CN105884699B

CN105884699B - 4-Substituted aniline quinazoline derivatives and preparation method and use thereof

Info

Publication number: CN105884699B
Application number: CN201610321501.9A
Authority: CN
Inventors: 孙丽萍; 张海琪; 张驰; 龚飞虎; 徐云根
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2016-05-11
Filing date: 2016-05-11
Publication date: 2019-05-07
Anticipated expiration: 2036-05-11
Also published as: CN105884699A

Abstract

本发明公开了一类新型4‑取代苯胺喹唑啉类衍生物或其药学上可接受的盐、多晶型物、溶剂合物或立体异构体，及其制备方法和应用。本发明中的4‑取代苯胺喹唑啉类化合物在生物学测试中，对EGFR和VEGFR‑2具有良好的抑制活性，并在体外抗人肿瘤细胞增殖活性试验中显示出明显的效果。The invention discloses a new class of 4-substituted aniline quinazoline derivatives or pharmaceutically acceptable salts, polymorphs, solvates or stereoisomers thereof, as well as preparation methods and applications thereof. The 4-substituted aniline quinazoline compounds of the present invention have good inhibitory activity on EGFR and VEGFR-2 in biological tests, and show obvious effects in the in vitro anti-human tumor cell proliferation activity test.

Description

4- substituted aniline quinazoline derivative and its preparation method and application

Technical field

The present invention relates to pharmaceutical synthesis fields, more particularly to 4- substituted aniline quinazoline derivative and its preparation side Method, and the application containing these compounds in anti-tumor drug.

Background technique

Malignant tumour is to seriously threaten the common disease and frequently-occurring disease of human life.The essence of its canceration is abnormal gene expression The imbalance for causing Cell signal propagation pathways leads to cell infinite multiplication, and wherein tyrosine kinase (TKs) plays a key effect.

Protein tyrosine kinase is a kind of protein with tyrosine kinase activity, the signal transduction and tumour mediated Occurrence and development have substantial connection.Protein tyrosine kinase can be divided into receptor tyrosine kinase and non-receptor junket ammonia by its structure Acid kinase.EGF-R ELISA (EGFR) is typical receptor tyrosine kinase, it belongs to human epidermal growth factor acceptor (HER) family member.HER family member includes HER1 (EGFR/erbB1), HER2 (erbB2), HER3 (erbB3) and HER4 (erbB4).This receptoroid is highly expressed in epithelial cell tumour, and family member can occur under the induction of ligands specific Dimerization, thus downstream signaling pathway in active cell, the biological effects such as proliferation, differentiation and the migration of regulating cell. (.Nature such as Blume-Jensen P, 2001,411 (6835): 355-365.)

Based on the receptor tyrosine kinase of imbalance important function played in cancer pathology, specific ptk inhibitor Exploitation as potential anticancer therapeutic agent is the research hotspot of current antineoplastic.Since Fry in 1994 etc. has found 4- anilino- Since specific inhibitor of the quinazoline (PD 153035) as EGFR tyrosine kinase, quinazoline compounds are as junket ammonia Acid kinase inhibitor has obtained in-depth study (.Science1994 such as Fry, 265,1093.).Wherein 4- substituted aniline quinoline azoles Quinoline class compound is the higher a kind of compound of activity in quinazolines tyrosine kinase inhibitor.Targeting EGFR tyrosine kinase 4- substituted aniline quinazoline ditosylate salt listing small-molecule drug have: Gefitinib, Tarceva, Lapatinib, Conmana, Ah Method replaces Buddhist nun.Although single EGFR tyrosine kinase inhibitor has preferable anti-tumor activity, it is easy to generate drug resistance Property, such as Gefitinib drug resistance phenomenon (Kobayashi S .New England Journal of Medicine, 2005, 352 (8): 786-792.).So the tyrosine kinase inhibitor of multiple targeting generates therewith, the mechanism drugs that target simplify more Treatment procedure preferably overcomes drug resistance, becomes a new research tendency.Dual-target EGFR and VEGFR (blood vessel endothelium Growth factor receptors) tyrosine kinase inhibitor 4- substituted aniline quinazoline compounds on the one hand act on tumour cell and Receptor tyrosine kinase inhibits tumor cell proliferation；On the other hand, by inhibiting vascular endothelial growth factor, tumour blood is blocked Pipe generates.So EGFR/VEGFR-2 double inhibitor have the generation of more efficient inhibition tumour cell, growth, proliferation work With.The EGFR/VEGFR-2 double inhibitor listed has: Vande Thani (Vandetanib), it has EGFR and VEGFR There is preferable inhibitory activity.It is (fatal or very serious for diagnosing, preventing or treat that in November, 2005 medicine obtains Orphan drug Orphan disease drug) qualification, in April, 2011, Vande Thani by FDA approval be used as first advanced stage (metastatic) thyroid gland The therapeutic agent of cephaloma.

Summary of the invention

The object of the present invention is to provide a kind of novel 4- substituted aniline quinazoline derivative or its is pharmaceutically acceptable Salt, polymorph, solvate or stereoisomer, and its preparation method and application.4- substituted aniline quinoline azoles in the present invention Quinoline class compound has good inhibitory activity in biology test, to EGFR and VEGFR-2, and human tumor is thin in vitro Apparent effect is shown in the test of born of the same parents' proliferation activity.

1. the present invention relates to a kind of 4- substituted aniline quinazoline derivant as shown in logical formula (I) or its is pharmaceutically acceptable Salt, polymorph, solvate or stereoisomer:

Wherein, R₁And R₂For same or different group, it is respectively selected from hydrogen, C₁~C₃Alkoxy (preferably methoxyl group), or Person C₁~C₆(preferably C₁~C₃) alkoxy replace C₁~C₆(preferably C₁~C₃) alkoxy；Or R₁(R₂) it is amino or substitution The C that amino replaces₁~C₆(preferably C₁~C₃) alkoxy；Wherein, the substituent group on substituted-amino can be with the amino nitrogen atom one Playing cyclization becomes 4~9 yuan of saturated heterocyclics, and the saturated heterocyclic can additionally contain 1~2 hetero atom, hetero atom be nitrogen, oxygen or Sulphur (preferably nitrogen or oxygen), it is unsubstituted on the nitrogen-atoms or by C if additionally containing nitrogen-atoms₁~C₆(preferably C₁~C₃) alkyl (preferably methyl) replaces；Or R₁(R₂) it is the C that 4~9 yuan of saturated heterocyclics replace₁~C₆(preferably C₁~C₃) alkoxy, it embezzles Pass through carbon atom and C with heterocycle₁~C₆(preferably C₁~C₃) alkoxy connection, 1~2 miscellaneous original is contained in the saturated heterocyclic Son, hetero atom are nitrogen, oxygen or sulphur, if comprising nitrogen-atoms, it is unsubstituted on the nitrogen-atoms or by C₁~C₆(preferably C₁~C₃) alkane Base (preferably methyl) replaces；

R₃And R₄It independently is hydrogen, C₁~C₃Alkyl, C₁~C₃Alkoxy, halogen or cyano；

R₅For hydrogen, C₁~C₃Alkyl, C₁~C₃Alkoxy, halogen or cyano；

R₆、R₇、R₈And R₉It independently is hydrogen, C₁~C₃Alkyl, C₁~C₃Alkoxy, halogen or cyano；

L is-NHCO- ,-CONH- or-NHCONH-；

R₁₀For substituted or unsubstituted C₁~C₈Alkyl (preferably C₁~C₆Alkyl), substituted or unsubstituted C₃~C₈Cycloalkanes Base, substituted or unsubstituted C₆~C₁₄Aryl (preferably C₆~C₁₀Aryl, such as phenyl or naphthyl), substituted or unsubstituted C₃~C₉ Heteroaryl；Substituent group in the substituted alkyl is 4~6 yuan of saturated heterocyclyls, and the hetero atom number of the saturated heterocyclyl is 1 ~4, hetero atom is nitrogen, oxygen or sulphur；Substituent group in the substituted naphthenic base is C₁~C₃Alkyl, C₁~C₃Alkoxy or Halogen；Substituent group in the substituted aryl or substituted heteroaryl is C₁~C₃Alkyl, C₁~C₃Halogenated alkyl (such as three Methyl fluoride), C₁~C₃Alkoxy, C₂~C₃Alkenyl, C₂~C₃One of alkynyl, halogen or cyano are a variety of, every kind of substituent group Number is 0,1 or multiple, and the position of substitution is any substitutive position on aryl or heteroaryl, the hetero atom in the heteroaryl For nitrogen, oxygen or sulphur, hetero atom number is 1~5；

Or when L is-CONH-, R₁₀To contain C with what nitrogen-atoms in L was connected₁~C₈(preferably C₁~C₃) carboxylic acid shape At ester, the carboxylate be contain C₁~C₆Alcohol formed ester；

In the present invention, the pharmaceutically acceptable salt of the 4- substituted aniline quinazoline compounds is above-mentioned 4- substitution The salt that aniline quinazoline class compound and inorganic acid or organic acid are formed.

The crystal form of compound of formula I in the present invention can be polymorphic, these crystal forms include in the present invention. In addition, compound of formula I in the present invention can also form solvate with solvent, such as and water formation hydrate, or with it is organic Solvent forms organic solvent and closes object, these hydrates and organic solvent close object and be also included in the present invention.

The compound of the present invention may include asymmetric carbon atom, especially asymmetric carbon atom, therefore and generate solid Isomers is regarded as a part of the invention.

Compound I in the present invention can be prepared by following either method:

(1) be one of preparation method of the compounds of this invention below, each group definition with described in aforesaid compound I, but R₁For hydrogen, C₁~C₃Alkoxy (preferably methoxyl group) or C₁~C₆(preferably C₁~C₃) alkoxy replace C₁~C₆(preferably C₁ ~C₃) alkoxy, wherein initial compounds II can be made by the prior art, and R is the C that substituted-amino replaces in formula₁~C₆Alkane Base, wherein the substituent group on substituted-amino cyclization can become 4~9 yuan of saturated heterocyclics together with the amino nitrogen atom, described Saturated heterocyclic can additionally contain 1~2 hetero atom, and hetero atom is nitrogen, oxygen or sulphur (preferably nitrogen or oxygen), if additionally former containing nitrogen Son, then it is unsubstituted on the nitrogen-atoms or by C₁~C₆(preferably C₁~C₃) alkyl (preferably methyl) substitution；By compound II and RCl is reacted under alkaline condition, and the method and condition of the reaction is the conventional method and condition of such reaction.

(2) in acid condition, quinazoline parent nucleus (III) and the benzamide replaced or phenylurea (IV) reaction are made logical Compound of formula I, synthetic route are as follows:

Wherein X represents Cl or Br；R₁~R₉Defined as described above, the reaction method and condition is such reaction Conventional method and condition, compound III and IV can by the prior art be made.It prepares I by III and IV to be characterized in that, acid Property condition be reaction system PH 2~6；Solvent is selected from water, n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxy six Ring, methanol, ethyl alcohol, isopropanol or acetonitrile it is one or more；Unless otherwise specified, agents useful for same and raw material of the present invention are commercially available It can obtain.

The invention further relates to above compound I or its pharmaceutically acceptable salt, polymorph, solvate or solid are different Structure body preparation prevent and treat mammal especially people with protein kinase mediated signal transduction pathway imbalance or abnormal Application in the drug of the relevant disease of angiogenesis.The disease includes but is not limited to tumour, diabetes, autoimmune Disease, neurodegenerative disease, diabetic retinopathy, age-related macular degeneration, arteriosclerosis or inflammation.

In the present invention, the 4- substituted aniline quinazoline compounds are in biology test, to EGFR and VEGFR-2 Apparent effect is shown with good inhibitory activity, and in vitro in the test of human tumor's cell-proliferation activity.

The positive effect of the present invention is that: present invention finds a kind of 4- substituted aniline quinazolines shown in formula I Class compound has stronger anti-tumour cell proliferative activity, for protein kinase EGFR relevant to a variety of diseases and VEGFR-2 has stronger inhibitory activity.

Specific embodiment

The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.

First part's Chemical Example

1 N- of embodiment (4- nitrobenzophenone) benzamide

Under ice bath, nitrogen protection, by 4- nitroaniline (2.0mmol, 276mg), potassium carbonate (2.4mmol, 331mg) and Anhydrous THF 10ml is added in 50ml two-mouth bottle, and chlorobenzoyl chloride (0.28ml, 2.4mmol) is then slowly added dropwise, after being added dropwise, Room temperature reaction 2 hours.Into reaction solution plus a large amount of yellow solids are precipitated in 10% dilute hydrochloric acid (10ml), stirring, stand, filter, add Water washing filter cake, dry yellow solid 407mg, as N- (4- nitrobenzophenone) benzamide, yield 84%.

Chlorobenzoyl chloride is replaced with corresponding substituted benzoyl chloride, is prepared using identical method: N- (4- nitrobenzophenone) -2- Chlorobenzamide, yellow solid, yield 97.6%；N- (4- nitrobenzophenone) -3- chlorobenzamide, yellow solid, yield 98%； N- (4- nitrobenzophenone) -4- chlorobenzamide, yellow solid, yield 77.7%；N- (4- nitrobenzophenone) -4- methoxybenzoyl Amine, yellow solid, yield 67%；N- (4- nitrobenzophenone) -4- methyl benzamide, yellow solid, yield 88.9%.

2 N- of embodiment (4- aminophenyl) benzamide

By N- (4- nitrobenzophenone) benzamide (1.5mmol, 363mg), zinc powder (7.5mmol, 488mg) and 11ml first The mixed solvent of alcohol/water (V/V=10/1) is added in 50ml reaction flask, and glacial acetic acid (15mmol, 0.9ml) is then slowly added dropwise, After being added dropwise, it is heated to reflux 1 hour.It after fully reacting, filters, adds a small amount of methanol to wash, then filtrate is concentrated.Crude product is used Methanol-water recrystallization, dry yellow solid 261mg, as N- (4- aminophenyl) benzamide, yield 72%.

N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitrobenzophenone) -2- chlorobenzamide, using identical side Method prepares N- (4- aminophenyl) -2- chlorobenzamide, yellow solid, yield 80%；With N- (4- nitrobenzophenone) -3- chlorobenzene first Amide replaces N- (4- nitrobenzophenone) benzamide, prepares N- (4- aminophenyl) -3- chlorobenzamide using identical method, Yellow solid, yield 67.5%；N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitrobenzophenone) -4- chlorobenzamide, N- (4- aminophenyl) -4- chlorobenzamide, yellow solid, yield 60% are prepared using identical method；With N- (4- nitrobenzene Base) -4- methoxy benzamide is instead of N- (4- nitrobenzophenone) benzamide, using identical method preparation N- (4- aminobenzene Base) -4- methoxy benzamide, yellow solid, yield 75%；N- is replaced with N- (4- nitrobenzophenone) -4- methyl benzamide (4- nitrobenzophenone) benzamide prepares N- (4- aminophenyl) -4- methyl benzamide using identical method, and yellow is solid Body, yield 92.3%.N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitrobenzophenone) phenylurea, using identical method system Standby N- (4- aminophenyl) phenylurea, white solid, yield 92.1%；N- (4- nitre is replaced with N- (4- nitrobenzophenone) -4- chlorobenzene urea Base phenyl) benzamide, N- (4- aminophenyl) -4- chlorobenzene urea, faint yellow solid, yield are prepared using identical method 63.7%；N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitrobenzophenone) -3- chlorobenzene urea, is prepared using identical method N- (4- aminophenyl) -3- chlorobenzene urea, faint yellow solid, yield 78.6%；With the replacement of N- (4- nitrobenzophenone) -2- methyl phenylurea N- (4- nitrobenzophenone) benzamide prepares N- (4- aminophenyl) -2- methyl phenylurea, pale yellow colored solid using identical method Body, yield 94.4%；N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitrobenzophenone) -3,4- dimethyl phenylurea, is used Identical method prepares N- (4- aminophenyl) -3,4- dimethyl phenylurea, pink solid, yield 90.6%；With N- (4- nitro- 2- chlorphenyl) phenylurea is instead of N- (4- nitrobenzophenone) benzamide, using identical method preparation N- (4- amino -2- chlorphenyl) Phenylurea, faint yellow solid, yield 92.1%；N- (4- nitrobenzophenone) is replaced with N- (4- nitro -2- chlorphenyl) -2- methyl phenylurea Benzamide prepares N- (4- amino -2- chlorphenyl) -2- methyl phenylurea, faint yellow solid, yield using identical method 94%；N- (4- nitrobenzophenone) benzamide is replaced with N- (4- nitro -2- chlorphenyl) -4- chlorobenzene urea, using identical method Prepare N- (4- amino -2- chlorphenyl) -4- chlorobenzene urea, faint yellow solid, yield 89%；With N- (4- nitro -2- chlorphenyl) -3, 4- dimethyl phenylurea replaces N- (4- nitrobenzophenone) benzamide, prepares N- (4- amino -2- chlorphenyl)-using identical method 3,4- dimethyl phenylureas, faint yellow solid, yield 88.4%.

3 N- of embodiment (4- nitrobenzophenone) phenylurea

Triphosgene (2.97g, 10mmol) is dissolved in methylene chloride 20ml, be added dropwise 4- nitroaniline (1.38g, 10mmol) and The dichloromethane solution (10ml) of triethylamine (2.8ml), is added dropwise, continue stir 30min, then be added aniline (0.93g, 10mmol), 40 DEG C are warming up to, 30min is stirred at reflux, is spin-dried for methylene chloride, acetone: water (2: 1) 30ml is added, sufficiently vibrates, There is solid precipitation, filters, filter cake acetone: water (1: 1) 5ml is washed 2 times, is dried to obtain yellow solid 1.58g, as N- (4- Nitrobenzophenone) phenylurea, yield 61.7%.

Aniline is replaced with 4- chloroaniline, N- (4- nitrobenzophenone) -4- chlorobenzene urea is prepared using identical method, yellow is solid Body, yield 58.6%；Aniline is replaced with 3- chloroaniline, N- (4- nitrobenzophenone) -3- chlorobenzene urea is prepared using identical method, it is yellow Color solid, yield 62.1%；Aniline is replaced with 2-aminotoluene, N- (4- nitrobenzophenone) -2- first is prepared using identical method Base phenylurea, yellow solid, yield 48%；Aniline is replaced with 3,4- dimethylaniline, N- (4- nitro is prepared using identical method Phenyl) -3,4- dimethyl phenylurea, yellow solid, yield 56%；4- nitroaniline is replaced with the chloro- 4- nitroaniline of 2-, using phase Same method prepares N- (4- nitro -2- chlorphenyl) phenylurea, yellow solid, yield 69%；4- is replaced with the chloro- 4- nitroaniline of 2- Nitroaniline, 2-aminotoluene replace aniline, prepare N- (4- nitro -2- chlorphenyl) -2- methyl phenylurea using identical method, Yellow solid, yield 48%；4- nitroaniline is replaced with the chloro- 4- nitroaniline of 2-, 4- chloroaniline replaces aniline, and use is identical Method prepares N- (4- nitro -2- chlorphenyl) -4- chlorobenzene urea, yellow solid, yield 86.2%；With 2- chloro- 4- nitroaniline generation For 4- nitroaniline, 3,4- dimethylanilines replace aniline, prepare N- (4- nitro -2- chlorphenyl) -3 using identical method, 4- dimethyl phenylurea, yellow solid, yield 75.5%.

4 2- of embodiment (4- nitrobenzamide) acetic acid

Glycine (27.2mmol, 2.04g) is dissolved in 10%NaOH solution 12.24g, is slowly added dropwise and is dissolved in anhydrous ether The 4- nitrobenzoyl chloride (24.04mmol, 4.46g) of (30ml), drop finish, add 10%NaOH solution to PH 9-10, reacted Entirely, ether is spun off, dilute hydrochloric acid is acidified to PH 1-2, and ethyl acetate extraction merges organic phase, and column chromatographs to obtain faint yellow solid 4.32g, yield 80%.

5 2- of embodiment (4- nitrobenzamide) methyl acetate

2- (4- nitrobenzamide) acetic acid (13.4mmol, 3g) is dissolved in 22ml methanol, the dense sulphur of 0.44ml is slowly added dropwise Acid is heated to reflux 6 hours, is cooled to room temperature, is spin-dried for, ethyl acetate is added to dissolve, and saturated sodium bicarbonate solution is washed twice, saturation food Salt is washed twice, and re-crystallizing in ethyl acetate obtains 2.82g, yield 88%.

6 2- of embodiment (4- aminobenzamide) methyl acetate

2- (4- nitrobenzamide) methyl acetate (11.84mmol, 2.82g) is dissolved in methanol/water (V: V=55/ 5ml), zinc powder (35.52mmol, 2.31g) is added, glacial acetic acid 6.9ml is slowly added dropwise, drop finishes, and flows back 3 hours, filters while hot, revolves Fall methanol, add saturated sodium bicarbonate solution tune PH for neutrality, ethyl acetate extraction merges organic phase, saturated sodium-chloride washing, nothing Aqueous sodium persulfate is dry, is concentrated to give grease, re-crystallizing in ethyl acetate obtains 1.23g pale orange solid, yield 50%.

7 1- of embodiment (3- chloropropyl) -4- methyl piperazine dihydrochloride

Under ice bath, 100ml is added in N methyl piperazine (30mmol, 3.3ml), 4ml 25%NaOH solution, 40ml acetone Round-bottomed flask is then slowly added into the bromo- 3- chloropropane (30mmol, 3ml) of 1-, and it is molten to insoluble matter to continue ice bath stirring after finishing Solution, then reacts for 24 hours at room temperature.Solvent under reduced pressure is concentrated, 20ml water is added and dissolves concentrate, is extracted with dichloromethane, nothing Aqueous sodium persulfate is dry, filters, and concentration obtains transparent oil, reaction flask is placed in ice bath, 50ml ethyl acetate is added, slowly 2.5ml concentrated hydrochloric acid is added dropwise to there are a large amount of white solids to generate, when reaction controls PH about 2, solvent under reduced pressure concentration, the anhydrous second of 100ml Alcohol recrystallization, filters, dry 3.3g white solid, yield 44.1%

8 N- of embodiment (3- chloropropyl) morpholine hydrochloride

The bromo- 3- chloropropane (60mmol, 5.96ml) of 1- is added to the toluene (25ml) of morpholine (40mmol, 3.5ml) Solution, 70 DEG C are stirred 12 hours, filter out white solid, and filtrate enriching hydrochloric acid 2ml is precipitated white solid, is evaporated, ethyl alcohol is added to tie again It is brilliant to obtain 2.44g, yield 30.3%.

9 N- of embodiment (2- chloroethyl) piperidine hydrochlorate

N- hydroxyethyl piperidine (5ml) is dissolved in chloroform (12.5ml), under ice bath, thionyl chloride 3.4ml is slowly added dropwise, is dripped Finish, be to slowly warm up to flow back, react 3 hours, be cooled to room temperature, spin off solvent, there are a large amount of crystal to be precipitated, ethyl alcohol recrystallization obtains 5.88g, yield 85%.

10 3- methoxyl group -4- benzoxybenzaldehyde of embodiment

Vanillic aldehyde (75mmol, 11.4g) is added in 250ml reaction flask, be added 100ml ethyl alcohol, stirring and dissolving, then plus Enter K₂CO₃(97.6mmol, 13.5g), benzyl chloride (112.5mmol, 13ml) are heated to reflux 6 hours.Reaction solution is cooled to room temperature, It filters, filters off K₂CO₃Residue, filtrate are concentrated, and crystallize to obtain light yellow crystal in ethyl alcohol, filter, and filter cake ethanol washing is dried It is 3- methoxyl group -4- benzoxybenzaldehyde to faint yellow solid 17.3g, yield 95.7%,¹H-NMR(CDCl₃, 300MHz): δ 3.94 (s, 3H), 5.24 (s, 2H), 6.97-6.99 (d, 1H, J=8.16Hz), 7.25 (s, 1H), 7.29-7.45 (m, 6H), 9.83 (s, 1H)

11 3- methoxyl group -4- benzyloxy yl benzoic acid of embodiment

3- methoxyl group -4- benzoxybenzaldehyde (25mmol, 6.05g) is added in the round-bottomed flask of 250ml, then plus Enter acetone: water (V: V=75: 62.5ml) mixed solvent, stirring, then by KMnO₄(30mmol, 4.74g) is slowly added to reaction flask In, it is heated to reflux 1 hour.It after fully reacting, filters while hot, filters off residue, filtrate adjusts pH=with 40% sodium hydroxide solution 10-11, solution clarification, there is a small amount of insoluble residue, filters, and filters off residue, and then filtrate adjusts pH=2-3 with 6N HCl, is precipitated A large amount of white solids stir, and filter, and clear water washs filter cake, dry to obtain white solid 5.7g, are 3- methoxyl group -4- benzyloxy benzene Formic acid, yield 89%,¹H-NMR(CDCl₃, 300MHz): δ 3.94 (s, 3H), 5.22 (s, 2H), 6.90-6.92 (d, 1H, J= 8.4Hz), 7.31-7.44 (m, 5H), 7.60 (s, 1H), 7.65-7.68 (m, 1H)

12 3- methoxyl group -4- benzyloxy methyl benzoate of embodiment

By 3- methoxyl group -4- benzyloxy yl benzoic acid (20.9mmol, 5.4g), 50ml methanol is added in 250ml reaction flask, is stirred It mixes, the 1ml concentrated sulfuric acid is slowly added dropwise, be heated to reflux 10 hours.It being concentrated, is crystallized in methanol, filtered, filter cake is washed with a small amount of methanol, Drying obtain white solid 4.5g, be 3- methoxyl group -4- benzyloxy methyl benzoate, yield 80%,¹H-NMR(CDCl₃, 300MHz): δ 3.90 (s, 3H), 3.95 (s, 3H), 5.23 (s, 2H), 7.32-7.57 (m, 5H), 7.58 (s, 1H), 7.60- 7.61 (d, 1H, J=1.98Hz), 7.633-7.639 (d, 1H, J=1.80Hz)

13 2- nitro -4- benzyloxy -5- methoxyl methyl benzoate of embodiment

By 34ml glacial acetic acid, fuming nitric aicd (13.6mmol, 5.8ml) is added in the round-bottomed flask of 100ml, in ice bath 0 It is stirred at DEG C, then 3- methoxyl group -4- benzyloxy methyl benzoate (13.3mmol, 3.7g) is added slowly in solution by several times, 0 DEG C the reaction was continued 30 minutes, then reacts at room temperature 6 hours.Reaction solution is poured slowly into 120ml ice water, stirring has solid analysis Out, it filters, it is 2- nitro -4- benzyloxy -5- methoxybenzene first that a small amount of ether, which washs filter cake, and drying obtains yellow solid 4.0g Sour methyl esters, yield 94.7%,¹H-NMR(CDCl₃, 300MHz): δ 3.90 (s, 3H), 3.95 (s, 3H), 5.23 (s, 2H), 6.89 (s, 1H), 7.28 (s, 1H), 7.33-7.50 (m, 5H)

14 2- amino -4- benzyloxy -5- methoxyl methyl benzoate of embodiment

2- nitro -4- benzyloxy -5- methoxyl methyl benzoate (6.2mmol, 2.0g) is added in 100ml reaction flask, Then MeOH/H is added₂O (V/V=33/3ml), stirring, is subsequently added into Zn powder (19mmol, 1.2g), acetic acid is slowly added dropwise (63.3mmol, 3.6ml) is heated to reflux 3 hours.It after fully reacting, filters while hot, filters off residue, the methanol in filtrate is revolved Fall, 50ml water is then added, extracted with ethyl acetate (30ml × 2), separate organic phase, successively uses saturated sodium bicarbonate (30ml × 2) solution, saturated sodium-chloride (30ml × 2) solution are respectively washed twice, and organic layer is dry with anhydrous sodium sulfate, filter, filtrate is revolved It is dry, obtain faint yellow solid 1.5g, 2- amino -4- benzyloxy -5- methoxyl methyl benzoate, yield 84.7%,¹H-NMR (CDCl₃, 300MHz): δ 3.83-3.84 (s, 6H), 3.95 (s, 3H), 5.14 (s, 2H), 6.19 (s, 2H), 7.31-7.44 (m, 7H).

15 4- hydroxyl -6- methoxyl group -7- benzyloxy quinazoline of embodiment

By 6- amino -3- methoxyl group -4- benzyloxy methyl benzoate (2.0g, 6.97mmol), ammonium formate (393mg, 6.27mmol), formamide (10ml) is added in the round-bottomed flask of 100ml, is warming up to 150 DEG C of return stirrings 3 hours.It has reacted Quan Hou is cooled to room temperature, there is solid precipitation, filters, and filter cake is washed with clear water, and drying obtains field gray solid 1.3g, is 4- hydroxyl- 6- methoxyl group -7- benzyloxy quinazoline, yield 82%,¹H-NMR(CDCl₃, 300MHz): δ 4.01 (s, 3H), 5.29 (s, 2H), 7.19-7.46 (m, 5H), 7.48 (s, 1H), 7.99 (s, 1H), 8.20 (s, 1H), 11.54 (s, 1H)

The chloro- 6- methoxyl group -7- benzyloxy quinazoline of 16 4- of embodiment

By 9.5ml SOCl₂It is added in 25ml round-bottomed flask, adds 4- hydroxyl -6- methoxyl group -7- benzyloxy quinazoline (860mg, 3.04mmol), stirring are added dropwise 0.2ml DMF, pyridine (0.23ml) are slowly added dropwise and is heated to reflux 1 hour.It has reacted Entirely, it is cooled to room temperature, is slowly dropped in 50ml ice water, stir, yellow solid is precipitated, filter, clear water washs filter cake, dries 810mg, be the chloro- 6- methoxyl group -7- benzyloxy quinazoline of 4-, yield 88.6%,¹H-NMR(DMSO-d₆, 300MHz): δ 3.99 (s, 3H), 5.36 (s, 2H), 7.37-7.56 (m, 7H), 8.87 (s, 1H)

17 2- nitro -4- hydroxy-5-methyl p-methoxybenzoic acid methyl esters of embodiment

2- nitro -4- benzyloxy -5- methoxyl methyl benzoate (4.1mmol, 1.3g) is dissolved in trifluoroacetic acid 8ml, is returned Stream 1 hour, spins off TFA, adds water, and it is 2- nitro -4- that ethyl acetate extraction, which merges organic phase, concentration, and column chromatographs to obtain 0.796g Hydroxy-5-methyl p-methoxybenzoic acid methyl esters, yield 86%,¹H-NMR(CDCl₃, 300MHz): δ 3.89 (s, 3H), 4.01 (s, 3H), 6.04 (s, 1H), 7.14 (s, 1H), 7.47 (s, 1H)

Embodiment 18 2- nitro -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) methyl benzoate

By 2- nitro -4- hydroxy-5-methyl p-methoxybenzoic acid methyl esters (0.8g, 3.52mmol), N- (2- chloroethyl) piperidinium salt 40ml is added in hydrochlorate (0.7781g, 4.23mmol), potassium carbonate (2.48g, 17.96mmol), potassium iodide (0.7g, 3.52mmol) In acetone, 55 DEG C are heated to, 10h is reacted, is cooled to room temperature, is filtered, filtrate concentration, column chromatographs to obtain 1.044g yellow oil, For 2- nitro -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) methyl benzoate, yield 87.7%,¹H-NMR(CDCl₃, 300MHz): δ 1.44-1.62 (m, 6H), 2.51 (s, 4H), 2.83 (t, 2H), 3.89 (s, 3H), 3.95 (s, 3H), 4.22 (t, 2H), 7.06 (s, 1H), 7.52 (s, 1H)

Embodiment 19 2- amino -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) methyl benzoate

By 2- nitro -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) methyl benzoate (1.044g, 3.09mmol) It is dissolved in 15ml methanol, 10%Pd/C 0.205g is added, is passed through hydrogen, is stirred overnight at room temperature, end of reaction, suction filtered through kieselguhr, filter Liquid is spin-dried for obtaining rufous grease 0.9348g, is 2- amino -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) benzoic acid first Ester yield 98.3%,¹H-NMR(CDCl₃300MHz): δ 1.45-1.65 (m, 6H), 2.55 (s, 4H), 2.85 (t, 2H), 3.79 (s, 3H), 3.83 (s, 3H), 4.14 (t, 2H), 5.55 (s, 2H), 6.16 (s, 1H), 7.29 (s, 1H)

Embodiment 20 4- hydroxyl -6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline

2- amino -5- methoxyl group -4- (2- (piperidin-1-yl) ethyoxyl) methyl benzoate (2.59mmol, 0.8g) is molten In dehydrated alcohol 10ml, Formamidine acetate is added, flows back 12 hours, is cooled to room temperature, filters to obtain white solid, a small amount of ethyl alcohol is washed It washs, dry 0.73g, yield 93.6%,¹H-NMR(CDCl₃, 300MHz): δ 1.46-1.64 (m, 6H), 2.58 (s, 4H), 2.93 (t, 2H), 3.97 (s, 3H), 4.31 (t, 2H), 7.14 (s, 1H), 7.57 (s, 1H), 8.00 (s, 1H), 11.40 (s, 1H).

The chloro- 6- methoxyl group -7- of 21 4- of embodiment (2- (piperidin-1-yl) ethyoxyl) quinazoline

4- hydroxyl -6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline 100mg is dissolved in 2ml phosphorus oxychloride, 100 DEG C are flowed back 8 hours, and phosphorus oxychloride is spun off, and add trash ice, saturated sodium bicarbonate tune PH about 7-8, methylene chloride extraction, anhydrous sulphur Sour sodium is dry, is spin-dried for obtaining 89.6mg, the chloro- 6- methoxyl group -7- of as 4- (2- (piperidin-1-yl) ethyoxyl) quinazoline, yield 84.5%,¹H-NMR(CDCl₃300MHz): δ 1.24 (s, 2H), 1.80 (s, 4H), 2.82 (s, 4H), 3.15 (s, 2H), 4.03 (s, 3H), 4.50 (t, 2H), 7.33 (s, 1H), 7.37 (s, 1H), 8.86 (s, 1H)

22 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) benzamide (I-1) preparation

By the chloro- 6- methoxyl group -7- benzyloxy quinazoline (178mg, 0.59mmol) of 4-, N- (4- aminophenyl) benzamide (104mg, 0.49mmol), 5ml isopropanol add in 25ml reaction flask, and stirring is heated to reflux 30min, have precipitating to generate.Reaction It after completely, is cooled to room temperature, filters, wash filter cake with a small amount of methylene chloride and THF, be dried to obtain yellow solid 250mg, be N- (4- ((6- methoxyl group -7- benzyloxy quinazoline -4- base) amino) phenyl) benzamide, yield 88%,¹H-NMR(DMSO-d₆, 300MHz): δ 4.03 (s, 3H), 5.30 (s, 2H), 7.34-7.63 (m, 11H), 7.90-7.93 (d, 2H), 7.96-7.99 (d, 2H), 8.38 (s, 1H), 8.79 (s, 1H), 10.42 (s, 1H), 11.47 (s, 1H) .ESI-MS:m/z 477 [M+H]⁺.

N- (4- ((6- methoxyl group -7- benzyloxy quinazoline -4- base) amino) phenyl) benzamide (200mg, 0.42mmol) reflux 6 hours in trifluoroacetic acid (6ml).After fully reacting, reaction solution is cooled to room temperature, is slowly dropped to It in 30ml ice water, stirs, filters, be dried to obtain brown-green solid 150mg, be N- (4- (6- methoxyl group -7- hydroxyquinazoline -4- Amino) phenyl) benzamide, yield 92.5%,¹H-NMR(DMSO-d₆, 300MHz): δ 4.18 (s, 3H), 7.13 (s, 1H), 7.85 (s, 1H), 7.49-7.85 (m, 2H), 7.97-7.99 (d, 2H), 8.35 (s, 1H), 9.54 (s, 1H), 10.27 (s, 1H)

By N- (4- ((6- methoxyl group -7- hydroxyquinazoline -4- base) amino) phenyl) benzamide (150mg, 0.39mmol), potassium carbonate (325mg, 2.35mmol), 5ml DMF are added in the round-bottomed flask of 25ml, stir 30min, then will 4- methyl -3- chloropropyl piperazine hydrochloride (118mg, 0.47mmol), potassium iodide (65mg, 0.39mmol) are added to reaction solution In, 82 DEG C are warming up to, is stirred 18 hours.After fully reacting, it is cooled to room temperature, 30ml water is added, with ethyl acetate (30ml × 2) It is extracted twice, merges organic layer, then washed respectively (30ml × 2) twice with saturated sodium bicarbonate and saturated salt solution, collect organic Layer, anhydrous sodium sulfate is dry, concentration, and with petroleum ether: ethyl acetate (3: 1) recrystallizes, and filters while hot, and concentration filtrate obtains yellowish Color solid 21mg is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) amino) benzene Base) benzamide (I-1), yield 20%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.92-2.00 (m, 2H), 2.14 (s, 3H), 2.32-2.50 (m, 10H), 3.96 (s, 3H), 4.14-4.18 (t, 2H), 7.15 (s, 1H), 7.51-7.62 (m, 5H), 7.77- 7.78 (d, 2H, J=2.64), 7.88 (s, 1H), 7.96-7.99 (d, 2H), 8.42 (s, 1H), 9.56 (s, 1H), 10.29 (s, 1H) .ESI-MS:m/z 527 [M+H]⁺.

23 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -3- chlorobenzamide (I-2) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -3- chlorobenzamide, using the preparation of I-1 Method prepares I-2, obtains faint yellow solid 90mg, is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third oxygen Base) quinazoline -4- base) amino) phenyl) -3- chlorobenzamide (I-2), yield 22%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.89-1.98 (m, 2H), 2.14 (s, 3H), 2.32-2.49 (m, 10H), 3.96 (s, 3H), 4.14-4.18 (t, 2H), 7.15 (s, 1H), 7.50-7.60 (m, 1H), 7.65-7.66 (d, 2H, J=0.9Hz), 7.74-7.78 (t, 3H), 7.84-7.86 (d, 1H, J=6.42Hz), 7.930-7.934 (d, 1H, J=1.26Hz), 8.03 (s, 1H), 8.43 (s, 1H), 9.50 (s, 1H), 10.37 (s, 1H) .ESI-MS:m/z 561 [M+H]⁺.

24 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -2- chlorobenzamide (I-3) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -2- chlorobenzamide, using the preparation of I-1 Method prepares I-3, obtains faint yellow solid 21mg, is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third oxygen Base) quinazoline -4- base) amino) phenyl) -2- chlorobenzamide (I-3), yield 20%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.90-1.99 (m, 2H), 2.12 (s, 3H), 2.30-2.48 (m, 10H), 3.94 (s, 3H), 4.12-4.16 (t, 2H), 7.13 (s, 1H), 7.44-7.59 (m, 4H), 7.62-7.75 (m, 4H), 7.84 (s, 1H), 8.40 (s, 1H), 9.50 (s, 1H), 10.47 (s, 1H) .ESI-MS:m/z 561 [M+H]⁺.

25 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -4- chlorobenzamide (I-4) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -4- chlorobenzamide, using the preparation of I-1 Method prepares I-4, obtains faint yellow solid 30mg, is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third oxygen Base) quinazoline -4- base) amino) phenyl) 4- chlorobenzamide (I-4), yield 15%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.90-1.99 (m, 2H), 2.12 (s, 3H), 2.25-2.48 (m, 10H), 3.94 (s, 3H), 4.12-4.16 (t, 2H), 7.13 (s, 1H), 7.58-7.61 (d, 2H, J=8.40Hz), 7.75 (s, 4H), 7.85 (s, 1H), 7.98-8.00 (d, 2H, J= 8.37Hz), 8.41 (s, 1H), 9.51 (s, 1H), 10.33 (s, 1H) .ESI-MS:m/z 561 [M+H]⁺.

26 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -4- methyl benzamide (I-5) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -4- methyl benzamide, using the system of I-1 Preparation Method prepares I-5, obtains faint yellow solid 50mg, is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third oxygen Base) quinazoline -4- base) amino) phenyl) -4- methyl benzamide (I-5), yield 10%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.87-1.96 (m, 2H), 2.12 (s, 3H), 2.30-2.48 (m, 13H), 3.95 (s, 3H), 4.12-4.16 (t, 2H), 7.13 (s, 1H), 7.30-7.33 (d, 2H, J=7.98Hz), 7.66-7.78 (m, 4H), 7.87-7.88 (d, 2H, J=4.23Hz), 8.40 (s, 1H), 9.54 (s, 1H), 10.17 (s, 1H) .ESI-MS:m/z 541 [M+H]⁺.

27 N- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -4- methoxy benzamide (I-6) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -4- methoxy benzamide, using I-1's Preparation method prepares I-6, obtains faint yellow solid 54mg, is N- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third Oxygroup) quinazoline -4- base) amino) phenyl) -4- methoxy benzamide (I-6), yield 20%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.87-1.97 (m, 2H), 2.13 (s, 3H), 2.30-2.48 (m, 10H), 3.83 (s, 3H), 3.94 (s, 3H), 4.12-4.17 (t, 2H), 7.03-7.06 (d, 2H, J=8.85Hz), 7.13 (s, 1H), 7.70-7.77 (m, 4H), 7.83 (s, 1H), 7.94-7.97 (d, 2H, J=8.79Hz), 8.40 (s, 1H), 9.44 (s, 1H), 10.07 (s, 1H) .ESI-MS:m/z 557[M+H]⁺.

28 N- of embodiment (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzene Base) benzamide (I-7) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-7, obtains faint yellow solid 42mg, is N- (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) Quinazoline -4- base) amino) phenyl) benzamide (I-7), yield 14.8%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.25- 1.52 (m, 6H), 2.35-2.42 (m, 4H), 2.57 (s, 2H), 3.96 (s, 3H), 4.15-4.24 (t, 2H), 7.20 (s, 1H), 7.48-7.62 (m, 5H), 7.73-7.85 (m, 3H), 7.96-7.99 (d, 2H, J=6.81Hz), 8.43 (s, 1H), 9.49 (s, 1H), 10.28 (s, 1H) .ESI-MS:m/z 498 [M+H]⁺.

29 N- of embodiment (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) phenyl) -4- chlorine The preparation of benzamide (I-8)

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (3- chloropropyl) morpholine hydrochloride, using I-1's Preparation method prepares I-8, obtains faint yellow solid 70mg, is N- (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline - 4- yl) amino) phenyl) -4- chlorobenzamide (I-8), yield 20%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.81-1.98 (m, 2H), 2.07-2.50 (m, 6H), 3.41-3.72 (m, 4H), 3.96 (s, 3H), 4.18-4.33 (t, 2H), 7.17 (s, 1H), 7.61-7.63 (d, 2H, J=8.07Hz), 7.77-7.85 (d, 4H, J=22.7Hz), 7.99-8.02 (d, 2H, J= 8.16Hz), 8.43 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H) .ESI-MS:m/z 570 [M+Na]⁺.

30 N- of embodiment (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzene Base) -4- chlorobenzamide (I-9) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-9, obtains faint yellow solid 40mg, is N- (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) Quinazoline -4- base) amino) phenyl) -4- chlorobenzamide (I-9), yield 12%,¹H-NMR(DMSO-d₆, 300MHz): δ 0.98-1.51 (m, 6H), 2.28-2.50 (t, 4H), 2.64-2.84 (t, 2H), 3.96 (s, 3H), 4.23-4.52 (t, 2H), 7.20 (s, 1H), 7.61-7.63 (d, 2H, J=8.07Hz), 7.77-7.85 (d, 4H, J=23.91Hz), 7.99-8.02 (d, 2H, J=7.44Hz), 8.43 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H) .ESI-MS:m/z 532 [M+H]⁺.

31 N- of embodiment (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) phenyl) -4- first The preparation of yl-benzamide (I-10)

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (3- chloropropyl) morpholine hydrochloride, using I-1's Preparation method prepares I-10, obtains faint yellow solid 135.8mg, is N- (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline azoles Quinoline -4- base) amino) phenyl) -4- methyl benzamide (I-10), yield 43%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.92- 1.96 (t, 2H), 2.06 (s, 3H), 2.37-2.48 (m, 6H), 3.55-3.58 (t, 4H), 3.94 (s, 3H), 4.14-4.18 (t, 2H), 7.15 (s, 1H), 7.31-7.33 (d, 2H, J=8.16Hz), 7.70-7.79 (m, 4H), 7.83 (s, 1H), 7.86-7.89 (d, 2H, J=8.1Hz), 8.41 (s, 1H), 9.45 (s, 1H), 10.15 (s, 1H) .ESI-MS:m/z 566.2 [M+K]⁺.

32 N- of embodiment (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzene Base) -4- methyl benzamide (I-11) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-11, obtains faint yellow solid 73.9mg, is N- (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethoxy Base) quinazoline -4- base) amino) phenyl) -4- methyl benzamide (I-11), yield 24%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.20-1.53 (m, 6H), 2.37 (s, 3H), 2.42-2.64 (t, 4H), 2.83 (t, 2H), 3.94 (s, 3H), 4.00-4.26 (t, 2H), 7.19 (s, 1H), 7.31-7.33 (d, 2H, J=7.92Hz), 7.71-7.79 (m, 4H), 7.82- 7.89 (m, 3H), 8.41 (s, 1H), 9.49 (s, 1H), 10.16 (s, 1H) .ESI-MS:m/z 534.2 [M+Na]⁺.

33 N- of embodiment (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) phenyl) -3- chlorine The preparation of benzamide (I-12)

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (3- chloropropyl) morpholine hydrochloride, using I-1's Preparation method prepares I-12, obtains faint yellow solid 112mg, is N- (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline azoles Quinoline -4- base) amino) phenyl) -3- chlorobenzamide (I-12), yield 36%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.92- 1.96 (t, 2H), 2.36-2.48 (m, 6H), 3.55-3.58 (t, 4H), 3.94 (s, 3H), 4.14-4.18 (t, 2H), 7.15 (s, 1H), 7.56-7.58 (t, 1H), 7.64-7.66 (d, 1H, J=7.77Hz), 7.76 (s, 4H), 7.83 (s, 1H), 7.90-7.93 (d, 1H, J=7.74), 8.01 (s, 1H), 8.41 (s, 1H), 9.47 (s, 1H), 10.34 (s, 1H) .ESI-MS:m/z 570.1 [M+Na]⁺.

34 N- of embodiment (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzene Base) -3- chlorobenzamide (I-13) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-13, obtains faint yellow solid 57.8mg, is N- (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethoxy Base) quinazoline -4- base) amino) phenyl) -3- chlorobenzamide (I-13), yield 19%,¹H-NMR(DMSO-d₆, 300MHz): δ 0.81-0.86 (t, 2H), 1.33-1.51 (m, 8H), 2.47-2.74 (t, 2H), 3.94 (s, 3H), 4.20-4.29 (t, 2H), 7.18 (s, 1H), 7.53-7.58 (t, 1H), 7.64-7.66 (d, 1H, J=7.62Hz), 7.76 (s, 4H), 7.84 (s, 1H), 7.90-7.93 (d, 1H, J=7.62), 8.01 (s, 1H), 8.42 (s, 1H), 9.47 (s, 1H), 10.34 (s, 1H) .ESI-MS: m/z 554.2[M+Na]⁺.

35 1- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -3- phenylurea (I-14) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) phenylurea, is prepared using the preparation method of I-1 I-14 obtains faint yellow solid 36mg, is 1- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinoline azoles Quinoline -4- base) amino) phenyl) -3- phenylurea (I-14), yield 11.1%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.89-1.97 (m, 2H), 2.04-2.48 (m, 13H), 3.93 (s, 3H), 4.13-4.17 (t, 2H), 6.94-6.97 (d, J=7.05Hz, 2H), 7.13 (s, 1H), 7.24-7.34 (m, 3H), 7.43-7.46 (d, J=8.94Hz, 2H), 7.62-7.65 (d, J=8.82Hz, 2H), 542 [M+ of 7.81 (s, 1H), 8.26 (s, 1H), 8.38 (s, 1H), 8.64 (s, 1H), 9.38 (s, 1H) .ESI-MS:m/z H]⁺.

36 1- of embodiment (4- chlorphenyl) -3- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinoline Oxazoline -4- base) amino) phenyl) and urea (I-15) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -4- chlorobenzene urea, using the preparation method of I-1 I-15 is prepared, faint yellow solid 55mg is obtained, is 1- (4- chlorphenyl) -3- (4- ((6- methoxyl group -7- (3- (4- methyl piperazine - 1- yl) propoxyl group) quinazoline -4- base) amino) phenyl) urea (I-15), yield 21%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.88-2.07 (m, 2H), 2.15 (s, 3H), 2.34-2.48 (m, 10H), 3.93 (s, 3H), 4.12-4.16 (t, 2H), 7.12 (s, 1H), 7.28-7.31 (d, J=8.70Hz, 2H), 7.38-7.50 (m, 4H), 7.63-7.66 (d, J=8.76Hz, 2H), 7.81 (s, 1H), 7.38 (s, 1H), 8.76 (s, 1H), 8.87 (s, 1H), 9.38 (s, 1H) .ESI-MS:m/z 576 [M+H]⁺.

37 1- of embodiment (3- chlorphenyl) -3- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinoline Oxazoline -4- base) amino) phenyl) and urea (I-16) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -3- chlorobenzene urea, using the preparation method of I-1 I-16 is prepared, faint yellow solid 40mg is obtained, is 1- (3- chlorphenyl) -3- (4- ((6- methoxyl group -7- (3- (4- methyl piperazine - 1- yl) propoxyl group) quinazoline -4- base) amino) phenyl) urea (I-16), yield 16.8%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.89-2.03 (m, 2H), 2.12 (s, 3H), 2.30-2.48 (m, 10H), 3.93 (s, 3H), 4.11-4.15 (t, 2H), 7.12 (s, 1H), 7.22-7.31 (m, 3H), 7.38 (s, 1H), 7.45-7.48 (d, J=7.41Hz, 2H), 7.631-7.639 (d, J= 2.4Hz, 2H), 7.72 (s, 1H), 7.82 (s, 1H), 8.26 (s, 1H), 8.38 (s, 1H), 9.41 (s, 1H) .ESI-MS:m/z 576[M+H]⁺.

38 1- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -3- o-methyl-benzene urea (I-17) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -2- methyl phenylurea, using the preparation side of I-1 Method prepares I-17, obtains faint yellow solid 60mg, is 1- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) Quinazoline -4- base) amino) phenyl) -3- o-methyl-benzene urea (I-17), yield 20.5%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.88-1.97 (m, 2H), 2.12 (s, 3H), 2.24 (s, 3H), 2.33-2.48 (m, 10H), 3.94 (s, 3H), 4.12-4.16 (t, 2H), 7.12-7.25 (m, 4H), 7.47-7.48 (d, J=1.56Hz, 2H), 7.63-7.64 (d, J=1.92Hz, 2H), 7.85-7.96 (m, 3H), 8.38 (s, 1H), 8.98-9.03 (d, 1H), 9.37 (s, 1H) .ESI-MS:m/z 556 [M+H]⁺.

39 1- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) phenyl) -3- (3,4- 3,5-dimethylphenyl) urea (I-18) preparation

N- (4- aminophenyl) benzamide is replaced with N- (4- aminophenyl) -3,4- dimethyl phenylurea, using the system of I-1 Preparation Method prepares I-18, obtains faint yellow solid 25mg, is 1- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third Oxygroup) quinazoline -4- base) amino) phenyl) -3- (3,4- 3,5-dimethylphenyl) urea (I-18), yield 11.7%,¹H-NMR (DMSO-d₆, 300MHz): δ 1.88-2.00 (m, 2H), 2.19 (s, 6H), 2.30 (s, 1H), 2.40-2.48 (m, 10H), 3.93 (s, 3H), 4.12-4.16 (t, 2H), 7.12 (s, 1H), 7.18-7.26 (m, 2H), 7.44-7.47 (d, J=8.79Hz, 2H), 7.55-7.65 (m, 3H), 7.81 (s, 1H), 8.03 (s, 1H), 8.38 (s, 1H), 8.96 (s, 1H), 9.38 (s, 1H) .ESI- MS:m/z 570 [M+H]⁺.

40 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- Base) amino) phenyl) and -3- phenylurea (I-19) preparation

N- (4- aminophenyl) benzamide is replaced with N- (the chloro- 4- aminophenyl of 2-) phenylurea, using the preparation method of I-1 I-19 is prepared, faint yellow solid 25mg is obtained, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third oxygen Base) quinazoline -4- base) amino) phenyl) -3- phenylurea (I-19), yield 14%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.88- 1.91 (d, J=10.08Hz, 2H), 2.13 (s, 3H), 2.32-2.48 (m, 10H), 3.94 (s, 3H), 4.14-4.36 (t, 2H), 6.97-7.33 (m, 6H), 7.44-7.47 (d, J=7.71Hz, 1H), 7.68 (s, 1H), 7.80 (s, 1H), 8.05-8.11 (t, 2H), 8.27 (s, 1H), 8.46 (s, 1H), 9.47 (s, 1H) .ESI-MS:m/z 576 [M+H]⁺.

41 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- Base) amino) phenyl) and -3- o-methyl-benzene urea (I-20) preparation

N- (4- aminophenyl) benzamide is replaced with N- (the chloro- 4- aminophenyl of 2-) -2- methyl phenylurea, using I-1's Preparation method prepares I-20, obtains faint yellow solid 30mg, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methyl piperazine - 1- yl) propoxyl group) quinazoline -4- base) amino) phenyl) -3- o-methyl-benzene urea (I-20), yield 10.4%,¹H-NMR(DMSO- d₆, 300MHz): δ 1.88-1.96 (m, 2H), 2.13 (s, 3H), 2.26 (s, 1H), 2.34-2.48 (m, 10H), 3.95 (s, 3H), 4.13-4.17 (t, 2H), 6.95-6.98 (d, J=7.62Hz, 1H), 7.10-7.26 (m, 3H), 7.66-7.69 (d, J= 8.85Hz, 1H), 7.76-7.86 (m, 2H), 8.03-8.08 (t, 2H), 8.46 (s, H), 8.52-8.58 (d, J=16.92Hz, 1H), 8.62-8.68 (d, J=19.77Hz, 1H), 9.47 (s, 1H) .ESI-MS:m/z 590 [M+H]⁺.

42 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- Base) amino) phenyl) and -3- (the chloro- 4- fluorophenyl of 3-) urea (I-21) preparation

N- (4- aminophenyl) benzamide is replaced with N- (the chloro- 4- aminophenyl of 2-) the chloro- 4- fluorobenzene urea of -3-, using I-1 Preparation method prepare I-21, obtain faint yellow solid 45mg, be 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- (4- methyl piperazine Piperazine -1- base) propoxyl group) quinazoline -4- base) amino) phenyl) -3- (the chloro- 4- fluorophenyl of 3-) urea (I-21), yield 12%,¹H- NMR(DMSO-d₆, 300MHz): δ (ppm) 2.07 (m, 2H), 2.47 (s, 3H), 2.82-3.00 (m, 10H), 3.98 (s, 3H), 4.22 (t, 2H), 7.20 (s, 1H), 7.25-7.27 (m, 1H), 7.32-7.38 (m, 1H), 7.58-7.61 (d, J=8.91Hz, 1H), 7.82-7.84 (d, J=4.98Hz, 1H), 7.90 (s, 1H), 8.01 (s, 1H), 8.18-8.21 (d, J=8.97Hz, 1H), 8.44 (s, 1H), 8.81 (s, 1H), 9.60 (s, 1H), 10.74 (s, 1H) .HRMS (ESI): m/z calcd for (C₃₀H₃₂Cl₂FN₇O₃+H)⁺: 628.2；Found:628.2004.

43 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) phenyl) - The preparation of 3- (4- chlorphenyl) urea (I-22)

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (3- chloropropyl) morpholine hydrochloride, using I-1's Preparation method prepares I-22, obtains faint yellow solid 90mg, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline Oxazoline -4- base) amino) phenyl) -3- (4- chlorphenyl) urea (I-22), yield 26.7%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.79-2.12 (m, 2H), 2.36-2.63 (m, 6H), 3.46-3.69 (t, 4H), 3.94 (s, 3H), 4.15-4.38 (t, 2H), 7.16 (s, 1H), 7.31-7.33 (d, J=7.8Hz, 2H), 7.47-7.50 (d, J=8.34Hz, 2H), 7.67-7.70 (d, J= 7.77Hz, 1H), 7.80 (s, 1H), 7.93-8.08 (t, 2H), 8.28 (s, 1H), 8.46 (s, 1H), 9.44-9.48 (d, J= 10.53Hz, 2H) .ESI-MS:m/z 619 [M+Na]⁺.

44 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) phenyl) - The preparation of 3- (3,4- 3,5-dimethylphenyl) urea (I-23)

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (3- chloropropyl) morpholine hydrochloride, using I-1's Preparation method prepares I-23, obtains faint yellow solid 34mg, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinoline Oxazoline -4- base) amino) phenyl) -3- (3,4- 3,5-dimethylphenyl) urea (I-23), yield 29%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.93 (m, 2H), 2.13-2.17 (d, 6H), 2.35-2.42 (m, 6H), 3.48-3.62 (m, 4H), 3.94 (s, 3H), 4.15 (t, 2H), 7.00-7.02 (d, J=7.86Hz, 1H), 7.15-7.23 (m, 3H), 7.66-7.68 (d, J= 8.04Hz, 1H), 7.83 (s, 1H), 8.06-8.09 (d, J=11.49Hz, 2H), 8.29 (s, 1H), 8.45 (s, 1H), 9.30 (s, 1H), 9.53 (s, 1H) .HRMS (ESI): m/z calcd for (C₃₁H₃₅ClN₆O₄+H)⁺: 591.2481；Found: 591.2483.

45 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) ammonia Base) phenyl) -3- (4- chlorphenyl) urea (I-24) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-24, obtains faint yellow solid 50mg, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (2- (piperidin-1-yl) second Oxygroup) quinazoline -4- base) amino) phenyl) -3- (4- chlorphenyl) urea (I-24), yield 26%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.36-1.60 (m, 6H), 2.70-2.75 (t, 4H), 2.86-2.92 (t, 2H), 3.94 (s, 3H), 4.20-4.24 (s, 2H), 7.04 (s, 1H), 7.20 (s, 1H), 7.31-7.34 (d, J=8.8Hz, 2H), 7.47-7.50 (d, J=8.34Hz, 2H), 7.67-7.70 (d, J=9.21Hz, 1H), 7.79 (s, 1H), 7.93 (s, 1H), 8.05-8.06 (d, J=2.07Hz, 1H), 8.29 (s, 1H), 8.40-8.46 (d, J=18Hz, 1H), 9.43-9.49 (t, 1H) .ESI-MS:m/z 581 [M+H]⁺

46 1- of embodiment (the chloro- 4- of 2- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) ammonia Base) phenyl) -3- (3,4- 3,5-dimethylphenyl) urea (I-25) preparation

1- (3- chloropropyl) -4- methyl piperazine dihydrochloride is replaced with N- (2- chloroethyl) piperidine hydrochlorate, using I-1's Preparation method prepares I-25, obtains faint yellow solid 40mg, is 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (2- (piperidin-1-yl) second Oxygroup) quinazoline -4- base) amino) phenyl) -3- (3,4- 3,5-dimethylphenyl) urea (I-25), yield 12%,¹H-NMR(DMSO- d₆, 300MHz): δ 1.40 (m, 2H), 1.52 (m, 4H), 2.13-2.17 (d, 6H), 2.50-2.90 (m, 6H), 3.94 (s, 3H), 4.25 (t, 2H), 7.00-7.03 (d, J=10.11Hz, 1H), 7.15 (d, 1H), 7.21-7.23 (d, J=7.59Hz, 2H), 7.65 (d, 1H), 7.82 (s, 1H), 8.05-8.08 (m, 2H), 8.23 (s, 1H), 8.46 (s, 1H), 9.20 (s, 1H), 9.51 (s, 1H) .HRMS (ESI): m/z calcd for (C₃₁H₃₅ClN₆O₃+H)⁺: 575.2532；Found:575.2531.

47 2- of embodiment (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) propoxyl group) quinazoline -4- base) ammonia Base) benzamido) methyl acetate (I-26) preparation

N- (4- aminophenyl) benzamide is replaced with 2- (4- aminobenzamide) methyl acetate, using the preparation of I-1 Method prepares I-26, obtains faint yellow solid 148.2mg, is 2- (4- ((6- methoxyl group -7- (3- (4- methylpiperazine-1-yl) third Oxygroup) quinazoline -4- base) amino) benzamido) methyl acetate (I-26), yield 72.3%,¹H-NMR(DMSO-d₆, 300MHz): δ 2.03-2.05 (m, 2H), 2.48 (s, 3H), 2.62-3.16 (m, 10H), 3.65 (s, 3H), 3.98 (s, 3H), 4.00-4.02 (d, J=5.76Hz, 2H), 4.21 (t, 2H), 7.21 (s, 1H), 7.87-7.95 (m, 4H), 7.96 (s, 1H), 8.67 (s, 1H), 8.89-8.93 (t, 1H), 10.23 (s, 1H) .HRMS (ESI): m/z calcd for (C₂₇H₃₄N₆O₅+H)⁺: 523.2663；Found:523.2671.

48 2- of embodiment (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) amino) benzamide Base) methyl acetate (I-27) preparation

N- (4- aminophenyl) benzamide is replaced with 2- (4- aminobenzamide) methyl acetate, using the preparation of I-1 Method prepares I-27, obtains faint yellow solid 55.7mg, is 2- (4- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline - 4- yl) amino) benzamido) methyl acetate (I-27), yield 45%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.93-1.97 (m, 2H), 2.40-2.48 (m, 6H), 3.51-3.61 (m, 4H), 3.64 (s, 3H), 3.96 (s, 3H), 3.99-4.01 (d, J= 5.46Hz, 2H), 4.17 (t, 2H), 7.19 (s, 1H), 7.85 (s, 1H), 7.87-7.98 (m, 4H), 8.51 (s, 1H), 8.82- 8.86 (t, 1H), 9.62 (s, 1H) .HRMS (ESI): m/z calcd for (C₂₆H₃₁N₅O₆+H)⁺: 510.2347；Found: 510.2358.

49 2- of embodiment (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzene first Amide groups) methyl acetate (I-28) preparation

By the chloro- 6- methoxyl group -7- of 4- (2- (piperidin-1-yl) ethyoxyl) quinazoline (20mg, 0.06mmol), 2- (4- ammonia Yl-benzamide) methyl acetate (13mg, 0.06mmol), isopropanol 1ml, one drop dilute hydrochloric acid (concentrated hydrochloric acid isopropanol floride of dropwise addition Release 20 times), reaction flask is added, is heated to 90 DEG C, reacts 12h, stops heating, is cooled to room temperature, filters, dries to obtain 11.2mg, For 2- (4- ((6- methoxyl group -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -4- base) amino) benzamido) methyl acetate (I-28), yield 36.6%,¹H-NMR(DMSO-d₆, 300MHz): δ 1.30-1.40 (m, 2H), 1.42-1.53 (m, 4H), 2.35-2.47 (m, 4H), 2.71 (t, 2H), 3.64 (s, 3H), 3.95 (s, 3H), 3.98-4.00 (d, J=5.46Hz, 2H), 4.22 (t, 2H), 7.22 (s, 1H), 7.84 (s, 1H), 7.87-7.97 (m, 4H), 8.51 (s, 1H), 8.81-8.91 (t, 1H), 9.63 (s, 1H) .HRMS (ESI): m/z calcd fbr (C₂₆H₃₁N₅O₅+H)⁺: 494.2398；Found:494.2407.

Second part Biological examples

The test of 50 tumor cell in vitro inhibitory activity of embodiment

1.1 test method

Cell strain: HT-29 (human colon cancer cell), MCF-7 (human breast cancer cell), H460 (human lung adenocarcinoma cell)

Cell covers with (about 90%), counts, contact plate, 6000, every hole, the every 100 μ l of hole point of half.Incubator culture 4-6h. After cell is adherent, the every 100 μ l. concentration of hole of dosing is respectively 50 μM, 10 μM, 2 μM, 0.4 μM, 0.08 μM.It cultivates for 24 hours, every hole Add the MTT (5mg/ml) of 20 μ l.The liquid in 96 orifice plates is all sopped up after 4h, the DMSO of 100 μ l is added.Finally it is in wavelength Absorbance is detected under 570nm.Data processing calculates IC₅₀。

1.2 test result

Test result is shown in Table 1

The external protein kinase of embodiment 51 inhibits test

Using Caliper Mobility Shift Assay, reference compound staurosporine, concentration gradient is adopted With 20 μM, 2 μM, 0.2 μM, 0.02 μM, 0.002 μM, inhibition of the compound to EGFR and VEGFR-2 is measured under ATP Km concentration Activity.

Test result is shown in Table 1.

1 Compound ira vitro anti-tumour cell proliferative activity of table and enzymatic activity data

N.D.Not determined.

Above be synthesis part 4- substituted aniline quinazoline derivative to tumor cell line (HT-29, MCF-7, ) and the inhibitory activity data of protein kinase (EGFR, VEGFR-2) H460.The result shows that 4- substituted aniline quinazoline derivative It is with higher inhibit growth of tumour cell activity, and for simultaneously for EGFR and VEGFR-2 multiple target point inhibitor.

Claims

1. a kind of 4- substituted aniline quinazoline derivative shown in formula I；

In formula, R₁For C₁~C₃Alkoxy；R₂The C replaced for substituted-amino₁~C₆Alkoxy, wherein the substitution on substituted-amino Base cyclization together with the amino nitrogen atom becomes 4~9 yuan of saturated heterocyclics；When saturated heterocyclic additionally contains 1~2 hetero atom When, hetero atom is nitrogen, oxygen or sulphur；It is unsubstituted on nitrogen or by C if the hetero atom is nitrogen₁~C₆Alkyl replaces；

R₃、R₄、R₅、R₆、R₇、R₈、R₉For hydrogen, C₁~C₃Alkyl, C₁~C₃Any one of alkoxy, halogen or cyano；

L is-NHCONH-；

R₁₀For substituted or unsubstituted C₁~C₈Alkyl, substituted or unsubstituted C₃~C₉Naphthenic base, substituted or unsubstituted C₆~ C₁₄Aryl, substituted or unsubstituted C₁~C₁₃Heteroaryl it is any；Wherein the substituent group in the alkyl is 4~9 yuan of saturations Heterocycle, the hetero atom number of saturated heterocyclyl are 1~4, and hetero atom is nitrogen, oxygen or sulphur；Substituent group in the naphthenic base is C₁~C₃Alkyl, C₁~C₃Alkoxy or halogen；Substituent group in the aryl or heteroaryl is C₁~C₃Alkyl, C₁~C₃Halogen Substituted alkyl, C₁~C₃Alkoxy, C₂~C₃Alkenyl, C₂~C₃One or more of alkynyl, halogen or cyano, the position of substitution are virtue Any substitutive position on base or heteroaryl, related hetero atom are nitrogen, oxygen or sulphur, and hetero atom number is 1~5.

2. 4- substituted aniline quinazoline derivative as described in claim 1, it is characterised in that R₁For methoxyl group；R₂To replace The C that amino replaces₁~C₃Alkoxy, wherein the cyclization together with the amino nitrogen atom of substituent group on substituted-amino becomes morphine Quinoline, piperidines or piperazine；R₃、R₄、R₅、R₆、R₇、R₉It is hydrogen；R₈For any one of hydrogen, fluorine, chlorine, bromine.

3. 4- substituted aniline quinazoline derivative application in preparation of anti-tumor drugs as claimed in claim 1 or 2.

4. 4- substituted aniline quinazoline derivative application in preparation of anti-tumor drugs as claimed in claim 3, special Sign is_∶The tumour be skin, brain, lung, lymph, kidney, liver, stomach, colon, rectum, bladder, prostate, mammary gland, Thyroid gland, oesophagus, the tumour of pancreas or malignant hematologic disease.