CN106317026B

CN106317026B - A kind of compound being able to suppress ErbB/HDAC and preparation method thereof includes its pharmaceutical composition and application thereof

Info

Publication number: CN106317026B
Application number: CN201610700292.9A
Authority: CN
Inventors: 蒋宇扬; 丁超; 张存龙; 谭春燕; 高春梅; 袁梓高; 李文璐
Original assignee: Shenzhen Graduate School Tsinghua University
Current assignee: Shenzhen Graduate School Tsinghua University
Priority date: 2016-08-22
Filing date: 2016-08-22
Publication date: 2019-03-22
Anticipated expiration: 2036-08-22
Also published as: CN106317026A

Abstract

The present invention relates to a kind of compound for being able to suppress ErbB/HDAC and preparation method thereof, include its medical composition and its use.The compound is as shown in Equation 1, the compound or its pharmaceutically acceptable salt, solvate, ester, acid, metabolin or prodrug, or the pharmaceutical composition comprising the compound, it can be used for preparing the preparation of ErbB kinases and HDAC activity inhibitor and the preparation of the disease curative mediated by ErbB kinases or HDAC activation.

Description

A kind of compound being able to suppress ErbB/HDAC and preparation method thereof includes its medicine Object combination and application thereof

Technical field

The invention belongs to field of medicaments, and in particular to a kind of compound for being able to suppress ErbB/HDAC and preparation method thereof, Include its pharmaceutical composition and application thereof.

Background technique

It includes four homologous members that ErbB protein tyrosine kinase family, which has altogether: EGFR (ErbB1, HER1), HER2 (ErbB2, Neu), HER3 (ErbB3) and HER4 (ErbB4) can excite ErbB to occur homologous when ligand is combined with receptor Dimerization or heterodimeric.Induce a series of tyrosine residues that phosphorylation occurs later, to raise a series of containing SH2 structural domain Aptamers and signal protein, provide binding site for some downstream albumen, finally have activated such as downstream PI3K and MAPK Access, to adjust the physiology courses such as proliferation and the survival of cell.

Therefore, EGFR and HER2 is selectively blocked to be turned out to be by clinic by monoclonal antibody or micromolecular inhibitor A kind of extremely effective strategy.As first generation small molecule EGFR inhibitor, Gefitinib (gefitinib) and Tarceva (erlotinib) greatly improve the non-small cell lung cancer patient's of EGFRL858R mutation and the mutation of 19 Exon deletions Overall survival.But due to the T790M bis- times mutation and the activation of other compensatory accesses in albumen conserved region, these drugs Drug resistance is generated in patient quickly, thus lacks lasting therapeutic effect.The patient that T790M bis- times are mutated, at present U.S. FDA has had been approved by second generation EGFR inhibitor Afatinib and third generation EGFR inhibitor osimertinib (AZD9291) is right It is treated, and has good effect.But for by PI3K, the compensatory access abnormal activation such as Met, B-Raf and cause The solution that has been short of always of resistance problems.

It is activated while for a variety of bypasses, there has been proposed many strategies to be coped with.One has much the side of potentiality Method is to inhibit while inhibiting EGFR and HER2 to HDAC.HDAC can be by some histones and nonhistones reality Deacetylation effect is applied, shrinks chromosome, and prevent the transcription of gene.The activity for adjusting HDAC can influence tubulin, p53 The activity of many albumen of albumen and heat shock protein HSP90 etc. one, so regulate and control it is a series of as cell-cycle arrests, cell differentiation and The processes such as apoptosis.In past more than ten years, the research and development of HDAC micromolecular inhibitor obtain considerable progress.Vorinostat (vorinostat), romidepsin (romidepsin), pabishta (panobinostat) is successively successfully by U.S. FDA batch The mutatis mutandis treatment in skin T cell lymphoma and Huppert's disease.

Many studies have shown that there is the dialogue effects of collaboration between EGFR, HER2 and HDAC.The inhibition of HDAC6 can be drawn The increase of HSP90 Acetylation Level is played, and then the client protein of some HSP90 is caused to be degraded.These client proteins include Mutant egf R, HER2, AKT, c-Raf and ABL etc..Therefore HDAC6 inhibitor can be shown and HSP90 inhibitor phase Similar effect.In addition, hdac inhibitor can also influence genetic transcription, increase the expression of active oxygen radical (ROS), and Lead to cell-cycle arrest, these effects can often promote the cancer resistant effect of EGFR and HER2 inhibitor indirectly.Document is It reports in EGFR or the highly expressed tumour cell of HER2 by SAHA and LBH-589 processing, the horizontal of HSP90 acetylation obtains To up-regulation, EGFR or HER2 degrade, and these hdac inhibitors and EGFR or HER2 inhibitor Tarceva, Lapatinib And Herceptin generates significant synergistic effect.Therefore it is advantageously possible for simultaneously for EGFR, HER2 and HDAC to swollen The therapeutic effect of tumor.

Summary of the invention

The purpose of the present invention is to provide a kind of compound for being able to suppress ErbB/HDAC and preparation method thereof, include it Pharmaceutical composition and application thereof.

An aspect of of the present present invention provides a kind of compound of ErbB/HDA always and its pharmaceutically acceptable of being able to suppress Salt, solvate, ester, acid, metabolin or prodrug.

The compound is the 4- fragrant amino quinazoline compounds that hydroxamic acid replaces, and structure is shown in formula I；

In above-mentioned Formulas I, R can be selected from having structure unit:

Wherein, R₁, R₂It independently is H, F, Cl, Br, I, CF₃、OCF₃、OH、CN、NO₂、NH₂、C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino, C_1-6Alkylthio group, C_1-6Alkyl-carbonyl, C_1-6Alkylamidoalkyl, C_1-6Alkyl sulphonyl, C_1-6Alkyl sulphinyl, C_2-6Alkenyl, C_2-6Alkynyl, C_6-10Aryloxy group, C_6-10Fragrant amino, C_6-10Aryl C_1-6Alkyl, C_6-10Aryl C_1-6Alkoxy, C_1-9It is miscellaneous Aryloxy group, C_1-9Heteroaryl C_1-6Alkyl, C_1-9Heteroaryl C_1-6Alkoxy；

R is selected from And/or the B is selected from C3, C4, C5 or C6 Linear paraffin, preferably unsubstituted C3, C4, C5 or C6 linear paraffin or by F, Cl, Br, I, O, N, S, SO, SO₂In CN At least one group replaces；

In formula 1It is connected on the position C6 or C7 of quinazoline.

The salt is inorganic acid salt or acylate, and the inorganic acid salt is selected from what any one following inorganic acid were formed Salt: hydrochloric acid, sulfuric acid or phosphoric acid；The acylate be selected from any one following organic acid formed salt: acetic acid, trifluoroacetic acid, Malonic acid, citric acid and p-methyl benzenesulfonic acid.

Above-mentioned Formulas I compound represented be preferably it is following any one:

On the other hand, the application provides a kind of pharmaceutical composition comprising the shown compound of at least one Formulas I, pharmacy Upper acceptable carrier or excipient and optional other therapeutic agents.

The invention further relates to compound shown in above-mentioned Formulas I and its pharmaceutically acceptable salt, solvate, ester, acid, metabolism Object or prodrug and pharmaceutical composition comprising them, in the purposes for being used to prepare ErbB kinases and HDAC activity inhibitor.

The invention further relates to compound shown in above-mentioned Formulas I and solvate, ester, acid, metabolin or prodrug and include it Pharmaceutical composition, preparation treatment by ErbB kinases or HDAC activation mediate disease drug in purposes.The disease Disease is selected from: lung cancer, breast cancer, head-neck carcinoma, colon cancer, sdenocarcinoma of stomach, bladder cancer, kidney, liver cancer, thyroid cancer, prostate cancer, Cancer of pancreas, central nervous system cancer, glioblastoma, leukaemia, nasopharyngeal carcinoma, cervical carcinoma, oophoroma, cutaneum carcinoma or transfer Cancer.

The present invention also provides a kind of preparation methods of compound shown in above-mentioned Formulas I, include the following steps:

A, formamide and 2- amino -5- iodo-benzoic acid are reacted 2-5 hours at 160-220 DEG C, after reaction, is added Methanol, filtering reacting liquid, filter cake are rinsed with methanol, obtain compound 102 after dry；

B, the compound 102 is dissolved in thionyl chloride, the anhydrous n,N-Dimethylformamide of catalytic amount is added, flowed back Reaction 2-12 hours, after reaction, vacuum distillation remove excessive thionyl chloride, obtain compound 103,

Or the compound 102 is dissolved in phosphorus oxychloride, the anhydrous n,N-diisopropylethylamine of catalytic amount is added, flows back Reaction 2-12 hours, after reaction, vacuum distillation remove excessive phosphorus oxychloride, obtain compound 103；

C, at room temperature, amino benzenes compounds are added in the aqueous isopropanol containing the compound 103, at 60-100 DEG C Reaction 1-3 hours, after being cooled to room temperature, filtering reacting liquid, filter cake is rinsed with isopropanol, obtains compound 104 after dry；D, will Tetrahydrofuran mixed liquor or N,N-dimethylformamide mixed liquor is added in trimethyl acetenyl silicon and triethylamine under protection of argon gas In, it back flow reaction 2-24 hours, after reaction, is concentrated under reduced pressure, is rinsed with methylene chloride/methanol on short silicagel column to remove Catalyst obtains compound 105,

The tetrahydrofuran mixed liquor contains the compound 104, bis-triphenylphosphipalladium palladium dichloride and cuprous iodide,

The N,N-dimethylformamide mixed liquor contains the compound 104, [two cyclopentadienyl of 1,1'- bis- (diphenylphosphinos) Iron] palladium chloride and cuprous iodide；

E, compound 105 is dissolved in tetrahydrofuran after flushing liquor concentration, the tetrahydro furan of the tetrabutyl amine fluoride of 1.0M is added It mutters solution, is reacted half an hour under argon gas, after reaction, water quenching is added to go out, extracted through ethyl acetate, wash, saturated salt solution It washes, after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, compound 106 is obtained after post separation；

F, the N containing compound 6- bromocaproic acid or 7- bromine enanthic acid, N- dimethyl formyl at room temperature, is added in sodium azide It in amine aqueous solution, is to slowly warm up to react 24-72 hours at 60-100 DEG C, after reaction, be extracted through ethyl acetate, wash, satisfy It is washed with salt, anhydrous sodium sulfate is dry, and compound 108 is obtained after reduced pressure；

G, 4-dimethylaminopyridine is added in chloroformic solution, reacts 2-24 hours, after reaction, depressurizes dense at room temperature Contracting, extracts through methylene chloride, and saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and post separation obtains compound 109,

The chloroformic solution contains compound 108, THP trtrahydropyranyl azanol and 1- (3- dimethylaminopropyl) -3- ethyl Carbodiimide；

H, cupric sulfate pentahydrate and sodium ascorbate are added in n,N-Dimethylformamide solution, react 2- at 50-70 DEG C 24 hours extract through ethyl acetate after reaction, washing, and saturated common salt washing after anhydrous sodium sulfate is dry, is depressurized dense Contracting, post separation obtain compound 110；

The N,N-dimethylformamide solution contains the compound 106 and compound 109；

I, hydrochloric acid dioxane solution is added dropwise in the dioxane solution containing the compound 110, at room temperature Reaction, to which after reaction, filtering reacting liquid, filter cake washed with ether obtains compound of formula I after dry.

The amino benzenes compounds are selected from: the chloro- 4- fluoroaniline of 3-, the chloro- 2- fluoroaniline of 3-, 3- fluorine benzyloxy-aniline, 4- (3- Fluorine benzyloxy) aniline, 4- (thiazole -2- methoxyl group) aniline, 4- ((substitution of 6- picoline -3) oxygroup) aniline, 3- methoxyl group - The bromo- 2- fluoroaniline of 4- phenoxybenzamine, 4- or 3- aminoanisole.

A, formamide and 2- amino -4- bromobenzoic acid are reacted 2-5 hours at 160-220 DEG C, after reaction, is added Methanol, filtering reacting liquid, filter cake are rinsed with methanol, obtain compound 202 after dry；

B, the compound 202 is dissolved in thionyl chloride, the anhydrous n,N-Dimethylformamide of catalytic amount is added, flowed back Reaction 2-12 hours, after reaction, vacuum distillation remove excessive thionyl chloride, obtain 203,

Or the compound 202 is dissolved in phosphorus oxychloride, the anhydrous n,N-diisopropylethylamine of catalytic amount is added, flows back Reaction 2-12 hours, after reaction, vacuum distillation remove excessive phosphorus oxychloride, obtain compound 203；

C, at room temperature, amino benzenes compounds are added in the aqueous isopropanol containing the compound 203, at 60-100 DEG C Reaction 1-3 hours, after being cooled to room temperature, filtering reacting liquid, filter cake is rinsed with isopropanol, obtains compound 204 after dry；

D, tetrahydrofuran mixed liquor or N, N- dimethyl is added in trimethyl acetenyl silicon and triethylamine under protection of argon gas In formamide mixed liquor, back flow reaction 2-24 hours, after reaction, it is concentrated under reduced pressure, with methylene chloride/methanol in short silicagel column Upper flushing obtains compound 205 to remove catalyst,

The tetrahydrofuran mixed liquor contains the compound 204, bis-triphenylphosphipalladium palladium dichloride and cuprous iodide,

The N,N-dimethylformamide mixed liquor contains the compound 204, [two cyclopentadienyl of 1,1'- bis- (diphenylphosphinos) Iron] palladium chloride and cuprous iodide；

E, compound 205 is dissolved in tetrahydrofuran after flushing liquor concentration, the tetrahydro furan of the tetrabutyl amine fluoride of 1.0M is added It mutters solution, is reacted half an hour under argon gas, after reaction, water quenching is added to go out, extracted through ethyl acetate, wash, saturated salt solution It washes, after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, compound 206 is obtained after post separation；

F, the N containing compound 6- bromocaproic acid or 7- bromine enanthic acid, N- dimethyl formyl at room temperature, is added in sodium azide It in amine aqueous solution, is to slowly warm up to react 24-72 hours at 60-100 DEG C, after reaction, be extracted through ethyl acetate, wash, satisfy It is washed with salt, anhydrous sodium sulfate is dry, and compound 208 is obtained after reduced pressure；

G, 4-dimethylaminopyridine is added in chloroformic solution, reacts 2-24 hours, after reaction, depressurizes dense at room temperature Contracting, extracts through methylene chloride, and saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and post separation obtains compound 209,

The chloroformic solution contains the compound 208, THP trtrahydropyranyl azanol and 1- (3- dimethylaminopropyl) -3- Ethyl carbodiimide；

H, cupric sulfate pentahydrate and sodium ascorbate are added in n,N-Dimethylformamide solution, react 2- at 50-70 DEG C 24 hours extract through ethyl acetate after reaction, washing, and saturated common salt washing after anhydrous sodium sulfate is dry, is depressurized dense Contracting, post separation obtain compound 210；

The N,N-dimethylformamide solution contains the compound 206 and compound 209；

I, hydrochloric acid dioxane solution is added dropwise in the dioxane solution containing the compound 210, at room temperature Reaction, to which after reaction, filtering reacting liquid, filter cake washed with ether obtains compound of formula I after dry.

Detailed description of the invention

Figure 1A indicates the Acetylation Level of phosphorylation and histone of the compound 4 in A549 cell to EGFR and HER2 It influences.

Figure 1B indicates the Acetylation Level of phosphorylation and histone of the compound 4 in BT-474 cell to EGFR and HER2 Influence.

Fig. 2A indicates the influence that cell cycle is distributed in A549 cell when 4 concentration of compound is 0nmol (control group).

Fig. 2 B indicates the influence that cell cycle is distributed in A549 cell when 4 concentration of compound is 200nmol.

Fig. 2 C indicates the influence that cell cycle is distributed in A549 cell when 4 concentration of compound is 600nmol.

Fig. 2 D indicates the influence that cell cycle is distributed in A549 cell when 4 concentration of compound is 1000nmol.

Fig. 3 A indicates that 4 concentration of compound is the influence of 0nmol (control group) to BT-474 Apoptosis.

Fig. 3 B indicates that 4 concentration of compound is influence of 1 μm of ol to BT-474 Apoptosis.

Fig. 3 C indicates that 4 concentration of compound is influence of 2.5 μm of ol to BT-474 Apoptosis.

Fig. 3 D indicates that 4 concentration of compound is influence of 5 μm of ol to BT-474 Apoptosis.

Specific embodiment

The present invention will be described below by way of specific embodiments, but the present invention is not limited thereto.

Experimental method used in following embodiments is conventional method unless otherwise specified；Institute in following embodiments Reagent, biomaterial etc., are commercially available unless otherwise specified.

Herein, " compound shown in formula N " is otherwise referred to as " compound N ", and N herein is the arbitrary integer of 1-22, Such as " compound shown in formula 4 " is referred to as " compound 4 " herein.

Synthetic method 1, reaction reagent and condition: (a) formamide, reflux；(b) thionyl chloride, n,N-Dimethylformamide, Reflux；(c) isopropanol, 80 DEG C；(d) trimethyl acetenyl silicon, bis-triphenylphosphipalladium palladium dichloride, cuprous iodide, tetrahydrofuran/tri- Ethamine, 80 DEG C；(e) tetrabutyl amine fluoride, tetrahydrofuran, room temperature；(f) sodium azide, n,N-Dimethylformamide, 80 DEG C；(g) 1- (3- dimethylaminopropyl) -3- ethyl carbodiimide, 4-dimethylaminopyridine, chloroform, room temperature；(h) cupric sulfate pentahydrate resists Bad hematic acid sodium, n,N-Dimethylformamide, 60 DEG C；(i) hydrochloric acid, dioxane, room temperature.

Synthetic method 2, reaction reagent and condition: (a) formamide, reflux；(b) phosphorus oxychloride, n,N-diisopropylethylamine, Reflux；(c) isopropanol, 80 DEG C；(d) trimethyl acetenyl silicon, [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride, iodine Change cuprous, n,N-Dimethylformamide/triethylamine, 80 DEG C；(e) tetrabutyl amine fluoride, tetrahydrofuran, room temperature；(f) Azide Sodium, n,N-Dimethylformamide, 80 DEG C；(g) 1- (3- dimethylaminopropyl) -3- ethyl carbodiimide, 4- dimethylamino pyrrole Pyridine, chloroform, room temperature；(h) cupric sulfate pentahydrate, sodium ascorbate, n,N-Dimethylformamide, 60 DEG C；(i) hydrochloric acid, dioxane, Room temperature.

Embodiment 1:The preparation of (compound 1)

Step 1a, 6- iodine quinazoline-4-one (102) are prepared

Formamide (13.7g, 304mmol) and 2- amino -5- iodo-benzoic acid (compound 101,20g, 76.0mmol) are existed It is reacted 4 hours at 190 DEG C.After reaction, 100mL methanol, filtering reacting liquid is added, filter cake is rinsed with methanol, is obtained after dry To compound 102.Yield 80.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.42 (s, 1H), 8.42-8.34 (m, 1H), 8.14 (d, J=1.4Hz, 1H), 8.12-8.05 (m, 1H), 7.46 (t, J=6.8Hz, 1H)

Step 1b, the chloro- 6- iodine quinazoline (103) of 4- is prepared

Compound 102 (14.4g) is dissolved in thionyl chloride (50ml), the anhydrous DMF of 1mL catalytic amount is added, reflux is anti- It answers 4 hours.After reaction, vacuum distillation removes excessive thionyl chloride, obtains compound 103.Yield 92.4%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 8.67 (s, 1H), 8.41 (d, J=1.4Hz, 1H), 8.20 (d, J=6.2Hz, 1H), 7.59 (t, J=10.9Hz, 1H)

Step 1c, N- (the chloro- 4- fluorophenyl of 3-) -6- iodine quinazoline -4- amine (104a) is prepared

At room temperature, the chloro- 4- fluoroaniline (22mmol) of 3- is added to the aqueous isopropanol of compound 103 (5.8g, 20mmol) In, it is reacted 2 hours at 80 DEG C.After being cooled to room temperature, filtering reacting liquid, filter cake is rinsed with isopropanol, obtains compound after dry 104a.Yield 96.3%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.91 (s, 1H), 9.41 (s, 1H), 9.00 (s, 1H), 8.38 (dd, J=8.7, 1.1Hz, 1H), 8.05 (dd, J=6.8,2.5Hz, 1H), 7.82-7.73 (m, 3H), 7.56 (t, J=9.0Hz, 1H)

Step 1d, three silicon methylacetylenyl quinazoline -4- amine (105a) of N- (the chloro- 4- fluorophenyl of 3-) -6- is prepared

104a (10mmol), Pd (PPh is added in trimethyl acetenyl silicon and triethylamine under protection of argon gas₃)₂Cl₂ In the THF mixed liquor of (351mg, 0.5mmol) and CuI (97mg, 0.5mmol), back flow reaction 12 hours.After reaction, subtract Pressure concentration, is rinsed to remove catalyst on short silicagel column with methylene chloride/methanol (10/1), obtains compound 105a.

Step 1e, N- (the chloro- 4- fluorophenyl of 3-) -6- acetenyl quinazoline -4- amine (106a) is prepared

Compound 105a is dissolved in THF after flushing liquor concentration, be added the tetrabutyl amine fluoride of 1.0M THF solution (10ml, 10mmol), half an hour is reacted under argon gas.After reaction, add water quenching to go out, extracted through ethyl acetate, washed, saturated salt solution It washes, after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, compound 106a is obtained after post separation.The gross production rate 75.6% of step 1d and 1e.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.97 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 8.21 (dd, J=6.8, 2.5Hz, 1H), 7.90-7.82 (m, 2H), 7.77 (d, J=8.6Hz, 1H), 7.45 (t, J=9.1Hz, 1H), 4.44 (s, 1H)

Step 1f, 6- azido caproic acid (108a) is prepared

At room temperature, sodium azide (3.9g, 60mmol) is added in the DMF solution of 6- bromocaproic acid (107a, 20mmol), It is to slowly warm up to react 48 hours at 80 DEG C.After reaction, it extracts, washes through ethyl acetate, saturated common salt washing, anhydrous sulphur Sour sodium is dry, and compound 108a is obtained after reduced pressure.Yield 86.4%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,CDCl₃) δ 11.20 (s, 1H), 3.29 (t, J=6.9Hz, 2H), 2.38 (t, J=7.4Hz, 2H),1.73–1.58(m,4H),1.48–1.39(m,2H).

Step 1g, 6- azido-N- ((oxinane -2- substitution) oxygroup) caproamide (109a) is prepared

Compound 108a (10mmol) is added in DMAP, THP trtrahydropyranyl azanol (1.29g, 11mmol) and EDCI In the chloroformic solution of (2.52g, 13.2mmol), react 12 hours at room temperature.After reaction, it is concentrated under reduced pressure.Through methylene chloride Extraction, saturated common salt washing after anhydrous sodium sulfate is dry, are concentrated under reduced pressure, and post separation obtains compound 109a.Yield 91.3%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,CDCl₃) δ 8.38 (s, 1H), 4.94 (s, 1H), 3.95 (d, J=9.0Hz, 1H), 3.63 (m, 1H), 3.27 (t, J=6.8Hz, 2H), 2.14-1.76 (m, 4H), 1.74-1.50 (m, 8H), 1.47-1.35 (m, 2H)

Step 1h, 6- (4- (4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole-is prepared 1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (110a)

Compound 106a is added in cupric sulfate pentahydrate (0.15g, 0.6mmol) and sodium ascorbate (0.2g, 1mmol) In the DMF solution of (2mmol) and compound 109a (2mmol), 12 hours are reacted at 70 DEG C.After reaction, through acetic acid second Ester extraction, washing, saturated common salt washing after anhydrous sodium sulfate is dry, are concentrated under reduced pressure, and post separation obtains compound 110a.Yield 57.2%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),10.14(s,1H),9.06(s,1H),8.67(s,1H), 8.64 (s, 1H), 8.30 (dd, J=8.6,1.5Hz, 1H), 8.22 (dd, J=6.8,2.6Hz, 1H), 7.89 (m, 2H), 7.48 (t, J=9.1Hz, 1H), 4.76 (s, 1H), 4.47 (t, J=6.9Hz, 2H), 3.94-3.82 (m, 1H), 3.46 (d, J= 11.4Hz,1H),2.07–1.83(m,4H),1.69–1.39(m,8H),1.32–1.20(m,2H).

Step 1i, 6- (4- (4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole-is prepared 1- replaces)-N- hydroxyl hexanamide (1)

The hydrochloric acid dioxane solution (1mL, 2mmol) of 2.0M is added dropwise to the dioxy of compound 110a (0.5mmol) In six ring solution, react one hour at room temperature.To after reaction, filtering reacting liquid, filter cake washed with ether.It is obtained after drying Compound 1.Yield 85.3%.Mass spectrum (ESI): [M+H]⁺470.15。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.07(s,1H),10.43(s,1H),9.63(s,1H),8.99(s,1H), 8.96 (s, 1H), 8.56 (d, J=8.8Hz, 1H), 8.12 (dd, J=6.8,2.5Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.85 (ddd, J=8.8,4.2,2.7Hz, 1H), 7.57 (t, J=9.1Hz, 1H), 4.46 (t, J=7.0Hz, 2H), 2.05- 1.81(m,4H),1.64–1.43(m,2H),1.35–1.18(m,2H).

Embodiment 2:The preparation of (compound 2)

According to the step prepare compound 2 of embodiment 1, the difference is that:

1,7- azido enanthic acid (108b) is prepared

The 107a in the step 1f in embodiment 1 is changed into 7- bromine enanthic acid (107b) to react.Yield 81.5%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,CDCl₃) δ 11.36 (s, 1H), 3.27 (t, J=6.9Hz, 2H), 2.36 (t, J=7.4Hz, 2H),1.70–1.56(m,4H),1.45–1.34(m,4H).

2,7- azido-N- ((oxinane -2- substitution) oxygroup) heptamide (109b) is prepared

The 108a in the step 1g in embodiment 1 is changed into 108b to react.Yield 89.8%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,CDCl₃) δ 8.76 (s, 1H), 4.89 (s, 1H), 3.95 (d, J=9.4Hz, 1H), 3.63 (m, 1H), 3.26 (t, J=6.9Hz, 3H), 2.19-1.76 (m, 4H), 1.73-1.48 (m, 8H), 1.45-1.29 (m, 4H)

3, ((4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- ((oxinane -2- substitution) oxygroup) heptamide (110b)

The 109a in the step 1h in embodiment 1 is changed into 109b to react.Yield 59.7%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.91(s,1H),10.10(s,1H),9.04(s,1H),8.65(s,1H), 8.62 (s, 1H), 8.28 (d, J=8.6Hz, 1H), 8.20 (dd, J=6.8,2.4Hz, 1H), 7.88 (m, 2H), 7.45 (t, J= 9.1Hz, 1H), 4.80 (s, 1H), 4.46 (t, J=6.9Hz, 2H), 3.97-3.81 (m, 1H), 3.48 (d, J=11.4Hz, 1H),2.10–1.90(m,4H),1.72–1.40(m,8H),1.33–1.22(m,4H).

4, ((4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- hydroxyl heptamide (2)

The 110a in the step 1i in embodiment 1 is changed into 110b to react.Yield 93.5%, mass spectrum (ESI): [M+ H]⁺484.17。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.06(s,1H),10.40(s,1H),9.62(s,1H),8.99(s,1H), 8.95 (s, 1H), 8.56 (dd, J=8.7,1.3Hz, 1H), 8.13 (dd, J=6.8,2.5Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.85 (ddd, J=8.9,4.3,2.5Hz, 1H), 7.58 (t, J=9.1Hz, 1H), 4.46 (t, J=7.0Hz, 2H), 2.03–1.75(m,4H),1.56–1.40(m,2H),1.36–1.20(m,4H).

Embodiment 3:The preparation of (compound 3)

According to the step prepare compound 3 of embodiment 1, the difference is that:

1, N- (the chloro- 2- fluorophenyl of 3-) -6- iodine quinazoline -4- amine (104b) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 3- chloro- 2- fluoroaniline to react.Yield 95.1%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.26 (s, 1H), 9.48-9.34 (m, 1H), 8.97 (d, J=2.8Hz, 1H), 8.41 (dd, J=8.8,1.3Hz, 1H), 7.87-7.77 (m, 1H), 7.66 (t, J=7.4Hz, 1H), 7.58-7.50 (m, 1H), 7.37 (t, J=8.1Hz, 1H)

2, N- (the chloro- 2- fluorophenyl of 3-) -6- acetenyl quinazoline -4- amine (106b) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104b to react.Yield 69.3%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.90 (d, J= 8.5Hz, 1H), 7.79 (d, J=8.6Hz, 1H), 7.52 (t, J=7.4Hz, 2H), 7.29 (t, J=8.0Hz, 1H), 4.44 (s, 1H)

3, ((4- ((the chloro- 2- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 6- Generation)-N- ((oxinane -2- substitution) oxygroup) caproamide (110c)

The 106a in the step 1h in embodiment 1 is changed into 106b to react.Yield 66.5%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.91(s,1H),10.21(s,1H),9.01(s,1H),8.66(s,1H), 8.52 (s, 1H), 8.31 (d, J=8.5Hz, 1H), 7.89 (d, J=8.7Hz, 1H), 7.61-7.47 (m, 2H), 7.30 (t, J= 8.0Hz, 1H), 4.76 (s, 1H), 4.46 (t, J=6.9Hz, 2H), 3.94-3.80 (m, 1H), 3.45 (d, J=11.2Hz, 1H),2.07–1.81(m,4H),1.71–1.40(m,8H),1.32–1.20(m,2H).

4, ((4- ((the chloro- 2- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 6- Generation)-N- hydroxyl hexanamide (3)

The 110a in the step 1i in embodiment 1 is changed into 110c to react.Yield 78.5%, mass spectrum (ESI): [M+ H]⁺470.15。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.10(s,1H),10.38(s,1H),9.46(s,1H),8.95(s,1H), 8.84 (s, 1H), 8.58 (d, J=8.6Hz, 1H), 8.05 (d, J=8.7Hz, 1H), 7.68 (t, J=6.8Hz, 1H), 7.59 (t, J=6.7Hz, 1H), 7.40 (t, J=8.1Hz, 1H), 4.48 (t, J=6.9Hz, 2H), 2.02-1.81 (m, 4H), 1.65- 1.45(m,2H),1.37–1.17(m,2H).

Embodiment 4:The preparation of (compound 4)

According to the step prepare compound 4 of embodiment 3, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3, ((4- ((the chloro- 2- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- ((oxinane -2- substitution) oxygroup) heptamide (110d)

The 109a in the step 1h in embodiment 3 is changed into 109b to react.Yield 63.9%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.89(s,1H),10.19(s,1H),9.01(s,1H),8.66(s,1H), 8.53 (s, 1H), 8.31 (d, J=8.8Hz, 1H), 7.89 (d, J=8.7Hz, 1H), 7.62-7.45 (m, 2H), 7.31 (t, J= 8.1Hz, 1H), 4.79 (s, 1H), 4.45 (t, J=6.9Hz, 2H), 3.97-3.83 (m, 1H), 3.47 (d, J=11.7Hz, 1H),2.06–1.80(m,4H),1.72–1.38(m,8H),1.34–1.19(m,4H).

4, ((4- ((the chloro- 2- Fluorophenylamino of 3-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- hydroxyl heptamide (4)

The 110a in the step 1i in embodiment 1 is changed into 110d to react.Yield 91.2%, mass spectrum (ESI): [M+ H]⁺484.17。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.25(s,1H),10.39(s,1H),9.56(s,1H),8.95(s,1H), 8.88 (s, 1H), 8.60 (dd, J=8.7,1.4Hz, 1H), 8.07 (d, J=8.7Hz, 1H), 7.72-7.63 (m, 1H), 7.63- 7.52 (m, 1H), 7.39 (t, J=8.1Hz, 1H), 4.47 (t, J=7.0Hz, 2H), 2.01-1.79 (m, 4H), 1.60-1.40 (m,2H),1.38–1.20(m,4H).

Embodiment 5:The preparation of (compound 5)

According to the step prepare compound 5 of embodiment 1, the difference is that:

1, N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- iodine quinazoline -4- amine (104c) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 3- fluorine benzyloxy-aniline to react.Yield 94.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.82 (s, 1H), 9.38 (s, 1H), 8.96 (s, 1H), 8.36 (d, J= 8.7Hz, 1H), 7.91 (d, J=2.0Hz, 1H), 7.77 (d, J=8.7Hz, 1H), 7.70-7.62 (m, 1H), 7.47 (dd, J= 14.1,7.8Hz, 1H), 7.32 (t, J=6.6Hz, 3H), 7.19 (t, J=8.4Hz, 1H), 5.29 (s, 2H)

2, N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -6- acetenyl quinazoline -4- amine (106c) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104c to react.Yield 36.7%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.89 (s, 1H), 8.76 (d, J=1.2Hz, 1H), 8.62 (s, 1H), 8.07 (d, J=2.6Hz, 1H), 7.87 (dd, J=8.6,1.6Hz, 1H), 7.78 (d, J=2.8Hz, 1H), 7.75 (d, J=2.6Hz, 1H), 7.48 (m, 1H), 7.33 (m, 2H), 7.28 (d, J=9.0Hz, 1H), 7.19 (td, J=8.6,2.3Hz, 1H), 5.26 (s,2H),4.44(s,1H).

3,6- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (110e)

The 106a in the step 1h in embodiment 1 is changed into 106c to react.Yield 38.8%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.91(s,1H),10.00(s,1H),9.04(s,1H),8.64(s,1H), 8.59 (s, 1H), 8.28 (dd, J=8.6,1.6Hz, 1H), 8.05 (d, J=2.5Hz, 1H), 7.85 (d, J=8.7Hz, 1H), 7.78 (dd, J=8.9,2.5Hz, 1H), 7.52-7.43 (m, 1H), 7.37-7.26 (m, 3H), 7.19 (td, J=8.7, 2.1Hz, 1H), 5.27 (s, 2H), 4.77 (s, 1H), 4.47 (t, J=6.9Hz, 2H), 3.94-3.81 (m, 1H), 3.46 (d, J =11.1Hz, 1H), 2.07-1.83 (m, 4H), 1.71-1.37 (m, 8H), 1.34-1.18 (m, 2H)

4,6- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- hydroxyl hexanamide (5)

The 110a in the step 1i in embodiment 1 is changed into 110e to react.Yield 75.0%, mass spectrum (ESI): [M+ H]⁺576.19。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.90(s,1H),10.41(s,1H),9.55(s,1H),8.91(s,2H), 8.51 (d, J=8.7Hz, 1H), 8.04-7.90 (m, 2H), 7.71 (dd, J=8.9,2.3Hz, 1H), 7.49-7.42 (m, 1H), 7.35-7.26 (m, 3H), 7.21-7.12 (m, 1H), 5.28 (s, 2H), 4.43 (t, J=6.8Hz, 2H), 2.02-1.78 (m, 4H),1.61–1.42(m,2H),1.32–1.15(m,2H).

Embodiment 6:The preparation of (compound 6)

According to the step prepare compound 6 of embodiment 5, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3,7- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) heptamide (110f)

The 109a in the step 1h in embodiment 5 is changed into 109b to react.Yield 44.7%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.92(s,1H),10.03(s,1H),9.04(s,1H),8.67(s,1H), 8.59 (s, 1H), 8.28 (d, J=8.6Hz, 1H), 8.05 (d, J=2.2Hz, 1H), 7.85 (d, J=8.6Hz, 1H), 7.78 (dd, J=8.9,2.2Hz, 1H), 7.53-7.43 (m, 1H), 7.36-7.26 (m, 3H), 7.20 (t, J=8.6Hz, 1H), 5.27 (s, 2H), 4.79 (s, 1H), 4.46 (t, J=6.9Hz, 2H), 3.95-3.83 (m, 1H), 3.48 (d, J=11.2Hz, 1H), 2.06–1.80(m,4H),1.73–1.40(m,8H),1.35–1.20(m,4H).

4,7- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- hydroxyl heptamide (6)

The 110a in the step 1i in embodiment 1 is changed into 110f to react.Yield 47.1%, mass spectrum (ESI): [M+ H]⁺590.21。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.03(s,1H),10.31(s,1H),9.62(s,1H),8.95(s,2H), 8.55 (d, J=8.6Hz, 1H), 8.10-7.91 (m, 2H), 7.74 (d, J=8.9Hz, 1H), 7.54-7.43 (m, 1H), 7.38- 7.28 (m, 3H), 7.21-7.12 (m, 1H), 5.30 (s, 2H), 4.45 (t, J=6.1Hz, 2H), 2.23-1.78 (m, 4H), 1.61–1.42(m,2H),1.33–1.13(m,4H).

Embodiment 7:The preparation of (compound 7)

According to the step prepare compound 7 of embodiment 1, the difference is that:

1, N- (the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl) -6- iodine quinazoline -4- amine (104d) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 4- (3- fluorine benzyloxy) aniline to react.It produces Rate 90.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.90 (s, 1H), 9.40 (d, J=1.3Hz, 1H), 8.98 (s, 1H), 8.75 (d, J=4.5Hz, 1H), 8.39 (dd, J=8.7,1.6Hz, 1H), 8.18 (td, J=7.8,1.4Hz, 1H), 7.93 (d, J= 2.5Hz, 1H), 7.79 (t, J=9.2Hz, 2H), 7.68 (dd, J=8.9,2.5Hz, 1H), 7.65-7.61 (m, 1H), 7.38 (d, J=9.0Hz, 1H), 5.47 (s, 2H)

2, N- (the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl) -6- acetenyl quinazoline -4- amine (106d) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104d to react.Yield 44.2%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.87 (s, 1H), 8.74 (d, J=1.0Hz, 1H), 8.59 (d, J=5.1Hz, 2H), 8.06 (d, J=2.5Hz, 1H), 7.90-7.84 (m, 2H), 7.75 (d, J=2.0Hz, 1H), 7.73 (d, J=2.5Hz, 1H), 7.58 (d, J=7.8Hz, 1H), 7.36 (dd, J=6.9,5.1Hz, 1H), 7.26 (d, J=9.0Hz, 1H), 5.29 (s, 2H),4.41(s,1H).

3,6- (4- (4- ((the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl amino) quinazoline -6- substitution) -1 is prepared Hydrogen -1,2,3- triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (110g)

The 106a in the step 1h in embodiment 1 is changed into 106d to react.Yield 42.7%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.17 (s, 1H), 10.32 (s, 1H), 9.72 (d, J=4.8Hz, 1H), 9.00 (d, J=5.7Hz, 1H), 8.96 (s, 1H), 8.80 (d, J=4.9Hz, 1H), 8.59 (d, J=8.6Hz, 1H), 8.27 (t, J= 7.7Hz, 1H), 8.07 (d, J=8.7Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=7.8Hz, 1H), 7.79 (d, J=9.0Hz, 1H), 7.75-7.67 (m, 1H), 7.40 (d, J=9.0Hz, 1H), 5.43 (s, 2H), 4.80 (s, 1H), 4.47 (t, J= 6.5Hz, 2H), 3.95-3.83 (m, 1H), 3.48 (d, J=11.2Hz, 1H), 2.28-1.77 (m, 4H), 1.73-1.40 (m, 8H),1.34–1.18(m,2H).

4,6- (4- (4- ((the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl amino) quinazoline -6- substitution) -1 is prepared Hydrogen -1,2,3- triazole -1- replaces)-N- hydroxyl hexanamide (7)

The 110a in the step 1i in embodiment 1 is changed into 110g to react.Yield 87.7%, mass spectrum (ESI): [M+ H]⁺559.20。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.17(s,1H),10.32(s,1H),9.72(s,1H),9.00(s,1H), 8.96 (s, 1H), 8.80 (d, J=4.9Hz, 1H), 8.59 (d, J=8.6Hz, 1H), 8.27 (t, J=7.7Hz, 1H), 8.07 (d, J=8.7Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=7.8Hz, 1H), 7.79 (d, J=9.0Hz, 1H), 7.75-7.67 (m, 1H), 7.40 (d, J=9.0Hz, 1H), 5.43 (s, 2H), 4.47 (t, J=6.5Hz, 2H), 2.27-1.77 (m, 4H), 1.62–1.40(m,2H),1.38–1.05(m,2H).

Embodiment 8:The preparation of (compound 8)

According to the step prepare compound 8 of embodiment 7, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3, ((((the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl amino) quinazoline -6- takes 4- 4- preparation preparation 7- Generation) -1 hydrogen -1,2,3- triazole -1- substitution)-N- ((oxinane -2- substitution) oxygroup) heptamide (110h)

The 109a in the step 1h in embodiment 7 is changed into 109b to react.Yield 33.8%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.10 (s, 1H), 10.42 (s, 1H), 9.66 (s, 1H), 8.97 (d, J= 3.0Hz, 2H), 8.72 (d, J=4.7Hz, 1H), 8.57 (d, J=8.6Hz, 1H), 8.11 (t, J=7.7Hz, 1H), 8.02 (dd, J=13.1,5.5Hz, 2H), 7.76 (d, J=8.4Hz, 2H), 7.62-7.54 (m, 1H), 7.38 (d, J=9.1Hz, 1H), 5.44 (s, 2H), 4.80 (s, 1H), 4.46 (t, J=6.9Hz, 2H), 3.95-3.83 (m, 1H), 3.48 (d, J= 11.2Hz,1H),2.06–1.80(m,4H),1.73–1.40(m,8H),1.35–1.20(m,4H).

4,7- (4- (4- ((the chloro- 4- of 3- (pyridine -2- methoxyl group displacement) phenyl amino) quinazoline -6- substitution) -1 is prepared Hydrogen -1,2,3- triazole -1- replaces)-N- hydroxyl heptamide (8)

The 110a in the step 1i in embodiment 1 is changed into 110h to react.Yield 82.8%, mass spectrum (ESI): [M+ H]⁺573.21。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.10(s,1H),10.42(s,1H),9.66(s,1H),8.97(s,1H), 8.97 (s, 1H), 8.72 (d, J=4.7Hz, 1H), 8.57 (d, J=8.6Hz, 1H), 8.11 (t, J=7.7Hz, 1H), 8.04 (d, J=8.7Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.62-7.54 (m, 1H), 7.38 (d, J=9.1Hz, 1H), 5.44 (s, 2H), 4.46 (t, J=6.9Hz, 2H), 2.05-1.78 (m, 4H), 1.57-1.38 (m,2H),1.36–1.15(m,4H).

Embodiment 9:The preparation of (compound 9)

According to the step prepare compound 9 of embodiment 1, the difference is that:

1, N- (the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl) -6- iodine quinazoline -4- amine (104e) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 4- (thiazole -2- methoxyl group) aniline to carry out instead It answers.Yield 93.1%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.83 (s, 1H), 9.40 (s, 1H), 8.97 (s, 1H), 8.37 (d, J= 8.7Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.88 (d, J=3.2Hz, 1H), 7.83 (d, J=3.1Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.71 (dd, J=8.9,2.4Hz, 1H), 7.43 (d, J=9.0Hz, 1H), 5.62 (s, 2H)

2, N- (the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl) -6- acetenyl quinazoline -4- amine (106e) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104e to react.Yield 48.2%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.08 (d, J=2.4Hz, 1H), 7.89-7.85 (m, 2H), 7.81 (d, J=3.2Hz, 1H), 7.79-7.74 (m, 2H), 7.35 (d, J=9.0Hz, 1H), 5.56(s,2H),4.44(s,1H).

3,6- (4- (4- ((the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1,2,3- Triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (110i)

The 106a in the step 1h in embodiment 1 is changed into 106e to react.Yield 48.7%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 10.92 (s, 1H), 10.03 (s, 1H), 9.04 (d, J=1.3Hz, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.28 (dd, J=8.6,1.7Hz, 1H), 8.08 (d, J=2.5Hz, 1H), 7.90-7.77 (m, 4H), 7.37 (d, J=9.1Hz, 1H), 5.57 (s, 2H), 4.77 (s, 1H), 4.47 (t, J=6.9Hz, 2H), 3.94-3.80 (m, 1H), 3.46 (d, J=11.1Hz, 1H), 2.05-1.83 (m, 4H), 1.70-1.40 (m, 8H), 1.32-1.21 (m, 2H)

4, prepare 6- (4- (4- ((the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1, 2,3- triazole -1- replaces)-N- hydroxyl hexanamide (9)

The 110a in the step 1i in embodiment 1 is changed into 110i to react.Yield 89.2%, mass spectrum (ESI): [M+ H]⁺565.15。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.05(s,1H),10.41(s,1H),9.61(s,1H),9.03–8.83(m, 2H), 8.57 (dd, J=8.7,1.4Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.99 (d, J=2.5Hz, 1H), 7.89 (d, J =3.2Hz, 1H), 7.83 (d, J=3.2Hz, 1H), 7.75 (dd, J=8.9,2.5Hz, 1H), 7.45 (d, J=9.1Hz, 1H), 5.63 (s, 2H), 4.47 (t, J=6.9Hz, 2H), 2.03-1.81 (m, 4H), 1.63-1.46 (m, 2H), 1.36-1.19 (m, 2H).

Embodiment 10:The preparation of (compound 10)

According to the step prepare compound 10 of embodiment 9, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3, prepare 7- (4- (4- ((the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1, 2,3- triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) heptamide (110j)

The 109a in the step 1h in embodiment 9 is changed into 109b to react.Yield 65.2%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.92(s,1H),10.03(s,1H),9.04(s,1H),8.67(s,1H), 8.60 (s, 1H), 8.28 (d, J=8.6Hz, 1H), 8.08 (d, J=2.4Hz, 1H), 7.91-7.79 (m, 4H), 7.37 (d, J= 9.0Hz, 1H), 5.57 (s, 2H), 4.80 (s, 1H), 4.46 (t, J=6.7Hz, 2H), 4.00-3.82 (m, 1H), 3.48 (d, J =11.3Hz, 1H), 2.04-1.80 (m, 4H), 1.73-1.42 (m, 8H), 1.33-1.20 (m, 4H)

4, prepare 7- (4- (4- ((the chloro- 4- of 3- (thiazole -2- methoxyl group) phenyl amino) quinazoline -6- substitution) -1 hydrogen -1, 2,3- triazole -1- replaces)-N- hydroxyl heptamide (10)

The 110a in the step 1i in embodiment 1 is changed into 110j to react.Yield 91.6%, mass spectrum (ESI): [M+ H]⁺579.17。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.02(s,1H),10.42(s,1H),9.61(s,1H),9.07–8.83(m, 2H), 8.56 (dd, J=8.7,1.4Hz, 1H), 8.06-7.97 (m, 2H), 7.89 (d, J=3.2Hz, 1H), 7.84 (d, J= 3.2Hz, 1H), 7.78 (dd, J=8.9,2.4Hz, 1H), 7.44 (d, J=9.1Hz, 1H), 5.63 (s, 2H), 4.47 (t, J= 6.9Hz,2H),2.01–1.80(m,4H),1.62–1.41(m,2H),1.39–1.17(m,4H).

Embodiment 11:The preparation of (compound 11)

According to the step prepare compound 11 of embodiment 1, the difference is that:

1, the iodo- N- of 6- (3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl) quinazoline -4- amine (104f) is prepared

Change the chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 into 4- ((substitution of 6- picoline -3) oxygroup) benzene Amine is reacted.Yield 92.8%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.70(s,1H),9.39(s,1H),8.94(s,1H),8.37(s,2H),7.74 (m, 3H), 7.66-7.55 (m, 2H), 7.09 (d, J=7.8Hz, 1H), 2.58 (s, 3H), 2.25 (s, 3H)

2,6- acetenyl-N- (3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl) quinazoline -4- amine is prepared (106f)

The 104a in the step 1d/e in embodiment 1 is changed into 104f to react.Yield 56.1%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.88 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 8.18 (d, J=2.3Hz, 1H), 7.85 (dd, J=8.6,1.3Hz, 1H), 7.81 (d, J=2.1Hz, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.25- 7.16 (m, 2H), 6.96 (d, J=8.7Hz, 1H), 4.42 (s, 1H), 2.42 (s, 3H), 2.20 (s, 3H)

3, ((((3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl amino) quinazoline -6- takes 4- 4- preparation 6- Generation) -1 hydrogen -1,2,3- triazole -1- substitution)-N- ((oxinane -2- substitution) oxygroup) caproamide (110k)

The 106a in the step 1h in embodiment 1 is changed into 106f to react.Yield 39.5%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),10.02(s,1H),9.07(s,1H),8.65(s,1H), 8.60 (s, 1H), 8.28 (d, J=7.7Hz, 1H), 8.21 (s, 1H), 7.85 (d, J=7.4Hz, 1H), 7.81 (d, J= 2.1Hz, 1H), 7.74 (dd, J=8.7,2.4Hz, 1H), 7.32-7.14 (m, 2H), 6.98 (d, J=8.7Hz, 1H), 4.76 (s, 1H), 4.46 (t, J=6.9Hz, 2H), 3.94-3.78 (m, 1H), 3.45 (d, J=11.3Hz, 1H), 2.44 (s, 3H), 2.22(s,3H),2.06–1.83(m,4H),1.70–1.36(m,8H),1.33–1.17(m,2H).

4, ((((3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl amino) quinazoline -6- takes 4- 4- preparation 6- Generation) -1 hydrogen -1,2,3- triazole -1- substitution)-N- hydroxyl hexanamide (11)

The 110a in the step 1i in embodiment 1 is changed into 110k to react.Yield 55.3%, mass spectrum (ESI): [M+ H]⁺539.25。

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.16 (s, 1H), 10.33 (s, 1H), 9.75 (s, 1H), 9.02 (d, J= 6.0Hz, 1H), 8.96 (s, 1H), 8.59 (d, J=8.6Hz, 1H), 8.50 (d, J=2.3Hz, 1H), 8.08 (d, J=8.7Hz, 1H), 8.01-7.91 (m, 1H), 7.84 (s, 1H), 7.79 (d, J=8.8Hz, 1H), 7.74 (d, J=8.7Hz, 1H), 7.18 (d, J=8.7Hz, 1H), 4.47 (t, J=6.6Hz, 2H), 2.67 (s, 3H), 2.27 (s, 3H), 2.04-1.78 (m, 4H), 1.61–1.44(m,2H),1.37–1.18(m,2H).

Embodiment 12:The preparation of (compound 12)

According to the step prepare compound 12 of embodiment 11, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3, ((((3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl amino) quinazoline -6- takes 4- 4- preparation 7- Generation) -1 hydrogen -1,2,3- triazole -1- substitution)-N- ((oxinane -2- substitution) oxygroup) heptamide (110l)

The 109a in the step 1h in embodiment 11 is changed into 109b to react.Yield 50.3%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),10.01(s,1H),9.06(s,1H),8.66(s,1H), 8.58 (s, 1H), 8.28 (d, J=8.6Hz, 1H), 8.19 (d, J=1.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.81 (s, 1H), 7.75 (d, J=8.6Hz, 1H), 7.27-7.16 (m, 2H), 6.98 (d, J=8.7Hz, 1H), 4.79 (s, 1H), 4.46 (t, J=6.8Hz, 2H), 3.96-3.82 (m, 1H), 3.47 (d, J=11.3Hz, 1H), 2.44 (s, 3H), 2.22 (s, 3H),2.05–1.80(m,4H),1.72–1.38(m,8H),1.34–1.20(m,4H).

4, ((((3- methyl -4- ((substitution of 6- picoline -3) oxygroup) phenyl amino) quinazoline -6- takes 4- 4- preparation 7- Generation) -1 hydrogen -1,2,3- triazole -1- substitution)-N- hydroxyl heptamide (12)

The 110a in the step 1i in embodiment 1 is changed into 110l to react.Yield 41.5%, mass spectrum (ESI): [M+ H]⁺553.27。

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.19 (s, 1H), 10.31 (s, 1H), 9.76 (d, J=6.6Hz, 1H), 9.03 (d, J=6.0Hz, 1H), 8.97 (s, 1H), 8.60 (d, J=8.7Hz, 1H), 8.53 (s, 1H), 8.09 (d, J=8.7Hz, 1H), 8.05-7.95 (m, 1H), 7.84 (s, 1H), 7.80 (d, J=8.8Hz, 1H), 7.74 (d, J=8.7Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 4.47 (t, J=6.9Hz, 2H), 2.69 (s, 3H), 2.27 (s, 3H), 2.00-1.77 (m, 4H), 1.60–1.40(m,2H),1.37–1.20(m,4H).

Embodiment 13:The preparation of (compound 13)

According to the step prepare compound 13 of embodiment 1, the difference is that:

1, the iodo- N- of 6- (3- methoxyl group -4- Phenoxyphenyl) quinazoline -4- amine (104g) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 3- methoxyl group -4- phenoxybenzamine to carry out instead It answers.Yield 94.2%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.84 (s, 1H), 9.45 (s, 1H), 8.97 (s, 1H), 8.38 (d, J= 8.7Hz, 1H), 7.81 (d, J=8.7Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.43 (dd, J=8.5,1.8Hz, 1H), 7.34 (t, J=7.8Hz, 2H), 7.13 (d, J=8.6Hz, 1H), 7.05 (t, J=7.3Hz, 1H), 6.89 (d, J=7.9Hz, 2H),3.77(s,3H).

2,6- acetenyl-N- (3- methoxyl group -4- Phenoxyphenyl) quinazoline -4- amine (106g) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104g to react.Yield 68.8%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.91 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 7.86 (d, J=8.2Hz, 1H), 7.75 (s, 2H), 7.64 (d, J=7.6Hz, 1H), 7.30 (t, J=7.7Hz, 2H), 7.09 (d, J=8.6Hz, 1H), 7.00 (t, J=7.2Hz, 1H), 6.86 (d, J=8.0Hz, 2H), 4.43 (s, 1H), 3.78 (s, 3H)

3,6- (4- (4- ((3- methoxyl group -4- phenoxvphenylamino) quinazoline -6- substitution) -1 hydrogen -1,2,3- three is prepared Azoles -1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (110m)

The 106a in the step 1h in embodiment 1 is changed into 106g to react.Yield 62.9%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.92(s,1H),10.04(s,1H),9.08(s,1H),8.66(s,1H), 8.62 (s, 1H), 8.29 (dd, J=8.6,1.3Hz, 1H), 7.87 (d, J=8.6Hz, 1H), 7.74 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.6,2.1Hz, 1H), 7.32 (t, J=7.9Hz, 2H), 7.10 (d, J=8.6Hz, 1H), 7.02 (t, J= 7.3Hz, 1H), 6.89 (d, J=7.9Hz, 2H), 4.76 (s, 1H), 4.47 (t, J=6.7Hz, 2H), 3.94-3.83 (m, 1H), 3.78 (s, 3H), 3.45 (d, J=11.0Hz, 1H), 2.05-1.82 (m, 4H), 1.70-1.40 (m, 8H), 1.34-1.20 (m, 2H).

4,6- (4- (4- ((3- methoxyl group -4- phenoxvphenylamino) quinazoline -6- substitution) -1 hydrogen -1,2,3- three is prepared Azoles -1- replaces)-N- hydroxyl hexanamide (13)

The 110a in the step 1i in embodiment 1 is changed into 110m to react.Yield 76.5%, mass spectrum (ESI): [M+ H]⁺540.24。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.94(s,1H),10.43(s,1H),9.63(s,1H),8.97(s,1H), 8.96 (s, 1H), 8.57 (d, J=8.6Hz, 1H), 8.04 (d, J=8.7Hz, 1H), 7.72 (d, J=2.1Hz, 1H), 7.50 (dd, J=8.6,2.2Hz, 1H), 7.40-7.26 (m, 2H), 7.16 (d, J=8.6Hz, 1H), 7.06 (t, J=7.3Hz, 1H), 6.90 (d, J=7.9Hz, 2H), 4.47 (t, J=6.8Hz, 2H), 3.78 (s, 3H), 2.04-1.80 (m, 4H), 1.62-1.36 (m,2H),1.38–1.17(m,2H).

Embodiment 14:The preparation of (compound 14)

According to the step prepare compound 14 of embodiment 13, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3,7- (4- (4- ((3- methoxyl group -4- phenoxvphenylamino) quinazoline -6- substitution) -1 hydrogen -1,2,3- three is prepared Azoles -1- replaces)-N- ((oxinane -2- substitution) oxygroup) heptamide (110n)

The 109a in the step 1h in embodiment 13 is changed into 109b to react.Yield 53.4%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),10.07(s,1H),9.09(s,1H),8.69(s,1H), 8.63 (s, 1H), 8.30 (d, J=8.7Hz, 1H), 7.88 (d, J=8.6Hz, 1H), 7.75 (d, J=1.6Hz, 1H), 7.63 (d, J=8.6Hz, 1H), 7.33 (t, J=7.9Hz, 2H), 7.11 (d, J=8.6Hz, 1H), 7.03 (t, J=7.3Hz, 1H), 6.89 (d, J=7.9Hz, 2H), 4.80 (s, 1H), 4.47 (t, J=6.9Hz, 1H), 3.96-3.84 (m, 1H), 3.79 (s, 1H), 3.48 (d, J=11.2Hz, 1H), 2.06-1.80 (m, 4H), 1.73-1.41 (m, 8H), 1.35-1.18 (m, 4H)

4,7- (4- (4- ((3- methoxyl group -4- phenoxvphenylamino) quinazoline -6- substitution) -1 hydrogen -1,2,3- three is prepared Azoles -1- replaces)-N- hydroxyl heptamide (14)

The 110a in the step 1i in embodiment 1 is changed into 110n to react.Yield 88.2%, mass spectrum (ESI): [M+ H]⁺554.25。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.95(s,1H),10.39(s,1H),10.24(s,1H),9.59(s,1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.57 (d, J=8.8Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.68 (d, J= 2.2Hz, 1H), 7.47 (dd, J=8.6,2.4Hz, 1H), 7.39-7.32 (m, 2H), 7.17 (d, J=8.6Hz, 1H), 7.07 (t, J=7.4Hz, 1H), 6.90 (d, J=7.8Hz, 2H), 4.48 (t, J=6.9Hz, 2H), 3.79 (s, 3H), 1.98-1.82 (m,4H),1.57–1.41(m,2H),1.37–1.22(m,4H).

Embodiment 15:The preparation of (compound 15)

According to the step prepare compound 15 of embodiment 1, the difference is that:

1, N- (the bromo- 2- fluorophenyl of 4-) -6- iodine quinazoline -4- amine (104h) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 4- bromo- 2- fluoroaniline to react.Yield 95.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 12.02 (s, 1H), 9.35 (d, J=1.5Hz, 1H), 8.94 (s, 1H), 8.40 (dd, J=8.8,1.6Hz, 1H), 7.84-7.76 (m, 2H), 7.61-7.50 (m, 2H)

2, N- (the bromo- 2- fluorophenyl of 4-) -6- acetenyl quinazoline -4- amine (106h) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104h to react.Yield 59.0%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 10.01 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 7.89 (d, J= 8.5Hz, 1H), 7.78 (d, J=8.6Hz, 1H), 7.68 (dd, J=9.9,1.5Hz, 1H), 7.56-7.46 (m, 2H), 4.43 (s,1H).

3, ((4- ((the bromo- 2- Fluorophenylamino of 4-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 6- Generation)-N- ((oxinane -2- substitution) oxygroup) caproamide (110o)

The 106a in the step 1h in embodiment 1 is changed into 106h to react.Yield 72.3%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),10.12(s,1H),9.01(s,1H),8.66(s,1H), 8.51 (s, 1H), 8.31 (d, J=8.4Hz, 1H), 7.88 (d, J=8.2Hz, 1H), 7.69 (d, J=9.6Hz, 1H), 7.61- 7.52 (m, 1H), 7.50 (d, J=7.8Hz, 1H), 4.77 (s, 1H), 4.47 (t, J=6.8Hz, 2H), 3.95-3.77 (m, 1H), 3.47 (d, J=11.0Hz, 1H), 2.10-1.78 (m, 4H), 1.75-1.38 (m, 8H), 1.34-1.14 (m, 2H)

4, ((4- ((the bromo- 2- Fluorophenylamino of 4-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 6- Generation)-N- hydroxyl hexanamide (15)

The 110a in the step 1i in embodiment 1 is changed into 110o to react.Yield 94.3%, mass spectrum (ESI): [M+ H]⁺514.10。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.15(s,1H),10.41(s,1H),9.54(s,1H),8.93(s,1H), 8.88 (s, 1H), 8.59 (dd, J=8.7,1.3Hz, 1H), 8.08 (d, J=8.7Hz, 1H), 7.86-7.78 (m, 1H), 7.65- 7.48 (m, 2H), 4.47 (t, J=6.9Hz, 2H), 2.04-1.78 (m, 4H), 1.62-1.46 (m, 2H), 1.36-1.17 (m, 2H).

Embodiment 16:The preparation of (compound 16)

According to the step prepare compound 16 of embodiment 15, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3, ((4- ((the bromo- 2- Fluorophenylamino of 4-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- ((oxinane -2- substitution) oxygroup) heptamide (110p)

The 109a in the step 1h in embodiment 15 is changed into 109b to react.Yield 57.7%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.92(s,1H),10.11(s,1H),9.01(s,1H),8.67(s,1H), 8.51 (s, 1H), 8.31 (d, J=8.5Hz, 1H), 7.88 (d, J=8.5Hz, 1H), 7.69 (d, J=9.8Hz, 1H), 7.61- 7.53 (m, 1H), 7.49 (d, J=8.0Hz, 1H), 4.80 (s, 1H), 4.46 (t, J=6.8Hz, 2H), 3.97-3.83 (m, 1H), 3.48 (d, J=11.3Hz, 1H), 2.12-1.80 (m, 4H), 1.76-1.40 (m, 8H), 1.38-1.20 (m, 4H)

4, ((4- ((the bromo- 2- Fluorophenylamino of 4-) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- hydroxyl heptamide (16)

The 110a in the step 1i in embodiment 1 is changed into 110p to react.Yield 96.5%, mass spectrum (ESI): [M+ H]⁺528.12。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.20(s,1H),10.40(s,1H),9.57(s,1H),8.92(s,1H), 8.88 (s, 1H), 8.60 (dd, J=8.7,1.3Hz, 1H), 8.08 (d, J=8.7Hz, 1H), 7.87-7.78 (m, 1H), 7.66- 7.49 (m, 2H), 4.47 (t, J=6.9Hz, 2H), 2.00-1.77 (m, 4H), 1.55-1.38 (m, 2H), 1.37-1.18 (m, 4H).

Embodiment 17:The preparation of (compound 17)

According to the step prepare compound 17 of embodiment 1, the difference is that:

1, the iodo- N- of 6- (3- anisyl) quinazoline -4- amine (104i) is prepared

The chloro- 4- fluoroaniline of 3- in the step 1c in embodiment 1 is changed into 3- aminoanisole to react.Yield 91.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.76 (s, 1H), 9.42 (d, J=1.3Hz, 1H), 8.95 (s, 1H), 8.36 (dd, J=8.7,1.5Hz, 1H), 7.80 (d, J=8.7Hz, 1H), 7.42-7.30 (m, 3H), 6.90 (dd, J=7.3, 1.7Hz,1H),3.78(s,3H).

2,6- acetenyl-N- (3- anisyl) quinazoline -4- amine (106i) is prepared

The 104a in the step 1d/e in embodiment 1 is changed into 104i to react.Yield 78.6%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.85 (s, 1H), 8.81 (s, 1H), 8.63 (s, 1H), 7.87 (dd, J=8.5, 1.4Hz, 1H), 7.76 (d, J=8.6Hz, 1H), 7.57 (s, 1H), 7.52 (d, J=7.9Hz, 1H), 7.30 (t, J=8.1Hz, 1H), 6.72 (dd, J=8.1,1.9Hz, 1H), 4.44 (s, 1H), 3.78 (s, 3H)

3,6- (4- (4- ((3- Methoxyphenylaminol) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- substitution)-is prepared N- ((oxinane -2- substitution) oxygroup) caproamide (110q)

The 106a in the step 1h in embodiment 1 is changed into 106i to react.Yield 46.4%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.95(s,1H),9.97(s,1H),9.07(s,1H),8.67(s,1H),8.62 (s, 1H), 8.30 (d, J=8.6Hz, 1H), 7.87 (d, J=8.6Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=7.9Hz, 1H), 7.32 (t, J=8.1Hz, 1H), 6.74 (dd, J=8.2,2.2Hz, 1H), 4.77 (s, 1H), 4.48 (t, J=6.5Hz, 2H), 3.95-3.78 (m, 1H), 3.81 (s, 3H), 3.46 (d, J=10.9Hz, 1H), 2.05-1.83 (m, 4H), 1.70-1.40 (m,8H),1.32–1.20(m,2H).

4,6- (4- (4- ((3- Methoxyphenylaminol) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- substitution)-is prepared N- hydroxyl hexanamide (17)

The 110a in the step 1i in embodiment 1 is changed into 110q to react.Yield 73.8%, mass spectrum (ESI): [M+ H]⁺448.21。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.94(s,1H),10.45(s,1H),9.63(s,1H),8.98(s,1H), 8.94 (s, 1H), 8.56 (d, J=8.8Hz, 1H), 8.04 (d, J=8.7Hz, 1H), 7.49-7.27 (m, 3H), 7.00-6.81 (m, 1H), 4.46 (t, J=6.8Hz, 2H), 3.80 (s, 3H), 2.04-1.90 (m, 4H), 1.63-1.45 (m, 2H), 1.36- 1.17(m,2H).

Embodiment 18:Compound 18) preparation

According to the step prepare compound 18 of embodiment 17, the difference is that:

1,7- azido enanthic acid (108b) is prepared

3,7- (4- (4- ((3- Methoxyphenylaminol) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- substitution)-is prepared N- ((oxinane -2- substitution) oxygroup) heptamide (110r)

The 109a in the step 1h in embodiment 1 is changed into 109b to react.Yield 61.8%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.93(s,1H),9.97(s,1H),9.07(s,1H),8.68(s,1H),8.62 (s, 1H), 8.30 (dd, J=8.6,1.4Hz, 1H), 7.87 (d, J=8.6Hz, 1H), 7.58 (s, 1H), 7.53 (d, J= 8.0Hz, 1H), 7.32 (t, J=8.1Hz, 1H), 6.74 (dd, J=8.2,2.2Hz, 1H), 4.80 (s, 1H), 4.47 (t, J= 6.9Hz, 2H), 4.00-3.80 (m, 1H), 3.80 (s, 3H), 3.49 (d, J=11.2Hz, 1H), 2.10-1.78 (m, 4H), 1.72–1.40(m,8H),1.36–1.18(m,4H).

4,7- (4- (4- ((3- Methoxyphenylaminol) quinazoline -6- substitution) -1 hydrogen -1,2,3- triazole -1- substitution)-is prepared N- hydroxyl heptamide (18)

The 110a in the step 1i in embodiment 1 is changed into 110r to react.Yield 92.8%, mass spectrum (ESI): [M+ H]⁺462.22。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.89(s,1H),10.40(s,1H),9.60(s,1H),8.95(s,1H), 8.94 (s, 1H), 8.56 (d, J=8.7Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.52-7.29 (m, 3H), 6.93 (dd, J =7.5,4.0Hz, 1H), 4.46 (t, J=6.9Hz, 2H), 3.80 (s, 3H), 2.00-1.77 (m, 4H), 1.57-1.40 (m, 2H),1.38–1.17(m,4H).

Embodiment 19:The preparation of (compound 19)

Step 2a, 7- bromine quinazoline-4-one (202) are prepared

101 in the step 1a in embodiment 1 are changed into 2- amino -4- bromobenzoic acid (201) to react.Yield 76.5%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.96 (s, 1H), 8.15 (s, 1H), 8.04 (d, J=8.5Hz, 1H), 7.89 (d, J=1.8Hz, 1H), 7.69 (dd, J=8.5,1.9Hz, 1H)

Step 2b, the chloro- 7- bromine quinazoline (203) of 4- is prepared

By 102 in the step 1b in embodiment 1, thionyl chloride and DMF change 202 into, phosphorus oxychloride and N, N- diisopropyl Base ethamine is reacted.Yield 84.0%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,CDCl₃) δ 9.05 (s, 1H), 8.27 (d, J=1.8Hz, 1H), 8.14 (d, J=8.9Hz, 1H), 7.83 (dd, J=8.9,1.8Hz, 1H)

Step 2c, N- (the chloro- 4- fluorophenyl of 3-) -7- bromine quinazoline -4- amine (204a) is prepared

103 in the step 1c in embodiment 1 are changed into 203 to react.Yield 92.4%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.82 (s, 1H), 8.99 (s, 1H), 8.95 (d, J=8.6Hz, 1H), 8.23 (s, 1H), 8.14 (d, J=6.6Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.88-7.79 (m, 1H), 7.60 (t, J= 9.0Hz,1H).

Step 2d, three silicon methylacetylenyl quinazoline -4- amine (205a) of N- (the chloro- 4- fluorophenyl of 3-) -7- is prepared

By the 104a in the step 1d in embodiment 1, Pd (PPh₃)₂Cl₂204a, Pd (dppf) Cl are changed into THF₂And DMF It is reacted.

Step 2e, N- (the chloro- 4- fluorophenyl of 3-) -7- acetenyl quinazoline -4- amine (206a) is prepared

The 105a in the step 1e in embodiment 1 is changed into 205a to react.The gross production rate of step 2d and 2e is 34.8%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 10.00 (s, 1H), 8.67 (s, 1H), 8.53 (d, J=8.6Hz, 1H), 8.21 (dd, J=6.8,2.4Hz, 1H), 7.88 (s, 1H), 7.86-7.79 (m, 1H), 7.74-7.69 (m, 1H), 7.46 (t, J= 9.1Hz,1H),4.56(s,1H).

Step 2f, 6- azido caproic acid (208a) is prepared

With the preparation of the 108a in the step 1f in embodiment 1.

Step 2g, 6- azido-N- ((oxinane -2- substitution) oxygroup) caproamide (209a) is prepared

With the preparation of the 109a in the step 1g in embodiment 1.

Step 2h, 6- (4- (4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -7- substitution) -1 hydrogen -1,2,3- triazole-is prepared 1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (210a)

The 106a in the step 1h in embodiment 1 is changed into 206a to react.Yield 51.3%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.91(s,1H),9.96(s,1H),8.90(s,1H),8.69(s,1H),8.61 (d, J=8.7Hz, 1H), 8.24 (d, J=4.2Hz, 2H), 8.18 (d, J=8.6Hz, 1H), 7.92-7.81 (m, 1H), 7.47 (t, J=9.1Hz, 1H), 4.77 (s, 1H), 4.45 (t, J=6.9Hz, 2H), 3.94-3.85 (m, 1H), 3.47 (d, J= 11.3Hz,1H),2.06–1.84(m,4H),1.71–1.40(m,8H),1.32–1.22(m,2H).

Step 2i, 6- (4- (4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -7- substitution) -1 hydrogen -1,2,3- triazole-is prepared 1- replaces)-N- hydroxyl hexanamide (compound 19)

The 110a in the step 1i in embodiment 1 is changed into 210a to react.Yield 84.2%, mass spectrum (ESI): [M+ H]⁺470.15。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.91(s,1H),10.42(s,1H),9.15–8.90(m,3H),8.40(d,J =6.4Hz, 1H), 8.28 (d, J=7.9Hz, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.63-7.51 (m, 1H), 4.47 (t, J=6.2Hz, 2H), 2.05-1.77 (m, 4H), 1.64-1.46 (m, 2H), 1.35-1.15 (m, 2H)

Embodiment 20:The preparation of (compound 20)

According to the step prepare compound 20 of embodiment 19, the difference is that:

1,7- azido enanthic acid (208b, same to 108b) is prepared

2,7- azido-N- ((oxinane -2- substitution) oxygroup) heptamide (209b, same to 109b) is prepared

3, ((4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -7- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- ((oxinane -2- substitution) oxygroup) heptamide (210b)

The 209a in the step 2h in embodiment 19 is changed into 209b to react.Yield 43.1%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.90(s,1H),9.95(s,1H),8.91(s,1H),8.67(s,1H),8.61 (d, J=8.7Hz, 1H), 8.25 (s, 2H), 8.18 (d, J=8.6Hz, 1H), 7.93-7.81 (m, 1H), 7.47 (t, J= 9.1Hz, 1H), 4.80 (s, 1H), 4.44 (t, J=6.9Hz, 2H), 3.96-3.86 (m, 1H), 3.49 (d, J=11.2Hz, 1H),2.04–1.84(m,4H),1.70–1.43(m,8H),1.35–1.25(m,4H).

4, ((4- ((the chloro- 4- Fluorophenylamino of 3-) quinazoline -7- substitution) -1 hydrogen -1,2,3- triazole -1- takes 4- preparation 7- Generation)-N- hydroxyl heptamide (20)

The 110a in the step 1i in embodiment 1 is changed into 210b to react.Yield 88.9%, mass spectrum (ESI): [M+ H]⁺484.17。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ12.09(s,1H),10.31(s,1H),9.15–8.90(m,3H),8.38(s, 1H), 8.23 (d, J=8.0Hz, 1H), 8.03 (d, J=4.9Hz, 1H), 7.76 (s, 1H), 7.58-7.50 (m, 1H), 4.41 (t, J=6.5Hz, 2H), 2.00-1.70 (m, 4H), 1.55-1.38 (m, 2H), 1.35-1.12 (m, 4H)

Embodiment 21:The preparation of (compound 21)

According to the step prepare compound 21 of embodiment 19, the difference is that:

1, N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -7- bromine quinazoline -4- amine (204b) is prepared

The chloro- 4- fluoroaniline of 3- in the step 2c in embodiment 19 is changed into 3- fluorine benzyloxy-aniline to react.Yield 92.7%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 11.74 (s, 1H), 8.92 (s, 1H), 8.88 (d, J=8.9Hz, 1H), 8.18 (s, 1H), 8.03 (d, J=8.6Hz, 1H), 7.94 (d, J=2.0Hz, 1H), 7.68 (dd, J=8.8,1.9Hz, 1H), 7.48 (dd, J=14.2,7.8Hz, 1H), 7.38-7.27 (m, 3H), 7.20 (t, J=8.5Hz, 1H), 5.30 (s, 2H)

2, N- (the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl) -7- acetenyl quinazoline -4- amine (206b) is prepared

The 204a in the step 2d/e in embodiment 19 is changed into 204b to react.Yield 31.2%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 9.88 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=8.7Hz, 1H), 8.04 (d, J=2.2Hz, 1H), 7.86 (s, 1H), 7.77-7.65 (m, 2H), 7.51-7.44 (m, 1H), 7.36-7.24 (m, 3H), 7.23- 7.15(m,1H),5.26(s,2H),4.54(s,1H).

3,6- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -7- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) caproamide (210c)

The 206a in the step 2h in embodiment 19 is changed into 206b to react.Yield 42.4%.

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ10.91(s,1H),9.84(s,1H),8.89(s,1H),8.62(s,1H),8.25 (s, 1H), 8.14 (d, J=8.3Hz, 1H), 8.07 (s, 1H), 7.76 (d, J=7.4Hz, 1H), 7.48 (d, J=6.8Hz, 1H), 7.37-7.25 (m, 3H), 7.19 (t, J=7.6Hz, 1H), 5.27 (s, 2H), 4.77 (s, 1H), 4.44 (t, J= 6.9Hz, 2H), 3.94-3.84 (m, 1H), 3.47 (d, J=10.6Hz, 1H), 2.06-1.85 (m, 4H), 1.70-1.40 (m, 8H),1.32–1.20(m,2H).

4,7- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -7- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- hydroxyl hexanamide (21)

The 110a in the step 1i in embodiment 1 is changed into 210c to react.Yield 48.4%, mass spectrum (ESI): [M+ H]⁺576.19。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.86(s,1H),10.40(s,1H),9.07–8.97(m,3H),8.36(s, 1H), 8.24 (d, J=8.4Hz, 1H), 7.91 (d, J=2.0Hz, 1H), 7.66 (d, J=8.7Hz, 1H), 7.50-7.40 (m, 1H), 7.35-7.25 (m, 3H), 7.16 (t, J=8.4Hz, 1H), 5.27 (s, 2H), 4.43 (t, J=6.5Hz, 2H), 2.00- 1.78(m,4H),1.60–1.43(m,2H),1.34–1.15(m,2H).

Embodiment 22:The preparation of (compound 22)

According to the step prepare compound 22 of embodiment 21, the difference is that:

1,7- azido enanthic acid (208b, same to 108b) is prepared

3,7- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -7- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- ((oxinane -2- substitution) oxygroup) heptamide (210d)

The 209a in the step 2h in embodiment 21 is changed into 209b to react.Yield 32.5%.

Compound structure confirms data are as follows:

¹H NMR (400MHz, DMSO) δ 10.91 (s, 1H), 9.90 (s, 1H), 8.89 (s, 1H), 8.60 (d, J= 8.6Hz, 1H), 8.23 (s, 1H), 8.15 (d, J=8.5Hz, 1H), 8.07 (s, 1H), 7.76 (d, J=7.9Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 7.37-7.27 (m, 3H), 7.20 (t, J=7.6Hz, 1H), 5.27 (s, 2H), 4.77 (s, 1H), 4.45 (t, J=6.8Hz, 3H), 3.94-3.85 (m, 1H), 3.47 (d, J=11.2Hz, 1H), 2.05-1.84 (m, 4H), 1.69–1.41(m,8H),1.32–1.20(m,4H).

4,6- (4- (4- ((the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl amino) quinazoline -7- substitution) -1 hydrogen -1,2,3- is prepared Triazole -1- replaces)-N- hydroxyl heptamide (22)

The 110a in the step 1i in embodiment 1 is changed into 210d to react.Yield 64.5%, mass spectrum (ESI): [M+ H]⁺590.21。

Compound structure confirms data are as follows:

¹H NMR(400MHz,DMSO)δ11.75(s,1H),10.37(s,1H),9.05–8.97(m,3H),8.35(s, 1H), 8.25 (d, J=8.1Hz, 1H), 7.91 (s, 1H), 7.65 (d, J=7.9Hz, 1H), 7.50-7.40 (m, 1H), 7.35- 7.25 (m, 3H), 7.18 (t, J=8.4Hz, 1H), 5.27 (s, 2H), 4.44 (t, J=6.8Hz, 2H), 2.00-1.78 (m, 4H),1.55–1.38(m,2H),1.35–1.17(m,4H).

Embodiment 23: external inhibitory activity (enzyme activity) measurement

The IC of EGFR, HER2, HDAC1 and the HDAC6 of external enzyme activity measuring compound₅₀Value.EGFR and HER2 are purchased from Invitrogen (U.S.)；HDAC1 and HDAC6 is purchased from BPS Bioscience (U.S.).

The measurement of EGFR and HER2 inhibitory activity

1 × kinase buffer liquid is configured, DMSO solution three times multiple proportions gradient dilution to be measuredization of enzyme corresponding 2.5% is then used Close object, kinases, substrate and untested compound be added in Xiang Suoyou reacting hole, be incubated at room temperature 10 minutes after mixing, allow compound with Enzyme sufficiently acts on combination.The ATP solution of kinases corresponding concentration is added into all reacting holes to start kinase reaction, when enzyme reaction Between be 30 minutes.After kinase reaction, the Streptavidin-XL665 diluted is added in Xiang Suoyou reacting hole, mixes The TK antibody europium cryptate detection liquid diluted is added after even immediately.Sealing plate mixes, and reacts at room temperature 1h Afterwards, with ENVISION (Perkinelmer) instrument detection fluorescence signal (320nm is stimulated, 665nm, 615nm transmitting).By complete Active hole and background signal hole calculate the inhibiting rate in each hole, and multiple holes are averaged, while analyzing software with the picture of profession PRISM 5.0 carries out half inhibitory activity (IC to each untested compound₅₀) fitting.Experimental result is shown in Table 2.

The measurement of HDAC1 and HDAC6 inhibitory activity

Configure 1 × buffer, then with 100% DMSO three times multiple proportions gradient dilution untested compound, with 1 × buffer Trypsin and Ac-peptide is added into 1 × buffer to prepare substrate solution, into reacting hole for the solution for preparing enzyme Enzyme and untested compound is added, is incubated at room temperature 10 minutes after mixing.It is anti-to start that substrate solution is added into all reacting holes again It answers.After reacting at room temperature 1h, with Synergy MX instrument detection fluorescence signal (355nm is stimulated, 480nm transmitting).Pass through full activity Hole and background signal hole calculate the inhibiting rate in each hole, and multiple holes are averaged, while analyzing software PRISM with the picture of profession 5.0 pairs of each untested compounds carry out half inhibitory activity (IC₅₀) fitting.Experimental result is shown in Table 2.

Table 2. external inhibitory activity (enzyme activity) measurement result

Table 2 shows that the compounds of this invention has stronger inhibiting effect to EGFR, HER2, HDAC1 and HDAC6.

Embodiment 24: influence of the compound to cancer cell multiplication

By mtt assay, detect compound that embodiment 1-22 is prepared to A549, A431, BT-474, SK-BR-3 and NCI-H1975 Proliferation of Tumor Cells In Vitro inhibitory activity.

Firstly, it is 5mM/L that the compound (i.e. sample) that embodiment 1-22 is prepared is configured to compound concentration respectively DMSO (dimethyl sulfoxide) solution, then by the solution of acquisition through gradient dilution, a series of sample for obtaining concentration gradients is molten Liquid.

Logarithmic growth phase A549, A431, BT-474, SK-BR-3 and NCI-H1975 cell, according to the life of different cells Long speed, with every hole 3-8 × 10³A cell number is uniformly laid in 96 porocyte culture plates (100 hole μ L/), in 37 DEG C, contains 5% CO₂Or without CO₂Incubator in cultivate 12 hours.Old culture medium is sucked, the fresh cultured containing various concentration drug is added in every hole 100 μ L of base (drug is dissolved in DMSO, wherein final concentration of 1% (v/v) of DMSO), each concentration group sets 3 multiple holes.Yin is set simultaneously Property control group (normal incubation medium for adding same volume), DMSO control group (adding culture medium of the same volume containing 1%DMSO) and sky White control group (adding culture medium of the same volume containing 1%DMSO) continues culture 72 hours.Except blank control group, other groups add Enter the MTT solution of 5mg/mL, 10 holes μ L/.Continue culture 4 hours, absorbs the DMSO of 100 μ L of every hole addition after supernatant.Using micro- Oscillator oscillation is measured, DMSO is made to be completely dissolved first a ceremonial jade-ladle, used in libation.Then using the OD value at multi-functional detection microplate reader measurement 490nm, and The average value of every group of 3 multiple holes OD values is calculated, and inhibiting rate (inhibition rate, IR%): IR% is calculated as follows =(OD_DMSO-OD_Dosing)/(OD_DMSO-OD_Blank) × 100%, wherein ODDMSO is the OD value of DMSO control group, OD dosing is dosing group OD value, OD blank be blank control group OD value.It is drawn according to inhibiting rate using mapping software, finds out IC₅₀Value.Experimental result It is shown in Table 3.

3. cancer cell multiplication inhibitory activity measurement result of table

Table 3 shows the compounds of this invention to A549, A431, BT-474, SK-BR-3 and NCI-H1975 tumour cell has Stronger inhibiting effect.

Embodiment 25: influence of the compound 4 to the phosphorylation of EGFR and HER2 and the Acetylation Level of histone

In human lung carcinoma cell line A549 and Breast cancer lines BT-474, by the phosphorylation for measuring EGFR and HER2 With the Acetylation Level of histone, influence of the compound 4 to EGFR, HER2 and HDAC in cell is had evaluated.

A549 and BT-474 cell is handled respectively with the compound 4 of various concentration, and then taking out pretreatment cell, (60mm is thin Born of the same parents' culture dish), supernatant is sucked, with 1 × PBS of 2mL washing 2 times.According to the stand density of cell, 50-80 μ L NP-40 eggs are added White lysate is set and is cracked 30 minutes on ice using cell scraper scraping cells.It 4 DEG C, 20000g, is centrifuged 10 minutes.Supernatant is taken, It is transferred to new centrifuge tube and records supernatant volume.5 μ L supernatants are taken, carry out protein quantification with BCA quantification of protein kit.It is surplus 5 × SDS-PAGE sample-loading buffer is added in remaining supernatant, and (volume that 5 × SDS-PAGE sample-loading buffer is added is remaining supernatant volume 1/4), mix, 100 DEG C, 10 minutes, -80 DEG C saved backup.

After the total protein of cell for extracting pretreatment cell, the expression of western blot detection GAP-associated protein GAP is utilized. According to BCA method protein quantification result equivalent loading (20-30 μ g), according to the size of testing goal albumen, carrying out concentration respectively is 7.5%, 10%, 12% or 15% SDS- polyacrylamide gel electrophoresis.After electrophoresis, gel is carefully taken out, is cut simultaneously Sanction and gel pvdf membrane of the same size, are soaked in anhydrous methanol and activate 10 seconds.Filter paper is stacked according to wet shifting method, is coagulated Glue, pvdf membrane and filter paper drive bubble therein out of using glass bar.Fixed current is in 260mA, and transferring film 1-3 hour, by gel In protein delivery to pvdf membrane on.After transferring film, pvdf membrane is taken out, is soaked in Ponceaux dyeing liquor, observation turns Film effect.It is washed with 1 × TBST, completely removes Ponceaux dyeing liquor, suitable 5% (w/v) BSA solution, room temperature envelope is added It closes 2-4 hours.After closing, pvdf membrane is slightly washed 2 times with 1 × TBST, the corresponding antibodies that then addition has diluted, and 4 DEG C It is incubated overnight.Pvdf membrane washs 3 times with 1 × TBST, 5 minutes every time, be added horseradish peroxidase-labeled goat antirabbit or The antibody (diluting corresponding antibodies, dilution ratio 1:3000 using 1 × TBST solution) of anti-mouse, is incubated at room temperature 1.5-2 hours. Pvdf membrane is washed 3 times with 1 × TBST, and 5 minutes every time, luminous substrate (ClarityTMWestern ECL Substrate is added Kit), make its uniform fold in pvdf membrane surface, then carries out development exposure using the chemiluminescence system of gel imager Light.As a result referring to Figure 1A and Figure 1B.

The experimental results showed that compound 4 has clearly the phosphorylation of EGFR and HER2 in A549 and BT-474 cell Inhibiting effect, and there is apparent up-regulation to act on the Acetylation Level of histone H 3.This absolutely proves that compound 4 is a more targets EGFR, HER2 and hdac inhibitor of point.

Embodiment 26: the influence of the cell cycle on cell of compound 4

A549 cell is handled with the compound 4 of various concentration, then takes out pretreatment cell, after 1 × PBS is washed 1 time, Pancreatin cell dissociation buffer vitellophag is added, collects cell.Take 1 × 10⁶A cell/pipe, 250g are centrifuged 5 minutes.It goes on to the greatest extent Clearly, 70% ethyl alcohol (- 20 DEG C of pre-coolings) 1mL of pre-cooling is added in precipitating, adds 70% ethyl alcohol in oscillation, mixes well cell.Sample Product are stored in -20 DEG C, until dyeing.The dyeing same day takes out sample, and 250g is centrifuged 5 minutes, removes most supernatant as far as possible.1mL is added DNA dyeing liquor sufficiently vibrates, and room temperature is protected from light dyeing 5 minutes.Flow cytomery is used later.As a result A to Fig. 2 D referring to fig. 2.

Experimental result is as shown in Fig. 2A to Fig. 2 D, in A549 cell, as the drug concentration of compound 4 increases from 0 μM To 1 μM, the G0/G1 phase cell of retardance rises to 76.1% from 56.3%.

The experimental results showed that compound 4 can be by A549 cell block in the G0/G1 phase.

Embodiment 27: compound 4 is on cell to the influence of Apoptosis

The Alexa that this experiment uses LifeTechnologies company to be soldAnnexinⅤ/Dead Cell Apoptosis kit (article No.: V13241) detects Apoptosis.The kit specifically includes that Alexa Annexin V (Component A), Propidium iodide (PI, Component B) and 5 × annexin-binding buffer(Component C).Specific experiment process is as follows: taking 5 × annexin-binding of 1mL buffer (Component C) is added 4mL ultrapure water, obtains 1 × annexin-binding buffer.The PI of 5 μ L 1mg/mL is taken to store up 45 μ 5 × annexin-binding of L buffer (Component C) are added in liquid storage (Component B), obtain PI dyeing Working solution.BT-474 cell is handled with the compound 4 of various concentration, takes out pretreatment cell, 1 × PBS is washed 1 time, and pancreas is added Enzyme cell dissociation buffer vitellophag collects cell.Supernatant is removed after centrifugation, is added 1 × PBS to wash 1 time, is centrifuged and removes supernatant.Add Enter 100 μ 1 × annexin-binding of L buffer and cell is resuspended, and adjusting cell density is 1 × 10⁶A cell/mL.Add Enter 5 μ L AlexaAnnexin V (Component A) and 1 μ L PI dyeing working fluid (solution that step 2 obtains). Room temperature is protected from light incubation 15 minutes.400 μ L 1 × annexin-binding buffer are added, slowly mix, ice bath avoid light place. With flow cytomery cell cycle apoptosis.As a result referring to Fig. 3 A to Fig. 3 D.

Experimental result is as shown in Fig. 3 A to Fig. 3 D, in BT-474 cell, as the drug concentration of compound 4 increases from 0 μM 5 μM are added to, the apoptotic cell of induction rises to 63.86% from 3.19%.

The experimental results showed that compound 4 can significantly induce BT-474 Apoptosis.

Claims

1. a kind of Formulas I compound represented or its pharmaceutically acceptable salt:

In above-mentioned Formulas I, R can be selected from having structure unit:

Wherein R₁, R₂It independently is H, F, Cl, Br, I, CF₃、OCF₃、OH、CN、NO₂、NH₂、C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkane Amino, C_1-6Alkylthio group, C_1-6Alkyl-carbonyl, C_1-6Alkylamidoalkyl, C_1-6Alkyl sulphonyl, C_1-6Alkyl sulphinyl, C_2-6Alkene Base, C_2-6Alkynyl, C_6-10Aryloxy group, C_6-10Fragrant amino, C_6-10Aryl C_1-6Alkyl, C_6-10Aryl；

The B is selected from unsubstituted C3, C4, C5 or C6 linear paraffin.

2. a kind of Formulas I compound represented or its pharmaceutically acceptable salt,

The R is selected from

Unsubstituted C3, C4, C5 or C6 linear paraffin is selected from the B.

3. Formulas I compound represented according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that in formula 1 'sIt is connected on the position C6 or C7 of quinazoline.

4. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: the salt is inorganic acid Salt or acylate；

The inorganic acid salt is selected from the salt that any one following inorganic acid are formed: hydrochloric acid, sulfuric acid and phosphoric acid；

The acylate be selected from any one following organic acid formed salt: acetic acid, trifluoroacetic acid, malonic acid, citric acid and P-methyl benzenesulfonic acid.

5. compound shown in Formulas I or its pharmaceutically acceptable salt, wherein

It is characterized in that having a structure that

6. a kind of pharmaceutical composition comprising compound shown in Formulas I as claimed in any one of claims 1-3 pharmaceutically may be used The carrier or excipient of receiving and optional other therapeutic agents.

7. compound shown in Formulas I as claimed in any one of claims 1-3 or its pharmaceutically acceptable salt, or as right is wanted Pharmaceutical composition described in asking 6 is in the purposes for being used to prepare ErbB kinases and HDAC activity inhibitor.

8. compound shown in Formulas I as claimed in any one of claims 1-3 or its pharmaceutically acceptable salt, or as right is wanted Purposes of the pharmaceutical composition described in asking 6 in the drug for the disease that preparation treatment is mediated by ErbB kinases or HDAC activation.

9. purposes according to claim 8, the disease mediated by ErbB kinases or HDAC activation is proliferative disorders.

10. purposes according to claim 9, the proliferative disorders be selected from lung cancer, breast cancer, head-neck carcinoma, colon cancer, Sdenocarcinoma of stomach, bladder cancer, kidney, liver cancer, thyroid cancer, prostate cancer, cancer of pancreas, central nervous system cancer, glioblastoma, Leukaemia, nasopharyngeal carcinoma, cervical carcinoma, oophoroma, cutaneum carcinoma or metastatic carcinoma.

11. a kind of preparation method of compound shown in Formulas I described in claim 1, which is characterized in that the method includes as follows Step:

A, formamide and 2- amino -5- iodo-benzoic acid are reacted 2-5 hours at 160-220 DEG C, after reaction, first is added Alcohol, filtering reacting liquid, filter cake are rinsed with methanol, obtain compound 102 after dry；

B, the compound 102 is dissolved in thionyl chloride, the anhydrous n,N-Dimethylformamide of catalytic amount, back flow reaction is added 2-12 hours, after reaction, vacuum distillation removed excessive thionyl chloride, obtained compound 103,

Or the compound 102 is dissolved in phosphorus oxychloride, the anhydrous n,N-diisopropylethylamine of catalytic amount, back flow reaction is added 2-12 hours, after reaction, vacuum distillation removed excessive phosphorus oxychloride, obtained compound 103；

C, at room temperature, amino benzenes compounds are added in the aqueous isopropanol containing the compound 103, are reacted at 60-100 DEG C 1-3 hours, after being cooled to room temperature, filtering reacting liquid, filter cake was rinsed with isopropanol, obtained compound 104 after dry；

D, tetrahydrofuran mixed liquor or N, N- dimethyl formyl is added in trimethyl acetenyl silicon and triethylamine under protection of argon gas In amine mixed liquor, back flow reaction 2-24 hours, after reaction, it is concentrated under reduced pressure, is rushed on short silicagel column with methylene chloride/methanol It washes to remove catalyst, obtains compound 105,

The N,N-dimethylformamide mixed liquor contains the compound 104, [bis- (diphenylphosphino) ferrocene of 1,1'-] two Palladium chloride and cuprous iodide；

E, compound 105 is dissolved in tetrahydrofuran after flushing liquor concentration, the tetrahydrofuran that the tetrabutyl amine fluoride of 1.0M is added is molten Liquid reacts half an hour under argon gas, after reaction, water quenching is added to go out, extracted through ethyl acetate, washes, saturated common salt washing, nothing It after aqueous sodium persulfate is dry, is concentrated under reduced pressure, compound 106 is obtained after post separation；

F, at room temperature, that n,N-Dimethylformamide of the sodium azide addition containing compound 6- bromocaproic acid or 7- bromine enanthic acid is molten It in liquid, is to slowly warm up to react 24-72 hours at 60-100 DEG C, after reaction, be extracted through ethyl acetate, wash, saturation food Salt washing, anhydrous sodium sulfate is dry, and compound 108 is obtained after reduced pressure；

G, 4-dimethylaminopyridine is added in chloroformic solution, reacts 2-24 hours, after reaction, is concentrated under reduced pressure at room temperature, It being extracted through methylene chloride, saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and post separation obtains compound 109,

The chloroformic solution contains compound 108, THP trtrahydropyranyl azanol and 1- (3- dimethylaminopropyl) -3- ethyl carbon two Imines；

H, cupric sulfate pentahydrate and sodium ascorbate are added in n,N-Dimethylformamide solution, 2-24 is reacted at 50-70 DEG C Hour, it after reaction, extracts, washes through ethyl acetate, saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, column Isolated compound 110；

I, hydrochloric acid dioxane solution is added dropwise in the dioxane solution containing the compound 110, is reacted at room temperature, To which after reaction, filtering reacting liquid, filter cake washed with ether obtains compound of formula I after dry；

Alternatively,

The preparation method of compound shown in the Formulas I, includes the following steps:

A, formamide and 2- amino -4- bromobenzoic acid are reacted 2-5 hours at 160-220 DEG C, after reaction, first is added Alcohol, filtering reacting liquid, filter cake are rinsed with methanol, obtain compound 202 after dry；

B, the compound 202 is dissolved in thionyl chloride, the anhydrous n,N-Dimethylformamide of catalytic amount, back flow reaction is added 2-12 hours, after reaction, vacuum distillation removed excessive thionyl chloride, obtained 203,

Or the compound 202 is dissolved in phosphorus oxychloride, the anhydrous n,N-diisopropylethylamine of catalytic amount, back flow reaction is added 2-12 hours, after reaction, vacuum distillation removed excessive phosphorus oxychloride, obtained compound 203；

C, at room temperature, amino benzenes compounds are added in the aqueous isopropanol containing the compound 203, are reacted at 60-100 DEG C 1-3 hours, after being cooled to room temperature, filtering reacting liquid, filter cake was rinsed with isopropanol, obtained compound 204 after dry；

D, tetrahydrofuran mixed liquor or N, N- dimethyl formyl is added in trimethyl acetenyl silicon and triethylamine under protection of argon gas In amine mixed liquor, back flow reaction 2-24 hours, after reaction, it is concentrated under reduced pressure, is rushed on short silicagel column with methylene chloride/methanol It washes to remove catalyst, obtains compound 205,

The N,N-dimethylformamide mixed liquor contains the compound 204, [bis- (diphenylphosphino) ferrocene of 1,1'-] two Palladium chloride and cuprous iodide；

E, compound 205 is dissolved in tetrahydrofuran after flushing liquor concentration, the tetrahydrofuran that the tetrabutyl amine fluoride of 1.0M is added is molten Liquid reacts half an hour under argon gas, after reaction, water quenching is added to go out, extracted through ethyl acetate, washes, saturated common salt washing, nothing It after aqueous sodium persulfate is dry, is concentrated under reduced pressure, compound 206 is obtained after post separation；

F, at room temperature, that n,N-Dimethylformamide of the sodium azide addition containing compound 6- bromocaproic acid or 7- bromine enanthic acid is molten It in liquid, is to slowly warm up to react 24-72 hours at 60-100 DEG C, after reaction, be extracted through ethyl acetate, wash, saturation food Salt washing, anhydrous sodium sulfate is dry, and compound 208 is obtained after reduced pressure；

G, 4-dimethylaminopyridine is added in chloroformic solution, reacts 2-24 hours, after reaction, is concentrated under reduced pressure at room temperature, It being extracted through methylene chloride, saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and post separation obtains compound 209,

H, cupric sulfate pentahydrate and sodium ascorbate are added in n,N-Dimethylformamide solution, 2-24 is reacted at 50-70 DEG C Hour, it after reaction, extracts, washes through ethyl acetate, saturated common salt washing after anhydrous sodium sulfate is dry, is concentrated under reduced pressure, column Isolated compound 210；

I, hydrochloric acid dioxane solution is added dropwise in the dioxane solution containing the compound 210, is reacted at room temperature, To which after reaction, filtering reacting liquid, filter cake washed with ether obtains compound of formula I after dry.

12. the preparation method of compound shown in a kind of Formulas I as claimed in claim 11, which is characterized in that the phenyl amines It closes object to be selected from: the chloro- 4- fluoroaniline of 3-, the chloro- 2- fluoroaniline of 3-, 3- fluorine benzyloxy-aniline, 4- (3- fluorine benzyloxy) aniline 4- (thiophene Azoles -2- methoxyl group) aniline, 4- ((substitution of 6- picoline -3) oxygroup) aniline, 3- methoxyl group -4- phenoxybenzamine, the bromo- 2- of 4- Fluoroaniline or 3- aminoanisole.