]-6-amino-7-ethoxyquinoline (5n)

By 10m (3.80g, 13.00mmol) with 3n (3.10g, 13.00mmol) add in dehydrated alcohol (100mL), add methylsulfonic acid (2), return stirring 2h, obtained compound 4n does not need to be separated and directly reaction solution is cooled to room temperature, adds 0.6mol/L hydrochloric acid (170mL), back flow reaction 3h.Cooling, suction filtration, is dissolved in methyl alcohol (100mL) by gained crude product, add 1mol/L wet chemical (70mL), stirring is spent the night, suction filtration, washing, dry white-yellowish solid 4.80g, yield 82.8%, mp 232 ~ 234 DEG C.ESI-MS：445[M-H] ^-； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.45(t，3H，J＝6.9Hz)，4.21(q，2H，J＝4.1Hz)，5.25(s，2H)，5.46(s，2H)，7.06(dd，1H，J ₁＝2.8Hz，J ₂＝8.40Hz)，7.19～7.27(m，4H)，7.37(t，1H，J＝5.00Hz)，7.57(d，1H，J＝7.70Hz)，7.87(t，1H，J＝7.80Hz)，8.30(s，1H)，8.59(d，1H，J＝4.1Hz)，9.13(s，1H).

The synthesis of 3-cyano group-4-[3-chloro-(pyridine-2-methoxyl group) anilino]-6-cyano-acetamide amido-7-ethoxyquinoline (6n)

With reference to the synthetic method of 12m, be that raw material obtains with 5n, yield 73%, mp 255 DEG C decomposition. ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.46(t，3H，J＝6.87Hz)，4.09(s，2H)，4.34(q，2H，J＝7.20Hz)，5.30(s，2H)，7.19～7.21(m，2H)，7.32～7.34(m，3H)，7.56～7.58(m，1H)，7.87～7.89(m，1H)，8.47(s，1H)，8.84～8.86(m，1H)，8.90(s，1H)，9.58(s，1H)，9.81(s，1H).

The synthesis of N-[4-[(the chloro-4-of 3-(pyridine-2-methoxyl group) phenyl) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide (LP-45)

With reference to the synthetic method of LP-37, with 6n and phenyl aldehyde for raw material obtains, yield 83%, mp 230 ~ 234 DEG C.ESI-MS：623.1[M+Na] ⁺； ¹H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.47(t，3H，J＝7.08Hz)，4.33(q，2H，J＝6.84Hz)，5.30(s，2H)，7.24～7.26(m，2H)，7.37～7.39(m，1H)，7.43(s，1H)，7.46(s，1H)，7.58～7.64(m，4H)，7.87～7.89(m，1H)，8.02～8.04(m，2H)，8.37(s，1H)，8.52(s，1H)，8.59(d，1H，J＝4.65Hz)，8.87(s，1H)，9.73(s，1H)，9.75(s，1H).

Embodiment 46

The EGFR kinase inhibiting activity test of the compounds of this invention

Adopt Z-lyte FRET (fluorescence resonance energy transfer) method test the compounds of this invention to EGFR (WT), EGF (T790M), EGFR (L861Q), EGFR (L858R) kinase whose inhibit activities.The method is with Z-lyte ^tMfRET peptide class is substrate, and second order reaction detection compound is to kinase whose activity.Concrete grammar is: respectively to the compound adding FRET peptide, ATP and different concns in the dissimilar EGFR kinases after stepwise dilution, site-specific protease is added after reaction 1h, identify and cut unphosphorylated FRET peptide, after reaction 1h, use 400nm excitation wavelength, detect the absorption of 445nm and 520nm, according to fluorescence ratio computerized compound to the inhibiting rate of enzyme reaction:

With the IC of each compound of GraphPad Prism 5.0 computed in software ₅₀value, result is as shown in table 1.

EGFR kinase activity test (the IC of table 1 the compounds of this invention ₅₀: nM)

EGFR kinase inhibiting activity test result shows, and the compounds of this invention has good inhibit activities to EGFR (WT), EGF (T790M), EGFR (L861Q), EGFR (L858R).Wherein, part of compounds to EGFR (WT), EGFR (L861Q), EGFR (L858R) inhibit activities and positive drug dacomitinib and WZ4002 quite or be better than positive drug.

Embodiment 47

Part of compounds cell inhibitory effect active testing of the present invention

The blue colorimetry (MTT) of tetramethyl-nitrogen azoles is adopted to evaluate the inhibit activities of part of compounds of the present invention to humanized's tumor cell proliferation.Mtt assay has been widely used in large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy sensitivity and has measured.

Tumor cell line: A549 lung carcinoma cell (WT EGFR); HCC827 lung carcinoma cell (EGFR del E746-A750); A431 epithelial cell (EGFR of overexpression); H1975 lung carcinoma cell (EGFR L858R/T790M); MCF-7 breast cancer cell (not expressing EGFR and HER-2); SK-Br-3 breast cancer cell (HER-2 overexpression); N87 stomach cancer cell (EGFR of overexpression); LoVo colon cancer cell (EGFR of overexpression).

Experimental technique: the cell in vegetative period of taking the logarithm is made into 4.5 × 105/mL cell suspension, is seeded in 96 well culture plates, every hole 180 μ L, and often group establishes 5 parallel holes, adds each 20 μ L of different concns tested material respectively.Be placed in constant temperature CO2 incubator to cultivate 48 hours, tetramethyl-nitrogen azoles indigo plant added in 96 orifice plates, every hole 20 μ L, continue cultivation 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, jolting 5 minutes on plate shaker.Be the optical density in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, each repetition of above experiment 3 times.Calculate cell proliferation inhibition rate (inhibiting rate %=(negative control group OD value-tested group OD value)/negative control group OD value × 100%), set up linear regression equation according to inhibiting rate and try to achieve half-inhibition concentration IC50 value.The results are shown in Table 2.

Table 2 part of compounds anti-tumour cell proliferative activity of the present invention (IC ₅₀: μM)

Tumor cell proliferation inhibition activity result shows, and the majority of compounds of testing has good inhibit activities to HCC827 (human lung carcinoma cell line EGFR del E746-A750).

Claims

1. alpha-cyano-the α shown in general formula (I), beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt:

Wherein:

A represents N or CR ₄;

R ₂represent hydrogen, halogen, NR ₅r ₆or OR ₇;

R ₄represent CN;

2. alpha-cyano-α according to claim 1, beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt, is characterized in that:

A represents N or CR ₄;

R ₂represent NR ₅r ₆or OR ₇;

R ₄represent CN;

R ₇represent C ₁-C ₈alkyl or C ₃-C ₆heterocyclylalkyl.

3. alpha-cyano-α according to claim 2, beta-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt, is characterized in that:

A represents N or CR ₄;

R ₄represent CN.

4. alpha-cyano-α, 3-unsaturated acyl aminated compounds according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that described compound is selected from:

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-Phenyl Acrylamide;

N-[2-(diethylin) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrroles-3-carboxylic acid amides;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-dimethylin acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-cyclopropyl acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-N-tert-butyl acrylamide;

5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-2,4-Dimethyl-pyrrol-3-carboxylic acid, ethyl esters;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide;

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazol-4 yl) acrylamide;

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(pyrazole-3-yl) acrylamide;

(S)-N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-[7-(tetrahydrofuran base-3-oxygen base)] quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide;

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide;

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide;

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-(imidazoles-2-base) allylamine;

(S)-[N-[4-[(2-hydroxyl-1-styroyl) amido]-7-methoxyquinazoline hydrochloride]-6-base]-2-cyano group-3-cyclopropyl acrylamide;

N-[4-[(2-hydroxyethyl) amido]-7-methoxyquinazoline hydrochloride-6-base]-2-cyano group-3-(pyrroles-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-dimethylin quinazoline-6-base]-2-cyano group-3-Phenyl Acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-cyclopropyl acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(imidazoles-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N methyl piperazine-1-base) quinazoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(pyrrolidin-1-yl) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-7-(N, N-dimethylated propyl diethylenetriamine-1-base) quinazoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(pyridine-2-base) acrylamide;

N-[2-(dimethylamino) ethyl]-2,4-dimethyl-5-[3-[[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base] amido]-2-cyano group-3-oxopropyl-1-alkene-1-base]-pyrroles-3-carboxylic acid amides;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(4-trifluoromethyl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(3-trifluoromethyl) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-(furans-2-base) acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-cyclopropyl acrylamide;

N-[4-[(the chloro-4-fluorophenyl of 3-) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-N-tert-butyl acrylamide;

N-[4-[(the chloro-4-of 3-(pyridine-2-methoxyl group) phenyl) amido]-3-cyano group-7-ethoxyquinoline-6-base]-2-cyano group-3-Phenyl Acrylamide.

5. treat the pharmaceutical composition of tumour for one kind, its alpha-cyano-α according to any one of the claim 1-4 treating upper significant quantity, B-unsaturated acyl aminated compounds, its steric isomer or its pharmacy acceptable salt and pharmaceutically acceptable carrier or auxiliary material composition.

6. the compound according to any one of claim 1-4, its steric isomer, its pharmacy acceptable salt or the composition described in claim 5 are preparing the application in antitumor drug.

7. application according to claim 6, wherein said tumour is non-small cell type lung cancer, mammary cancer, cancer of the stomach, colorectal carcinoma, carcinoma of the pancreas, bladder cancer or cervical cancer.