CN1882576A

CN1882576A - Quinazoline derivatives

Info

Publication number: CN1882576A
Application number: CN 200480033524
Authority: CN
Inventors: L·F·A·亨内奎恩; C·T·哈尔萨尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-09-16
Filing date: 2004-09-13
Publication date: 2006-12-20
Also published as: ZA200602188B; GB0321621D0; ZA200603039B; CN1882577A

Abstract

The invention concerns quinazoline derivatives of the Formula (I); wherein each of R<1>, R<2>, W, X<1>, X<2>, Z, a and b are as defined in the description; processes for their preparation; pharmaceutical compositions containing them and their use in the manufacture of a medicament for providing an anti-proliferative effect. The quinazoline derivatives of Formula (I) are expected to be useful in the treatment of diseases such as certain cancers mediated by erbB receptor tyrosine kinases, particularly EGFR tyrosine kinase.

Description

Quinazoline derivant

The present invention relates to some novel quinazoline derivant, or their pharmacy acceptable salt, they have anti-tumor activity and are useful in human or animal's methods of treatment therefore.The invention still further relates to the preparation method of described quinazoline derivant, relate to the medicinal compositions that contains them and the purposes in methods of treatment, for example prevention or treatment warm-blooded animal such as the purposes in the preparation of the medicine of people's solid tumor disease.

The disease that causes for the improper adjusting of being undertaken by on cell proliferation is psoriasis and treatment for cancer for example, and present most of method is to use the compound that suppresses the synthetic and cell proliferation of DNA.Up to date, the general pair cell of compound that uses in the treatment of this class has toxicity, but for example the effect of cancer cells is stronger to quick splitted cell, is favourable therefore.Developing the another kind of method of cytotoxin antitumour drug, for example cell signaling approach restrainer optionally.The inhibitor of this class type can have has stronger selectivity therefore can reduce the potentiality of the unnecessary side effect of therapeutic process to cancer cells.

Eukaryotic cell is constantly to making the mutual alternative extracellular various signals of iuntercellular react in organism.The intracellular various physiological responses of this class Signal Regulation comprise propagation, differentiation, apoptosis and reactivity.The extracellular signal is taked the form of various soluble factors, comprises somatomedin and paracrine and endocrine factor.By with the special receptor combination of crossing over cytolemma, this class part makes that signal transduction path combines in extracellular signal and the cell, thereby signal was transmitted plasma membrane and allowed individual cells pair cell external signal to react.Most of this class signal conversion process has been utilized the proteinic reversible phosphorylation process that promotes various cell responses that participates in.The phosphorylation state of target protein is to be regulated by specific kinases and Phosphoric acid esterase, all protein that the mammalian genes group is coded wherein 1/3rd be responsible for adjusting by this class kinases and phosphoric acid.Because phosphorylation is very important regulation mechanism in the signal conductive process, so to the abnormal cell growth that causes by conduction abnormalities in this class cell and differentiation and promote just not to be astonished transformation (summary is not seen Cohen etc., Curr Opin Chem Biol, 1999,3,459-465).

Many these class tyrosine sport the constitutively activate form and/or have served as scale when reaching, and just cause human various kinds of cell to transform, and this is broadly understood.The kinases form of sudden change of this class and overexpression be present in most of ratio of human tumor (summary is seen Kolibaba etc., Biochimica et Biophysica Acta, 1997,133, F217-F248).Because Tyrosylprotein kinase is the important role of performer in the propagation of many tissues and differentiation, so be the center of interest with this fermentoid all much in the exploitation of new antitumoral methods of treatment.It is that acceptor and nonreceptor tyrosine kinase for example are respectively EGF acceptor and SRC family that this enzyme family is divided into two groups.From comprising many results of study of the Human Genome Project, about 90 kinds of Tyrosylprotein kinases determine at human genome, this wherein 58 kinds be receptor type, 32 kinds is non-receptor type.This class can be divided into 20 kinds of receptor tyrosine kinases and 10 kinds of nonreceptor tyrosine kinase subfamilies (Robinson etc., Oncogene, 2000,19,5548-5557).

Receptor tyrosine kinase is propagated at the mitotic division signal that trigger cell duplicates special vital role.The glycoprotein across cytoplasmic membrane that this class is big has the land, extracellular to they specific ligand (being Urogastron (EGF) to the EGF acceptor for example).The combination of part makes by the coded receptor kinase enzymic activity activation of the part of intracellular receptor.This activity has produced the result that proliferation signal passes through the plasma membrane of cell with the amino acid phosphorylation of the crucial tyrosine on the target protein.

The erbB family of known receptor Tyrosylprotein kinase comprises EGFR, erbB2, and erbB3 and erbB4 are in the frequent propagation that participates in the promotion cancer cells and the activity of survival (summary is seen Olayioye etc., EMBO J., 2000,19,3159).This one of them sophisticated mechanism is that acceptor is in the excessive expression of protein level, the result that this is normally caused by gene amplification.This phenomenon is observed (summary is seen Klapper etc., Adv.Cancer Res., 2000,77,25), for example mammary cancer (Sainsbury etc., Brit.J.Cancer, 1988,58,458 in many general population's cancers; Guerin etc., Oncogene Res., 1988,3,21; Slamon etc., Science, 1989,244,707; Klijn etc., Breast Cancer Res.Treat., 1994,29,73 and summary see Salomon etc., Crit.Rev.Oncol.Hemato., 1995,19,183), nonsmall-cell lung cancer (NSCLCs) comprises gland cancer (Cerny etc., Brit.J.Cancer, 1986,54,265; Reubi etc., Int.J.Cancer, 1990,45,269; Rusch etc., Cancer Research, 1993,53,2379; Brabender etc., Clin.Cancer Res., 2001,7,1850) and other lung cancer (Hendler etc., Cancer Cells, 1989,7,347; Ohsaki etc., Oncol.Rep., 2000,7,603), bladder cancer (Neal etc., Lancet, 1985,366; Chow etc., Clin.Cancer Res., 2001,7,1957, Zhau etc., Mol Carcinog., 3,254), the esophageal carcinoma (Mukaida etc., Cancer, 1991,68,142), gastrointestinal cancer is colon for example, rectum or cancer of the stomach (Bolen etc., Oncogene Res., 1987,1,149; Kapitanovic etc., Gastroenterolosv.2000,112,1103; Ross etc., Cancer Invest., 2001,19,554), prostate cancer (Visakorpi etc., Histochem.J., 1992,24,481; Kumar etc., 2000,32,73; Scher etc., J.Natl.Cancer Inst., 2000,92,1866), leukemia (Konaka etc., Cell, 1984,37,1035, Martin-Subero etc., Cancer GenetCytogenet., 2001,127,174), ovarian cancer (Hellstrom etc., Cancer Res., 2001,61,2420), neck tumour (Shiga etc., Head Neck, 2000,22,599) or carcinoma of the pancreas (Ovotny etc., Neoplasm, 2001,48,188).When increasing body tumor tissue detects the expression of receptor tyrosine erbB family, can predict in the further enhancing of their popular and importance in the future.

As the result that the mistake of one or more these receptoroids is regulated, think deteriorations that become clinically of many tumours widely, so and patient worse prognosis interrelate (Brabender etc., Clin.Cancer Res., 2001,7,1850 are arranged; Ross etc., CancerInvestigation, 2001,19,554; Yu etc., Bioessays, 2000,22.7,673).Except the discovery clinically of this class, the erbB family of a large amount of clinical preceding information hint receptor tyrosine kinases participates in the process of cell transformation.This has comprised that this class observe phenomena is one or more erbB acceptors of many tumor cell line overexpressions, and when transfected when advancing non-tumor cell EGFR or erbB2 have the ability that transforms this class cell.Along with the transgenic mice of overexpression erbB2 spontaneous at the mammary gland place develop into tumour, further verified to cause the tumour potentiality.In addition, a large amount of preclinical studies shows the activity that knocks out one or more erbB by micromolecular inhibitor, dominance feminine gender or inhibiting antibody, can impel antiproliferative effect (summary is seen Mendelsohn etc., Oncogene, 2000,19,6550).This receptoroid tyrosine kinase inhibitor has value (Yaish etc., Science, 1988,242 as the selective depressant of mammalian cancer cells propagation, 933, Kolibaba etc., Biochimica etBiophysica Acta, 1997,133, F217-F248; Al-Obeidi etc., 2000, Oncogene, 19,5690-5701; Mendelsohn etc., 2000, Oncogene, 19,6550-6565).Except the preclinical data of this class, the inhibiting antibody that find to use EGFR and erbB2 (being respectively c-225 and trastuzumab) to selectivity solid tumor clinical treatment be effectively (summary is seen Mendelsohn etc., 2000, Oncogene, 19,6550-6565).

Detected erbB type receptors Tyrosylprotein kinase member's amplification and/or activity, and hint is in many non-malignant proliferation disorders psoriasis (Ben-Bassat, Curr.Pharm.Des., 2000,6,933 for example; Elder etc., Science, 1989,243,811), benign prostatic hyperplasia (BPH) (Kumar etc., Int.Urol.Nephrol., 2000,32,73) is bringing into play acting in arteriosclerosis and the restenosis (Bokemeyer etc., Kidney Int., 2000,58,549).Therefore predict that erbB type receptors tyrosine kinase inhibitor is effective to the treatment of the non-pernicious disorder of excessive cell proliferative.

European patent application EP 566226 discloses some 4-quinazoline compounds of receptor tyrosine kinase inhibitors.

International Patent Application Publication No. WO 96/33977, WO 96/33978, WO96/33979, WO 96/33980, WO 96/33981, WO 97/30034 and WO97/38994 disclose some quinazoline derivant, they have the activity that suppresses receptor tyrosine kinase, 4 at them have the anilino substituting group at 6,7 replacement to be arranged also simultaneously.

European patent application EP 837063 discloses the 4-anilinoquinazoline derivatives that aryl replaces, and its integral part has aryl or heteroaryl 6 or 7 of quinazoline ring.It is effective that this compounds it is said to the high proliferation disorder treatment.

International Patent Application Publication No. WO 97/30035 and WO 98/13354 disclose the 4-anilinoquinazoline compounds of some 7 substd, and they are inhibitor of vascular endothelial growth factor receptor Tyrosylprotein kinase.

International Patent Application Publication No. WO 00/55141, WO 00/51991 and WO02/18372 disclose the 4-anilinoquinazoline compounds of 6,7 substds, it is characterized in that at 6 and/or 7 ester connection portion (RO-CO) or lactonic ring being arranged.

International Patent Application Publication No. WO 00/56720 discloses treatment cancer or anaphylactoid 6,7-dialkoxy-4-anilinoquinazoline compounds.

International Patent Application Publication No. WO 98/02434, WO 99/35132, WO00/44728 and WO 01/98277 disclose 4-anilinoquinazoline compounds, they 6 and/or 7 substituted pyrrolidyl-alkoxyl groups or piperidyl-alkoxyl group replace.

International Patent Application Publication No. WO 98/02434, WO 99/35132, WO00/44728 and WO 01/9827 disclose 4-anilinoquinazoline compounds, and wherein aniline group is contained aryl or heteroaryl moieties replacement.

Other 4-anilinoquinazoline analog derivative of our surprised discovery now has potent anti-tumor activity.We do not think only to hint that by acting on a kind of biological procedures compound disclosed by the invention has pharmacological activity, the antitumor curative effect that we be sure of this compound reaches by suppressing one or more receptor tyrosine kinase erbB family, and this receptoroid Tyrosylprotein kinase participates in the signal conduction step that causes tumor cell proliferation.More particularly, compound of the present invention reaches antitumor curative effect by suppressing EGFR and/or erbB2 receptor tyrosine kinase.

Common compound of the present invention has the activity of effective inhibition erbB2 receptor tyrosine kinase family, for example suppresses EGFR and/or erbB2 and/or erbB4 receptor tyrosine kinase, simultaneously to other kinase whose inhibition a little less than.In addition, some compound of the present invention is more much better than than erbB2 receptor tyrosine kinase to the inhibition of EGFR.The present invention has also comprised having the active compound that suppresses whole EGFR, erbB2 and erbB4 receptor tyrosine kinase or its combination, thereby they reach the potential curative effect by suppressing one or more these receptoroid Tyrosylprotein kinases.

Common compound of the present invention shows favourable physical properties, and for example the high while of solvability is keeping high antiproliferative activity again.Many compounds of the present invention have favourable DMPK characteristic, high and/or the favourable transformation period of the high and/or free plasma concentration of biological example availability, predict that simultaneously this class feature has better therapeutic in vivo, and the EGFR tyrosine kinase inhibitor of this medicine and for example Gefitinib relatively can reduce interpatient individual difference.In addition, a lot of these compounds of the present invention do not have activity or weak activity are only arranged in hERG analyzes.

The quinazoline derivant of formula I is provided according to first part of the present invention:

Wherein:

R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, or the group of following formula:

Q ¹-X ³

X wherein ³Be O or S, Q ¹Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹The optional group that is inserted in the chain of adjacent C atom in any (2-6C) alkylidene chain in the substituting group is separated, and described group is selected from O, S, SO, SO ₂, N (R ⁴), CO, CH (OR ⁴), CON (R ⁴), N (R ⁴) CO, SO ₂N (R ⁴), N (R ⁴) SO ₂, CH=CH and C ≡ C, wherein R ⁴Be hydrogen or (1-6C) alkyl,

Wherein at R ¹Any CH in the substituting group ₂=CH-or HC ≡ C-base are at CH ₂=or the optional substituting group that has of HC ≡ end, described substituting group be selected from halogen, carboxyl, formamyl, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or be selected from the group of following formula:

-Q ²-X ⁴

X wherein ⁴Be connecting key or be selected from CO and N (R ⁵) CO, wherein R ⁵Be hydrogen or (1-6C) alkyl, Q ²Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

Wherein at R ¹Any alkyl in the substituting group or alkylidene group be optional have one or more halogens, (1-6C) alkyl, hydroxyl, cyano group, amino, carboxyl, formamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl amido of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, NThe alkane sulfonamido of-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfonamido and N-(1-6C) alkyl-(1-6C), or be selected from the group of following formula:

-X ⁵-Q ³

X wherein ⁵Be connecting key or be selected from O, S, SO, SO ₂, N (R ⁶), CO, CH (OR ⁶), CON (R ⁶), N (R ⁶) CO, SO ₂N (R ⁶), N (R ⁶) SO ₂, C (R ⁶) ₂O, C (R ⁶) ₂S and C (R ⁶) ₂N (R ⁶), R wherein ⁶Be hydrogen or (1-6C) alkyl, Q ³Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

Wherein at R ¹Any heterocyclic radical in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; this class substituting group can be identical or different, they be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl amido of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfonamido of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ⁷

X wherein ⁶Be connecting key or be selected from O, N (R ⁸) and C (O), wherein R ⁸Be hydrogen or (1-6C) alkyl, R ⁷Be alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), carboxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of the alkyl of the alkyl of alkyl, (2-6C) alkanoylamino-(1-6C), (1-6C) alkoxycarbonyl amido-(1-6C), formamyl-(1-6C), N-(1-6C) alkyl of alkyl-carbamoyl-(1-6C), N, NAlkyl of the alkyl of-two-[(1-6C) alkyl] formamyls-(1-6C), (2-6C) alkyloyl-(1-6C) or (1-6C) alkyl of carbalkoxy-(1-6C),

Wherein at R ¹Any heterocyclic radical in the last substituting group is optional to have 1 or 2 oxos or sulfo-substituting group;

X ¹Be (C (R ⁹) ₂) _n, each R wherein ⁹Can be identical or different, be selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, (1-4C) alkyl, halogen (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (3-7C) cycloalkyl and (3-7C) cycloalkyl-(1-4C) alkyl, or two R ⁹Group forms (3-7C) cycloalkyl ring with the carbon that connects them, and n is 1 or 2, and condition is to work as R ⁹Group is a hydroxyl or (1-4C) during alkoxyl group, n is 2, connect hydroxyl or (1-4C) carbon atom of alkoxyl group no longer be connected with other oxygen or nitrogen-atoms.

Q ^aBe the undersaturated heterocyclic radical of saturated or part of non-aromaticity, heterocyclic radical contains a nitrogen heteroatom and optional 1,2 or 3 other heteroatoms that is selected from O, S and N, and described group passes through Q ^aIn heteroatoms and the X among the formula I ¹Link to each other;

Q is 0,1,2,3 or 4;

Each W; can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, oxo, amino, carboxyl, formamyl, amino-sulfonyl, formyl radical, sulfydryl, (1-6C) alkyl, (1-6C) alkoxyl group, (2-6C) thiazolinyl, (2-6C) alkynyl, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) carbalkoxy, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, N-(1-6C) alkylamino, N, N-two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, R ¹⁰Be selected from (1-6C) alkyl, its optional by one or more halogens, hydroxyl, (1-6C) alkoxyl group, cyano group, amino, N-(1-6C) alkylamino, N, N-two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl and (2-6C) alkanoyloxy replacement,

Or two W groups form (1-4C) alkylidene bridge, should (1-4C) alkylidene bridge is optional have 1,2 or 3 substituting group, and this class substituting group can be identical or different, they be selected from halogen, hydroxyl, oxo, (1-6C) alkyl, (1-6C) alkoxyl group, amino, N-(1-6C) alkylamino and N, N-two-[(1-6C) alkyl] amino;

X ²Be selected from CH ₂C (O), CH ₂SO ₂, C (O) and SO ₂

Z is selected from the alkyl of the alkyl of hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), heterocyclic radical, heterocyclic radical-(1-4C) alkyl, aryl and aryl-(1-4C),

The optional group that is inserted in the chain of adjacent carbons in any (2-6C) alkylidene chain in the Z substituting group is separated, and described group is selected from O, S, SO, SO ₂, N (R ¹²) and CO, wherein R ¹²Be selected from hydrogen and (1-6C) alkyl,

Any CH in the Z substituting group wherein ₂=CH-or HC ≡ C-base are chosen wantonly at CH ₂=or HC ≡ end have substituting group, this substituting group is selected from halogen, carboxyl, formamyl,

The wherein any alkyl in the Z substituting group, alkylidene group or (3-7C) cycloalkyl is optional has one or more halogens or (1-6C) alkyl substituent, or be selected from following substituting group: hydroxyl, cyano group, amino, carboxyl, formamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino, N-(1-6C) alkane sulfuryl amino, (3-7C) cycloalkyl and the heterocyclic radical of alkyl-(1-6C),

Wherein optionally on any aryl in the Z substituting group or the heterocyclic radical have one or more substituting groups, this class substituting group be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (1-3C) alkoxyl group, (1-4C) alkylthio, (1-4C) alkyl sulphinyl, (1-4C) alkyl sulphonyl, (2-6C) alkyloyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, (1-4C) carbalkoxy, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyls,

Wherein optionally on any heterocyclic radical in the Z substituting group have one or two oxo or sulfo-substituting group, condition is on any described oxo substituting group carbon atom that the oxygen annular atoms in heterocyclic radical is not adjacent.

R ²⁰Be hydrogen, (1-6C) alkyl, hydroxyl-(2-6C) alkyl or (1-6C) alkoxyl group (2-6C) alkyl;

A is 1,2,3,4 or 5;

Each R ³Can be identical or different, be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, N-(1-6C) alkyl amino sulfonyl and N, N-two-[(1-6C) alkyl] amino-sulfonyls;

Or its pharmacy acceptable salt.

This class foundation previous section of the present invention provides the quinazoline derivant of formula I, and it has formula IA:

Wherein:

R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, or be selected from the group of following formula:

Q ¹-X ³

R wherein ¹The optional group that is inserted in the chain of adjacent C atom in any (2-6C) alkylidene chain in the substituting group is separated, and described separation group is selected from O, S, SO, SO ₂, N (R ⁴), CO, CH (OR ⁴), CON (R ⁴), N (R ⁴) CO, SO ₂N (R ⁴), N (R ⁴) SO ₂, CH=CH and C ≡ C, wherein R ⁴Be hydrogen or (1-6C) alkyl,

-Q ²-X ⁴

-X ⁵-Q ³

-X ⁶-R ⁷

X ¹Be (C (R ⁹) ₂) _n, each R wherein ⁹Can be identical or different, be selected from hydrogen, hydroxyl, (1-4C) alkyl, halogen (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, n is 1 or 2, or two R ⁹Group forms (3-7C) cycloalkyl ring with the carbon atom that is connected them, and condition is to work as R ⁹When group was hydroxyl, n was 2;

Each W; can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, oxo, amino, carboxyl, formamyl, amino-sulfonyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) carbalkoxy, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, R ¹⁰Be (1-6C) alkyl, its optional by one or more halogens, hydroxyl, (1-6C) alkoxyl group, cyano group, amino, N-(1-6C) alkylamino, N, N-two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl and (2-6C) alkanoyloxy replacement,

X ²Be selected from C (O) and SO ₂

Z is selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl,

Any CH in the Z substituting group wherein ₂=CH-or HC ≡ C-base are chosen wantonly at CH ²=or HC ≡ end have substituting group, this substituting group is selected from halogen, carboxyl, formamyl,

Wherein any alkyl in the Z substituting group or alkylidene group are optional has one or more halogens or (1-6C) alkyl substituent, or is selected from following substituting group: hydroxyl, cyano group, amino, carboxyl, formamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C) alkane sulfuryl amino or (3-8C) cycloalkyl or heterocyclic radical, any one is all chosen wantonly by one or more and is selected from following group and replaces: halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (1-3C) alkoxyl group, (2-4C) alkene oxygen base, (2-4C) alkynyloxy group, (1-4C) alkylthio, (1-4C) alkyl sulphinyl, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, (1-4C) carbalkoxy;

X ⁸Be selected from CH ₂, O or NR ¹³, R wherein ¹³Be hydrogen, halogen, trifluoromethyl, carboxyl, formamyl, amino-sulfonyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) carbalkoxy, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁷-R ¹⁰

X wherein ⁷And R ¹⁰As defined above;

A is 1,2,3,4 or 5;

B is 0 or 1;

Q is 0,1,2,3 or 4; And

R ²⁰Be hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group (2-6C) alkyl

Or its pharmacy acceptable salt.

Preferably in the quinazoline of formula IA, work as R ⁹When being hydroxyl, n is 2, and with hydroxyl or (1-4C) carbon that links to each other of alkoxyl group no longer link to each other with another oxygen or nitrogen-atoms.

" alkyl " comprises straight chain and branched-chain alkyl in this manual, for example propyl group, sec.-propyl and the tertiary butyl, (3-8C) for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl of cycloalkyl.But only refer in particular to straight chain for one alkyl such as " propyl group ", only refer in particular to side chain such as " sec.-propyl " for one branched paraffin, for one cycloalkyl for example " cyclopentyl " only refer in particular to five-ring.Similar conversion can be done in speech for other, comprise methoxyl group, oxyethyl group, ring propoxy-and cyclopentyloxy such as (1-6C) alkoxyl group, (1-6C) alkylamino comprises methylamino-, ethylamino, ring fourth amino and hexamethylene amino, two-[(1-6C alkyl)] amino comprise dimethylamino, diethylamino, N-cyclobutyl- N-methylamino and N-cyclohexyl- N-ethylamino.

Term " aryl " is meant aromatic hydrocarbon ring for example phenyl or naphthyl, particularly phenyl.Term " heterocycle " comprises monocycle or the dicyclo ring structure of this class by 3 to 15 atomic buildings, has one at least in this class atom, has 1-4 to be for example heteroatoms of oxygen, sulphur or nitrogen in the time of suitably.Except particularly pointing out, the ring in the heterocyclic group can be aromaticity, nonaromatic or the part aromaticity, the meaning be in a warm ring system ring can be aromaticity and other part is not.The object lesson of this class ring comprises furyl, benzofuryl, tetrahydrofuran base, chromanyl, thienyl, benzothienyl, pyridyl, piperidyl, quinolyl, 1,2,3, the 4-tetrahydric quinoline group, isoquinolyl, 1,2,3, the 4-tetrahydro isoquinolyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl, quinoxalinyl, quinazolyl, the cinnolines base, pyrryl, pyrrolidyl, indyl, indolinyl, imidazolyl, benzimidazolyl-, pyrazolyl, indazolyl,  azoles base, the benzoxazol base, different  azoles base, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl, 4 H-1,4-Benzoxazinyl, 4 H-1,4-benzothiazine base, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, the  di azoly, the furazan base, thiadiazolyl group, tetrazyl, dibenzofuran group, the dibenzothiophene base, the oxirane base, oxetanyl, azetidinyl, THP trtrahydropyranyl, the oxepane alkyl, oxa-azepan base, 1, the 3-thiazolidyl, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, homopiperidinyl, high piperazinyl, the dihydropyridine base, tetrahydro pyridyl, the dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base or thio-morpholinyl.

In containing the ring of nitrogen-atoms, for the value that satisfies nitrogen-atoms requires can to have on the nitrogen-atoms hydrogen atom or the substituting group of (1-6C) alkyl for example, or nitrogen-atoms can be connected with the other parts of ring.The heterocyclic nitrogen-atoms is oxidable to be the corresponding N oxide compound.

Terminology used here " heterocycle " is meant heterocyclic substituent, and it is complete aromaticity in nature.The example that this class ring system is concrete comprises furyl, benzofuryl, thienyl, benzothienyl, pyridyl, quinolyl, isoquinolyl, pyrazinyl, pyrimidyl, pyridazinyl, quinoxalinyl, quinazolyl, the cinnolines base, pyrryl, indyl, indolinyl, imidazolyl, benzimidazolyl-, pyrazolyl, indazolyl,  azoles base, the benzoxazol base, different  azoles base, thiazolyl, benzothiazolyl, isothiazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, the  di azoly, the furazan base, thiadiazolyl group, tetrazyl, dibenzofuran group, or dibenzothiophene base.

For example Z is heteroaryl or contains heteroaryl when group, and described heteroaryl is suitable 5 Yuans or a heteroaryl group of 6 Yuans, and it contains one or more heteroatomss that are selected from oxygen, nitrogen or sulphur.Specifically 5 Yuans or 6 Yuans heteroaryl group are selected from furyl, thienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,  di azoly, furazan base, thiadiazolyl group, tetrazyl.Heteroaryl group also can be 9 Yuans or 10 Yuans bicyclic heteroaryl ring systems for example quinolyl, isoquinolyl, cinnolines base, quinazolyl, phthalazinyl, quinoxalinyl, indyl, pseudoindoyl, benzofuryl, benzothienyl, benzimidazolyl-, benzothiazolyl or purine radicals.

The object lesson of heteroaryl comprises 5 Yuans rings such as furyl, thienyl, pyrryl, pyrazolyl, imidazolyl,  azoles base, different  azoles base, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,  di azoly, furazan base, thiadiazolyl group, tetrazyl.

The object lesson of heteroaryl also comprises 9 Yuans or 10 yuan of bicyclic systems such as indyl, quinolyl, benzofuryl or benzothienyl.

Heteroaryl is selected from different  azoles base, furyl, thienyl, pyridyl, pyrazolyl, pyrryl, indyl, quinolyl, benzofuryl and benzothienyl more specifically.

In particular of the present invention, when in formula (I) definition any Q group (such as Q ¹, Q ^a, Q ²Or Q ³) when being heterocyclic radical, they are monocycles of 3 Yuans to 10 Yuans of non-aromatic saturated group (promptly have high saturation) or fractional saturations (be ring system remain with part but be not whole degrees of unsaturation), the highest in the ring have 5 heteroatomss (but not containing O-O, O-S or S-S key) that are selected from oxygen, nitrogen and sulphur, and by carbon atom on the ring or nitrogen-atoms (if ring is not 4 Yuans).To Q ¹, Q ²Or Q ³The example of fit value comprise the oxirane base, oxetanyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, the oxepane alkyl, oxa-azepan base, pyrrolinyl, pyrrolidyl, morphine quinoline base, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the dihydropyridine base, tetrahydro pyridyl, the dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro-thienyl, 1, the 3-thiazolidyl, tetrahydro thiapyran base, thio-morpholinyl, example comprises tetrahydrofuran (THF)-3-base more specifically, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-4-base, tetramethylene sulfide-3-base, 1,3-thiazolidine-3-base, tetrahydric thiapyran-4-group, tetramethyleneimine-3-base, tetramethyleneimine-2-base, 3-pyrroline-3-base, morpholino, 1,1-dioxo tetrahydrochysene-4 H-1,4-thiazine-4-base, piperidino-(1-position only), piperidin-4-yl, piperidines-3-base, piperidines-2 base, high piperidines-3-base, high piperidin-4-yl, piperazine-1-base, 1,4-oxa-azepan base, or 1,2,3,6-tetrahydropyridine-4-base.Heterocyclic nitrogen or sulphur atom are oxidable to be the oxide compound of corresponding N or S, for example, 1,1-dioxo tetrahydro-thienyl, 1-oxo tetrahydrochysene tetrahydro-thienyl, 1,1-dioxo tetrahydro thiapyran base or 1-oxo tetrahydro thiapyran base.The example that contains one or two oxo or the substituent desired value of sulfo-in the group has 2-oxo-pyrrolidine base, 2-oxo piperazinyl, 2-sulfo-pyrrolidyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidyl or 2,6-dioxopiperidine base.

Q ¹, Q ²And Q ³The example of particular value comprise 3 to 7 Yuans monocyclic heterocycles of non-aromatic saturated or fractional saturation ring nitrogen or sulfur heteroatom being arranged, be selected from one or two heteroatoms of nitrogen, oxygen and sulphur.The example of this class ring comprises azetidine, oxa-azepan base, pyrrolinyl, pyrrolidyl, morpholinyl, 1,3-thiazolidyl, tetrahydrochysene-1,4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base or thio-morpholinyl.

Q ¹, Q ²Or Q ³The example of particular value comprise morpholinyl or 4 members, 5 Yuans or 6 Yuans contain a nitrogen-atoms and optional one or two heteroatomic heterocycle that is selected from nitrogen and sulphur such as azetidine, 1,3-thiazolidyl, piperazinyl, pyrrolidyl, piperidyl, particularly azetidine-1-base, tetramethyleneimine-2-base, piperazine-1-base or piperidyl.Q ¹, Q ²Or Q ³The more specifically example of suitable value comprise morpholinyl, tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidyl, piperidines-3-base or piperidin-4-yl.

Be appreciated that in formula I and X ¹The nitrogen-atoms that links to each other is heterocyclic group Q ^aNitrogen-atoms on the interior ring.Group Q ^aThe corresponding ring of representative contains one and X ¹The nitrogen heteroatom that links to each other, or optionally contain 1,2 or 3 heteroatoms that is selected from O, S and N.For Q ^aConcrete value is that 4,5,6 or 7 Yuans of non-aromaticity contain a nitrogen-atoms and optional one or two heteroatomic monocyclic heterocycles in oxygen, nitrogen and sulphur, and this class heterocycle can be saturated or fractional saturation and in formula I and X ¹What group linked to each other is nitrogen-atoms.Q ^aSaying so more specifically one to contain a nitrogen heteroatom and choose one wantonly is selected from heteroatomic 4 members of oxygen, nitrogen and sulphur, 5 Yuans or 6 Yuans monocyclic heterocycles in addition, and this heterocycle can be fractional saturation or preferably saturated.Q ^aSay so more specifically one 4 members containing a nitrogen-atoms, 5 Yuans or 6 Yuans monocycle saturated heterocyclics.Q ^aThe group of representative comprises the suitable nonaromatic heterocycles group of listing above, saying so more specifically, (this all class groups all is by nitrogen-atoms and X on the ring in formula I for azetidine, 1,3-thiazoles alkyl, pyrrolidyl, piperidyl, piperazinyl, homopiperidinyl or high piperazinyl ¹Link to each other).Q in particular ^aBe selected from azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only) 1,3-thiazoles alkane-3-base, morpholino and piperazine-1-base.Q in particular again ^aBe selected from azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only) 1,3-thiazoles alkane-3-base and morpholino.Preferred Q ^aBe selected from azetidine-1-base, tetramethyleneimine-1-base, piperidyl and morpholinyl.Preferred Q ^aBe selected from tetramethyleneimine-1-base, piperidino-(1-position only) and morpholino.Particularly preferred Q ^aIt is tetramethyleneimine-1-base.

Define in the example of the various substituent desired values in formula I such as this context, it comprises:

Halogenic substituent: fluorine, chlorine, bromine and iodine;

(1-6C) alkyl: methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl,

Amyl group and hexyl;

(1-4C) alkyl: methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl;

(1-6C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy and

Butoxy;

(2-8C) thiazolinyl: vinyl, pseudoallyl, allyl group and but-2-ene

Base;

(2-8C) alkynyl: ethynyl, 2-propynyl and fourth-2-alkynyl;

(2-6C) alkene oxygen base: vinyloxy group and allyloxy;

(2-6C) alkynyloxy group: second alkynyloxy group and 2-third alkynyloxy group;

(1-6C) alkylthio: methylthio group, ethylmercapto group and rosickyite base;

(2-6C) thiazolinyl sulfenyl: ethene sulfenyl and allyl sulfenyl;

(2-6C) alkynyl sulfenyl: acetylene sulfenyl and 2-propine sulfenyl;

(1-6C) alkyl sulphinyl: methylsulfinyl and ethyl sulfinyl;

(2-6C) thiazolinyl sulfinyl: ethene sulfinyl and allyl sulfinyl;

(2-6C) alkynyl sulfinyl: acetylene sulfinyl and 2-propine sulfinyl;

(1-6C) alkyl sulphonyl: methyl sulphonyl and ethylsulfonyl;

(2-6C) thiazolinyl alkylsulfonyl: ethene alkylsulfonyl and allyl alkylsulfonyl;

(2-6C) alkynyl alkylsulfonyl: acetylene alkylsulfonyl and 2-propine alkylsulfonyl;

(1-6C) alkylamino: methylamino-, ethylamino, third amino, isopropylamino and

Fourth amino;

Two-[(1-6C) alkyl] amino: dimethylamino, diethylin, N-ethyl-N-methylamino-

And diisopropylaminoethyl;

(1-6C) carbalkoxy: methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl and uncle's fourth

The oxygen carbonyl;

N-(1-6C) alkylamino formyl radical: N-methylamino formyl radical, N-ethylamino formyl

Base, N-propyl group formamyl and N-sec.-propyl amino

Formyl radical;

N, N-two-[(1-6C) alkyl] amino N, N-formyl-dimethylamino, N-ethyl-N-methyl

Formyl radical: aminoacyl and N, N-diethylamino formyl radical;

(2-6C) alkyloyl: ethanoyl, propionyl and isobutyryl;

(2-6C) alkanoyloxy: acetoxyl group and propionyloxy;

(2-6C) alkyl amido: kharophen and propionamido;

N-(1-6C) alkyl-(2-6C) alkane acyl N-methyl kharophen and N-methyl-prop amido;

Amino:

N-(1-6C) alkyl sulfonyl amino N-methylamino alkylsulfonyl, N-ethylamino alkylsulfonyl

Base: and N-sec.-propyl amino-sulfonyl;

N, N-two-[(1-6C) alkyl] amino N, N-dimethylamino alkylsulfonyl, N-methyl-N-ethyl

Alkylsulfonyl: amino-sulfonyl;

(1-6C) alkane sulfonamido: methanesulfonamido and ethanesulfonamido;

N-(1-6C) alkyl-(1-6C) alkane sulphur N-methyl methanesulfonamido and N-methyl second sulphonyl ammonia

Amido: base;

Amino-(1-6C) the alkyl aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-ammonia third

Base;

(1-6C) alkyl methyl amino methyl, ethylamino ethyl, the 1-methyl ammonia of alkylamino-(1-6C)

Base ethyl, 2-methylamino ethyl, 2-ethylamino second

Base and 3-methylamino propyl group

Two-[(1-6C) alkyl] amino-(1-dimethylaminomethyl, diethylamino methyl, 1-two

6C) alkyl methyl amino-ethyl, 2-dimethyl aminoethyl and 3-

Dimethylaminopropyl

Halogen-(1-6C) alkyl chloride methyl, 2-chloroethyl, 1-chloroethyl and 3-chloroethyl

Hydroxyl-(1-6C) alkyl hydroxy methyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-

Hydroxypropyl

Hydroxyl-(1-6C) alkoxyl group hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 1-hydroxyl second

Base, 3-hydroxyl propoxy-

(1-6C) alkyl methoxyl methyl, ethoxymethyl, 1-methoxyethyl, the 2-first of alkoxyl group-(1-6C)

Oxygen ethyl, 2-ethoxyethyl and 3-methoxycarbonyl propyl

Cyano group-(1-6C) alkyl cyanide ylmethyl, 2-cyano ethyl, 1-cyano ethyl and 3-

The cyano group propyl group;

Ammonia (2-6C) alkyloyl ammonia ethanoyl and 2-alanyl;

(1-6C) alkane acyl methylamino ethanoyl and 3-(methylamino) propionyl of alkylamino-(2-6C);

Base

N, N-two-[(1-6C) alkyl] amino-two-methylamino ethanoyl and 3-(dimethylamino) third

(2-6C) alkyloyl acyl group;

(2-6C) alkyl amido (1-6C) alkane acetylamino methyl, propionamido methyl and 2-acetyl

The base amino-ethyl

N-(1-6C) alkyl-(2-6C) alkane acyl N-methyl acetylamino methyl, N-methyl-prop amido

Amino (1-6C) alkyl methyl, 2-(N-methyl kharophen) ethyl and 2-(N-

The methyl-prop amido) ethyl

(1-6C) alkoxycarbonyl amido-(1-methoxycarbonyl amino methyl, amino first of ethoxycarbonyl

6C) alkyl base, t-butoxycarbonyl amino methyl and 2-methoxyl group carbonyl

The base amino-ethyl;

Carbamyl (1-6C) alkylcarbamoyl group methyl, 1-carbamyl ethyl, 2-ammonia first

Acyl group ethyl and 3-carbamyl propyl group,

N-(1-6C) alkylamino formyl radical (1-N-methylamino formyl radical methyl, N-ethylamino first

6C) alkyl: acyl group methyl, N-propyl group carbamyl ylmethyl, 1-

(N-methylamino formyl) ethyl, 2-(N-methylamino

Formyl) ethyl and 3-(N-methylamino formyl) third

Base,

N, N-two-(1-6C) alkylaminos N, N-formyl-dimethylamino methyl,

Formyl radical (1-6C) alkyl: N, N-diethylamino formyl radical methyl,

The N-methyl, N-ethylamino formyl radical methyl,

1-( N, N-formyl-dimethylamino) ethyl,

2-( N, N-formyl-dimethylamino) ethyl,

2-( N, N-diethylamino formyl radical) ethyl and

3-( N, N-formyl-dimethylamino) propyl group;

Amino-sulfonyl (1-6C) alkyl: aminosulfonyl ylmethyl, 1-amino-sulfonyl ethyl, 2-

Amino-sulfonyl ethyl and 3-amino-sulfonyl propyl group;

N-(1-6C) alkyl amino sulfonyl N-methylamino alkylsulfonyl methyl,

(1-6C) alkyl: N-ethylamino alkylsulfonyl methyl,

N-propyl group aminosulfonyl ylmethyl,

1-(N-methylamino alkylsulfonyl) ethyl,

2-(N-methylamino alkylsulfonyl) ethyl,

3-(N-methylamino alkylsulfonyl) propyl group,

N, N-two-(1-6C) alkylaminos N, N-dimethylamino alkylsulfonyl methyl,

Alkylsulfonyl (1-6C) alkyl: N, N-diethylamino alkylsulfonyl methyl,

The N-methyl, N-ethylamino alkylsulfonyl methyl,

1-( N, N-dimethylamino alkylsulfonyl) ethyl,

2-( N, N-dimethylamino alkylsulfonyl) ethyl,

2-( N, N-diethylamino alkylsulfonyl) ethyl and

3-( N, N-dimethylamino alkylsulfonyl) propyl group

(2-6C) alkyloyl (1-6C) alkyl acetylmethyl, propionyl methyl, 2-acetyl ethyl and 2-

The propionyl ethyl;

(2-6C) alkanoyloxy (1-6C) alkane acetyl-o-methyl, propionyl oxygen methyl, 2-acetyl oxygen ethyl

Base and 2-propionyl oxygen propyl group;

(1-6C) alkoxyl group (1-6C) alkyl 2-methoxy ethyl alkylsulfonyl,

S (O) _q2-methoxy ethyl sulfinyl and

2-methoxyl group ethylmercapto group;

Ammonia (1-6C) alkyl S (O) _q2-amino-ethyl alkylsulfonyl, 2-amino-ethyl sulfinyl

With the amino ethylmercapto group of 2-;

N-(1-6C) alkylamino (1-6C) 2-(methylamino) ethylsulfonyl,

Alkyl S (O) _q2-(ethylamino) ethyl sulfinyl and

2-(methylamino) ethylmercapto group;

N, N-two-[(1-6C) alkyl] amino 2-(dimethylamino) ethylsulfonyl,

(1-6C) alkyl S (O) _q3-(dimethylamino) sulfonyl propyl base,

2-(diethylamino) ethyl sulfinyl and

2-(N-methyl-N-ethylamino) ethylmercapto group;

Be appreciated that and work as R ¹Being (1-6C) alkoxyl group by for example amino when replacing the group that obtains 2-amino ethoxy for example, is that (1-6C) alkoxyl group links to each other with the quinazoline ring.Similar transformation applications is in defined other group here.

Definition as described above, any (2-6C) alkylidene chain is such as R ¹Substituent adjacent carbons can be chosen the group that is inserted in the chain wantonly and separate, and this class is separated group for example O, CON (R ⁴), N (R ⁴) or C ≡ C.For example a C ≡ C group is inserted in the ethylidene chain of 2-morpholino ethoxy group, obtains 4-morpholino fourth-2-alkynyloxy group, and for example a CONH group is inserted in the ethylidene chain of 3-methoxy propoxy, obtains 2-(2-methoxyl group kharophen) oxyethyl group.Should understand term (2-6C) alkylidene chain and be meant any CH ₂CH ₂Group is (for example at R ¹In), and be included in (1-6C) alkyl, (1-6C) alkoxyl group, (2-8C) thiazolinyl, (2-8C) alkene oxygen base, (2-8C) alkynyl and (2-8C) alkylidene chain in the alkynyloxy group.For example in third and fourth carbon atom of own-5-alkene oxygen base, insert a N (CH ₃) group, obtain 3-(N-methyl-N-allyl amino) propoxy-.

Definition as described above, R ¹Substituent any CH ₂The CH of=CH-or HC ≡ C-group ₂=or HC ≡ end is optional has a substituting group, and this substituting group is formula Q for example ⁴-X ⁴Group, X for example wherein ⁴Be NHCO and Q ⁴Be the alkyl of heterocycle-(1-6C), the R of suitable formation like this ¹Substituting group for example comprises the alkyl of N-[heterocyclic radical-(1-6C)] the formamyl vinyl; N-[2-tetramethyleneimine-1-base ethyl for example] the formamyl vinyl; or the alkyl of N-[heterocyclic radical-(1-6C)] the formamyl ethynyl, as N-[2-tetramethyleneimine-1-base ethyl] the formamyl ethynyl.

On mentioning any alkyl or alkylidene group here, choose when having one or more substituting group the CH of described alkyl or alkylidene group wantonly ₂Or CH ₃Upward each is chosen wantonly and has a CH ₂Or CH ₃Group or more group.Each described CH ₂Group has suitable 1 or 2 substituting groups, and at each described CH ₃Group has suitable 1,2 or 3 substituting groups.Be appreciated that the carbon atom that can have substituent alkyl or alkylidene group to comprise the carbon atom on the cycloalkyl ring and contain alkyl or alkylidene chain compound, for example (1-6C) alkoxyl group.The substituting group that is fit to that so forms comprises the alkoxyl group of the heterocyclic radical of for example hydroxyl-replacement-(1-6C), as 2-hydroxyl-3-piperidino-(1-position only) propoxy-and 2-hydroxyl-3-morpholino propoxy-.

When a group of indication (for example heterocyclic radical) here is optional when having " one or more " substituting group, this concrete group is fit to optionally has 1,2 or 3 substituting group, and they can be identical or different.

Work as X ²When being CO, it is interpreted as carbonyl.Work as X ²Be CH ₂C (O) or CH ₂SO ₂The time, CH ₂And Q ^aLink to each other, simultaneously NR among carbonyl or alkylsulfonyl and the formula I ²⁰The nitrogen-atoms of Z links to each other.

When this specification sheets was mentioned (1-4C) alkyl, it is interpreted as this alkyl was to contain maximum 4 carbon atoms.The technician will recognize that the representative instance of this group is the alkyl that contains 1 to 4 carbon atom above being listed in (1-6C) alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.Similar, (1-3C) alkyl is meant alkyl for example methyl, ethyl, propyl group and the sec.-propyl that contains 1 to 3 carbon atom.Similar conversion also is applied to top other listed group, for example (1-4C) alkoxyl group, (2-4C) thiazolinyl, (2-4C) alkynyl and (2-4C) alkyloyl.

When two W groups form (1-4C) alkylidene bridge, preferably this alkylidene bridge and Q ^aThe adjacent atom of ring links to each other.The example that is formed (1-4C) alkylidene bridge by two W groups comprises methylene radical (CH ₂-), ethylidene (CH ₂CH ₂-) and propylidene (CH ₂-CH ₂CH ₂-).When two W groups form (1-4C) alkylidene bridge ,-X ²NZR ²⁰Group can be at Q ^aOn the ring or on a carbon atom of (1-4C) alkylidene bridge.For example work as Q ^aWhen being tetramethyleneimine-1-base or piperidino-(1-position only), be formed on Q by two W groups ^aThe example of (1-4C) alkylidene bridge on the ring comprises:

In the compound of formula I, hydrogen atom appears on 2,5 and 8 of quinazoline ring.

R ¹Embodiment

In embodiments of the invention, R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group,, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, or be selected from the group of following formula:

Q ¹-X ³-

X wherein ³Be O, while Q ¹Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

And R wherein ¹The adjacent carbons of substituent (2-6C) alkylidene chain appoints the group that is inserted in the chain to separate, and described group is selected from O, N (R ⁴), CON (R ⁴), N (R ⁴) CO, CH=CH and C ≡ C, wherein R ⁴Be hydrogen or (1-6C) alkyl,

While is R wherein ¹Substituent any CH ₂The CH of=CH-or HC ≡ C-group ₂=or HC ≡ end is optional has a substituting group, this substituting group be selected from carbamyl, N-(1-6C) alkylamino formyl radical, N, NThe alkyl of alkyl and two-[(1-6C) alkyl] amine of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C)-(1-6C),

While is R wherein ¹Optional one or more for example (1, the 2 or 3) substituting group that has of substituent any alkyl or alkylidene group, they are selected from, and halogen, (1-6C) alkyl, hydroxyl, amino, cyano group, carbamyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] are amino, N-(1-6C) alkylamino formyl radical and N, N-two-[(1-6C) alkyl] formamyls, or be selected from the group of following formula:

-X ⁵-Q ³

X wherein ⁵Be connecting key or be selected from O, N (R ⁶), CON (R ⁶), N (R ⁶) CO and C (R ⁶) ₂O, wherein R ⁶Be hydrogen or (1-6C) alkyl, Q ³Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

While is R wherein ¹Substituent any heterocyclic radical is the heterocyclic group (preferably 4,5,6 or 7 Yuans non-aromaticity heterocyclic groups of monocycle) of the saturated or fractional saturation of 4,5,6 or 7 Yuans non-aromaticity,

R wherein ¹Substituent any heterocycle is chosen wantonly and is had 1,2 or 3 substituting group; they can be identical or different, be selected from halogen, trifluoromethyl, hydroxyl, amino, carbamyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkylamino alkylsulfonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylamino formyl radical, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, or be selected from the group of following formula:

X ⁶-R ⁷-

X wherein ⁶Be connecting key or be selected from O and N (R ⁸), R wherein ⁸Be hydrogen atom or (1-6C) alkyl, R ⁷Be alkyl and two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl

R wherein ¹Substituent any heterocyclic group is chosen wantonly and is had 1 or 2 oxo substituting group.

In another embodiment of the present invention, R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, or be selected from the group of following formula:

Q ¹-X ³-

X wherein ³Be O, Q ¹Be the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Substituent any heterocycle is the heterocyclic group of the saturated or fractional saturation of 4,5 or 6 Yuans monocycles,

R wherein ¹The optional group that is inserted in the chain of the adjacent carbons of substituent (2-6C) alkylidene chain is separated, and described group is selected from O and N (R ⁴), R wherein ⁴Be hydrogen atom or (1-6C) alkyl,

While is R wherein ¹Substituent any alkyl or alkylidene group are optional to have one or more substituting groups, and they are selected from halogen, (1-6C) alkyl, hydroxyl, amino, cyano group, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino,

While is R wherein ¹Substituent any heterocycle is chosen wantonly and is had 1,2 or 3 substituting group; they can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, carbamyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino alkylsulfonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylamino formyl radical, N, N-two-[(1-6C) alkyl] formamyls and (2-6C) alkyloyl,

In another embodiment, R ¹Be selected from hydroxyl, (1-6C) alkoxyl group, or be selected from the group of following formula:

Q ¹-X ³-

X wherein ³Be O, Q ¹It is the alkyl of alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of azetidine-3-base-(1-4C), azetidine-1-base-(2-4C), tetramethyleneimine-2-base-(1-4C), tetramethyleneimine-3-base-(1-4C), tetramethyleneimine-1-base-(2-4C), piperidines-2-base-(1-4C), piperidines-3-base-(1-4C), piperidin-4-yl-(1-4C), piperidino-(1-position only)-(2-4C), Piperazino-(2-4C) or morpholino-(2-4C)

R wherein ¹The optional group that is inserted in the chain of the adjacent carbons of substituent (2-6C) alkylidene chain is separated, and described group is selected from O and N (R ⁴), R wherein ⁴Be hydrogen atom or (1-4C) alkyl,

R wherein ¹Substituent any alkyl or alkylidene group are optional to have one or more substituting groups, and they are selected from fluorine, chlorine, hydroxyl, (1-4C) alkoxyl group, amino, (1-4C) alkylamino and two-[(1-4C) alkyl] amino,

R wherein ¹Substituent any heterocyclic group is chosen wantonly and is had 1,2 or 3 substituting group; they can be identical or different, be selected from halogen, hydroxyl, amino, carbamyl, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (1-4C) alkoxyl group, (1-4C) alkylamino alkylsulfonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, N-(1-4C) alkylamino formyl radical, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl,

R wherein ¹Substituent any heterocyclic group is optional to have 1 or 2 oxo substituting group (on the preferred described oxo substituting group discord heterocycle and ring go up the carbon atom that oxygen links to each other continuous);

In another embodiment, R ¹Be selected from the alkoxyl group of hydroxyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group, hydroxyl-(2-4C), or be selected from the group of following formula:

Q ¹-X ³-

X wherein ³Be O, Q ¹Be the alkyl of alkyl of the alkyl of the alkyl of the alkyl of azetidine-1-base-(2-4C), tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), Piperazino-(2-4C) or morpholino-(2-4C),

R wherein ¹Substituent any heterocyclic group is chosen wantonly and is had 1,2 or 3 substituting group; they can be identical or different; be selected from amino and (2-4C) alkyloyl of halogen, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino alkylsulfonyl, (1-4C) alkylamino, two-[(1-4C) alkyl]

R wherein ¹Substituent any heterocyclic group is optional to have 1 oxo substituting group (on the preferred described oxo substituting group discord heterocycle and ring go up the carbon atom that oxygen links to each other continuous);

In other embodiments of the present invention, R ¹Be selected from alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C).

In other embodiments of the present invention, R ¹Be selected from hydrogen, hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, the 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, cyclo propyl methoxy, 2-cyclopropyl oxyethyl group, vinyloxy group, allyloxy, the second alkynyloxy group, 2-third alkynyloxy group, tetrahydrofuran (THF)-3-ylmethoxy, 2-(tetrahydrofuran (THF)-2-yl) oxyethyl group, 3-(tetrahydrofuran (THF)-2-yl) propoxy-, 2-(tetrahydrofuran (THF)-3-yl) oxyethyl group, 3-(tetrahydrofuran (THF)-3-yl) propoxy-, the tetrahydropyrans ylmethoxy, 2-tetrahydropyrans base oxethyl, 3-THP trtrahydropyranyl propoxy-, 2-tetramethyleneimine-1-base oxethyl, 3-tetramethyleneimine-1-base propoxy-, tetramethyleneimine-3-base oxygen base, tetramethyleneimine-2-ylmethoxy, 2-tetramethyleneimine-2-base oxethyl, 3-tetramethyleneimine-2-base propoxy-, 2-morpholino oxyethyl group, 3-morpholino propoxy-, 2-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) oxyethyl group, 3-(1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propoxy-, piperidines-3-base oxygen base, piperidin-4-yl oxygen base, piperidines-3-ylmethoxy, 2-piperidines-3-base oxethyl, the piperidin-4-yl methoxyl group, 2-piperidin-4-yl oxyethyl group, the high piperidines of 2--1-base oxethyl, the high piperidines of 3--1-base propoxy-, 2-piperazine-1-base oxethyl, 3-piperazine-1-base propoxy-, the high piperazine of 2--1-base oxethyl, the high piperazine of 3--1-base propoxy-, tetramethyleneimine-1-base, morpholino, piperidino-(1-position only) and piperazine-1-base

R wherein ¹The optional group that is inserted in the chain of the adjacent carbons of substituent (2-6C) alkylidene chain is separated, and described group is selected from O, NH, N (CH ₃), CH=CH and C ≡ C,

Wherein any CH ₂Group, this CH ₂Group links to each other with two carbon or and is connected R ¹CH on substituent any alkyl or the alkylidene group carbon ₃Link to each other, at each described CH ₂Or CH ₃The optional substituting group that has 1,2 or 3 fluoro substituents or be selected from hydroxyl, amino, methoxyl group, oxyethyl group, methylsulfonyl, methylamino and dimethylamino on the group,

R wherein ¹Substituent any heterocyclic group is chosen wantonly and is had 1 or 2 substituting group; they can be identical or different; be selected from fluorine, chlorine, trifluoromethyl, hydroxyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamyl, methyl, ethyl, n-propyl, sec.-propyl and methoxyl group, R ¹The N-of substituent any piperidines-3-ylmethyl, piperidin-4-yl methyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group or piperazine-1-base goes up optional have 2-methoxy ethyl, 3-methoxy-propyl, 2-amino-ethyl, 3-aminopropyl, 2-methylamino-ethyl, 3-methylamino-propyl group, 2-dimethylaminoethyl, 3-dimethylamino-propyl, ethanoyl or propionyl

R wherein ¹Substituent any heterocyclic group is optional have 1 or 2 oxo substituting group (on the preferred described oxo substituting group discord heterocycle and ring to go up the carbon atom that oxygen links to each other continuous, more preferably R ¹Substituent any heterocyclic group does not have the oxo substituting group).

In another embodiment of the present invention, R ¹Be selected from methoxyl group, oxyethyl group, propoxy-, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2-ethoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy, 2-(tetramethyleneimine-1-yl) ethyl, 3-(tetramethyleneimine-1-yl) propyl group, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 2-Piperazino ethyl, 3-Piperazino propyl group, 2-morpholino ethyl and 3-morpholino propyl group.

In another embodiment, R ¹Be the group of hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group or following formula:

Q ¹-X ³

X wherein ³Be O, Q ¹Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Substituent any alkyl or alkylidene group be optional have one or more halogens, (1-6C) alkyl, hydroxyl, cyano group, amino, carboxyl, carbamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkylamino formyl radical, N, NThe alkyl amido of-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl-(2-6C), N-(1-6C) alkylamino alkylsulfonyl, N, NThe alkane sulfonamido of amino and N-(1-6C) alkyl of-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkyl sulfonyl-(1-6C),

R specifically ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹Substituent any (1-6C) alkoxyl group is optional have one or more hydroxyl substituents (suitable 1 or 2) and/or be selected from amino, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, carbamyl, N-(1-4C) alkylamino formyl radical with N, NThe substituting group of-two-[(1-4C) alkyl] amino-sulfonyls.

For example, R ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹Substituent any (1-6C) alkoxyl group is substituted with 1,2 or 3 substituting group, and they can be identical or different, are selected from hydrogen, fluorine and chlorine, for example R ¹Be selected from methoxyl group, oxyethyl group, isopropoxy, cyclopropane methoxyl group, 2-hydroxyl methoxyl group, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy.

Concrete R ¹Be selected from hydrogen, (1-4C) alkoxyl group and (1-4C) alkoxyl group (2-6C) alkoxyl group, R more specifically ¹Be selected from (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group and (1-3C) alkoxyl group (2-4C) alkoxyl group, R more specifically ¹Be selected from (1-3C) alkoxyl group and (1-3C) alkoxyl group (2-3C) alkoxyl group.R ¹(1-3C) alkoxyl group preferably.R for example ¹Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy or 2-hydroxyl-oxethyl.R ¹Specific examples be methoxyl group.

X ¹Embodiment

X in one embodiment ¹Be (C (R ⁹) ₂) _n, each R wherein ⁹Can be identical or different, be selected from the alkyl of hydroxyl, (1-4C) alkyl, halogen (1-4C) alkyl, hydroxyl-(1-4C), (1-4C) alkoxyl group (1-4C) alkyl, (3-6C) cycloalkyl and (3-6C) cycloalkyl-(1-2C) alkyl, or two R ⁹The carbon atom that connects by their forms (3-6C) naphthenic ring, and n is 1 or 2 (preferably 1).R in this embodiment ⁹Hydrogen atom preferably.

X in another embodiment ¹Be C (R ⁹) ₂, one of them R ⁹Be another R of hydrogen atom ⁹Be selected from hydrogen, (1-4C) alkyl, cyclopropyl and cyclopropyl methyl, or two R ⁹The carbon atom that connects by them forms (3-6C) naphthenic ring (for example cyclopropyl rings).

X ¹Suitable example be (C (R ⁹) ₂) _n, wherein n is 1 or 2, each R ⁹Can be identical or different, be selected from hydroxyl, (1-4C) alkyl, hydroxymethyl, hydroxyethyl or halogen (1-2C) alkyl, for example CH ₂CH ₂F, CH ₂CHF ₂Or CH ₂CF ₃In an object lesson, each R ⁹Can be identical or different, be selected from hydrogen atom and (1-4C) alkyl.

Two R ⁹When the carbon atom that connects by their forms (3-7C) naphthenic ring, preferred two R ⁹Group is on same carbon atom.Such specific examples comprises cyclopropane base, pentamethylene base or cyclohexyl, particularly the cyclopropane base.

As has a R at least ⁹, each R preferably ⁹It all is hydrogen atom.

Suitable n is 1.

According to a specific embodiments X ¹Be CHR ⁹, R wherein ⁹Be selected from the alkyl of the alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-3C).

In another specific embodiments, X ¹Be CHR ⁹, R wherein ⁹Be selected from hydrogen, (1-4C) alkyl (R for example ⁹Be selected from hydrogen, methyl, ethyl and sec.-propyl, R ⁹Concrete is hydrogen atom or methyl).X ¹CH preferably ₂

The embodiment of W

In one embodiment; each W; they can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, oxo, amino, carbamyl, amino-sulfonyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylamino formyl radical, N, NThe alkyl amido of-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl-(2-6C), N-(1-6C) alkylamino alkylsulfonyl, N, NThe group of alkane sulfonamido of-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfonamido and N-(1-6C) alkyl-(1-6C) or following formula:

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen atom or (1-6C) alkyl, R ¹¹Be the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), N-(1-6C) alkylamino-(1-6C), N, N-two-[(1-6C) alkyl] amino-(1-6C) alkyl of the alkyl of the alkyl of alkyl, (2-6C) alkyl amido-(1-6C), carbamyl-(1-6C), N-(1-6C) alkylamino formyl radical-(1-6C), N, NAlkyl of-two-[(1-6C) alkyl]-(1-6C) alkyl, (2-6C) alkyloyl-(1-6C) and (2-6C) alkyl of alkanoyloxy-(1-6C),

Or two W groups form (1-3C) alkylidene bridge, this (1-3C) alkylidene bridge is chosen wantonly and is had 1,2 or 3 substituting group, they can be identical or different, be selected from halogen, hydroxyl, oxo, (1-4C) alkyl, (1-4C) alkoxyl group, amino, N-(1-4C) alkylamino and N, N-two-[(1-4C) alkyl] amino.

Suitable q is 0,1 or 2.Concrete q is 0.Another selection of q is 1.

The W group preferably include halogen, trifluoromethyl, cyano group, nitro, hydroxyl, oxo, amino, carbamyl, amino-sulfonyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkylamino formyl radical, N, NThe alkyl amido of-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl-(2-6C), N-(1-6C) alkylamino alkylsulfonyl, N, NThe group of alkane sulfonamido of-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfonamido and N-(1-6C) alkyl-(1-6C) or following formula:

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen atom or (1-6C) alkyl, R ¹⁰Be the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), N-(1-6C) alkylamino-(1-6C), N, N-two-[(1-6C) alkyl] amino-(1-6C) alkyl of the alkyl of the alkyl of alkyl, (2-6C) alkyl amido-(1-6C), carbamyl-(1-6C), N-(1-6C) alkylamino formyl radical-(1-6C), N, NAlkyl of the alkyl of-two-[(1-6C) alkyl]-carbamyl-(1-6C), (2-6C) alkyloyl-(1-6C) and (2-6C) alkyl of alkanoyloxy-(1-6C).

In another embodiment, q is 0,1,2 or 3 (preferred 0 or 1, more preferably 0), each W of while, they can be identical or different, be selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C)

Or two W groups on the adjacent ring carbon atom are at Q ^aIn form (1-3C) alkylidene bridge, should (1-3C) alkylidene bridge is optional have 1 or 2 substituting groups, they can be identical or different, are selected from halogen, hydroxyl, oxo, (1-3C) alkyl and (1-3C) alkoxyl group.

Q is 0,1 or 2 (preferred 0 or 1 in another embodiment, more preferably 0), each W of while, they can be identical or different, be selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C)

In another embodiment, q is 0,1 or 2 (preferred 0 or 1, more preferably 0), each W of while, they can be identical or different, be selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C)

Or two W groups on the adjacent ring carbon atom are at Q ^aIn form (1-3C) alkylidene bridge, should (1-3C) alkylidene bridge is optional have 1 or 2 substituting groups, they can be identical or different, are selected from hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group.

Q is 0,1,2 or 3 (preferred 0 or 1 in another embodiment, more preferably 0), each W simultaneously, they can be identical or different, be selected from alkyl of hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C)

Or two W groups on the adjacent ring carbon atom are at Q ^aMiddle (1-3C) alkylidene bridge that forms.

In another embodiment, q is that 2 and two W groups on the adjacent ring carbon atom are at Q ^aIn form (1-3C) alkylidene bridge, should (1-3C) alkylidene bridge is optional have 1 or 2 substituting groups, they can be identical or different, are selected from hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group, example are that two W groups form a methylene bridge.

Q is 0,1 or 2 (preferred 0 or 1 in another embodiment, more preferably 0), each W simultaneously, they can be identical or different, be selected from alkoxyl group of hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C)

Q is 0 or 1 in another embodiment, more preferably 0 and W be selected from hydroxyl and (1-4C) alkoxyl group.

The particular value of W is formula-OR ²², R wherein ²²Be hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (2-6C) alkyloyl or radicals R ¹⁰, R wherein ¹⁰As definition in the front formula (I).

R ²²Specific examples comprise hydrogen, (1-6C) alkyl for example alkyl of the alkyl of methyl, ethyl, propyl group, normal-butyl, halogen-(1-6C), hydroxyl-(2-6C) or (1-6C) alkyl of alkoxyl group-(2-6C).

R more specifically ²²Example is selected from (1-4C) alkyl for example alkyl of the alkyl of methyl, ethyl, propyl group, sec.-propyl, normal-butyl, halogen-(1-6C), hydroxyl-(2-6C) or (1-6C) alkyl of alkoxyl group-(2-6C).

More specifically, R ²²Can be hydrogen atom or (1-6C) alkyl.R more specifically ²²It is for example methyl of (1-4C) alkyl.

Q is 0,1 or 2 (preferred 0 or 1) in another embodiment, each W of while, they can be identical or different, are selected from hydroxyl, amino, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, methylamino, ethylamino, dimethylamino and diethylamino.

Q is 0,1 or 2 (preferred 0 or 1) in another embodiment, each W of while, they can be identical or different, are selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-4C) and (1-3C) alkyl of alkoxyl group-(2-3C).For example q be 0 or 1 and W be selected from methyl, ethyl, hydroxyl, methoxyl group, oxyethyl group, 2-methoxy ethyl and 2-hydroxyethyl.More specifically, q be 0 or 1 and W be selected from methyl, ethyl, methoxyl group and oxyethyl group.

X ²Embodiment

Suitable X ²Be selected from C (O), SO ₂And CH ₂C (O).X in specific embodiment ²Be C (O).X in another example ²Be SO ₂

R ²⁰Embodiment

R in one embodiment ²⁰Be selected from hydrogen, (1-4C) alkyl and (1-3C) alkyl of alkoxyl group-(2-4C).More specifically, R ²⁰Be selected from hydrogen and (1-4C) alkyl.R ²⁰Example be hydrogen, methyl, ethyl and sec.-propyl.

That suitable is R ²⁰Hydrogen, methyl, ethyl or propyl group.

R ²⁰Hydrogen atom preferably.

The embodiment of Z

Z is selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl,

Wherein in Z substituent any (2-6C) alkylidene chain, the optional group that is inserted in the chain of adjacent C atom is separated, and described group is selected from O, S, SO, SO ₂And CO,

Any CH in the Z substituting group wherein ₂=CH-or HC ≡ C-group are chosen wantonly at CH ₂=or HC ≡ end have a substituting group, this substituting group is selected from halogen, carboxyl, carbamyl,

Wherein any alkyl in the Z substituting group or alkylidene group are optional has one or more halogens or (1-6C) alkyl substituent, or be selected from hydroxyl, cyano group, amino, carboxyl, carbamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkylamino formyl radical, N, NThe alkyl amido of-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl-(2-6C), N-(1-6C) alkylamino alkylsulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls; (1-6C) the alkyl sulfonyl amino of amino and N-(1-6C) alkyl of alkyl sulfonyl-(1-6C) or (3-8C) group of cycloalkyl or heterocyclic radical; wherein any one can be chosen wantonly by one or two group and replace, and substituting group is selected from halogen; cyano group; nitro; hydroxyl; amino; carboxyl; carbamyl; amino-sulfonyl; trifluoromethyl; (1-4C) alkyl; (2-4C) thiazolinyl; (2-4C) alkynyl; (1-3C) alkoxyl group; (2-4C) alkene oxygen base; (2-4C) alkynyloxy group; (1-4C) alkylthio; (1-4C) alkyl sulphinyl; (1-4C) alkyl sulphonyl; (1-4C) alkylamino; two-[(1-4C) alkyl] amino; (1-4C) alkoxy carbonyl.

In another embodiment, Z is selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (3-6C) cycloalkyl, (3-6C) alkyl of cycloalkyl-(1-4C), heterocyclic radical, the alkyl of heterocyclic radical-(1-4C), in the alkyl of heteroaryl and heteroaryl-(1-4C), azetidine, the alkyl of azetidine-(1-4C), pyrrolinyl, the alkyl of pyrrolinyl-(1-4C), pyrrolidyl, the alkyl of pyrrolidyl-(1-4C), morpholinyl, the alkyl of morpholinyl-(1-4C), piperidyl, the alkyl of piperidyl-(1-4C), piperazinyl, the alkyl of piperazinyl-(1-4C), phenyl, the alkyl of phenyl-(1-4C)

Wherein any heterocyclic group of Z is selected from different  azoles base, furyl, thienyl, pyridyl, pyrazolyl, pyrryl, indyl, quinolyl, benzofuryl and benzothienyl,

Wherein in Z substituent any (2-6C) alkylidene chain, the group that adjacent C atom is inserted in the chain is separated, and described group is selected from O and N (R ¹²), R wherein ¹²Be selected from hydrogen atom and (1-3C) alkyl,

Optional one or more halogens or (1-4C) alkyl substituent or be selected from hydroxyl, cyano group, amino, (1-4C) alkoxyl group, the amino substituting group of (1-4C) alkylamino and two-[(1-4C) alkyl] of having of the substituent any alkyl of Z, (3-6C) cycloalkyl or alkylidene group wherein

Wherein the substituent any phenyl of Z, heteroaryl or heterocyclic radical are optional has one or more substituting groups, substituting group is selected from that halogen (especially bromine, chlorine or fluorine), amino, nitro, cyano group, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group, (2-4C) alkyloyl, (1-4C) alkyl sulphonyl, carbamyl, [(1-4C) alkyl] are amino, two-[(1-4C) alkyl] amino for example dimethylamino, N-[(1-4C) alkyl] formamyl with N, N-two-[(1-4C) alkyl] formamyl is for example N, N-formyl-dimethylamino.

In another embodiment, Z is selected from the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl-(1-4C), heterocyclic radical, heterocyclic radical-(1-4C), azetidinyl, azetidinyl-(1-4C), pyrrolinyl, pyrrolinyl-(1-4C), pyrrolidyl, pyrrolidyl-(1-4C), piperidyl, piperidyl-(1-4C) alkyl, piperazinyl and piperazinyl-(1-4C)

Wherein in Z substituent any (2-6C) alkylidene chain, the group that adjacent C atom is inserted in the chain is separated, and described group is selected from O, NH and N (Me),

Wherein substituent any heteroaryl of Z or heterocyclic radical are optional has one or more substituting groups, substituting group is selected from that halogen (especially bromine, chlorine or fluorine), amino, nitro, cyano group, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group, (2-4C) alkyloyl, (1-4C) alkyl sulphonyl, carbamyl, [(1-4C) alkyl] are amino, two-[(1-4C) alkyl] amino for example dimethylamino, N-[(1-4C) alkyl] formamyl with N, N-two-[(1-4C) alkyl] formamyl is for example N, N-formyl-dimethylamino,

Wherein the substituent any pyrrolinyl of Z, pyrrolidyl, piperidyl and piperazinyl are chosen wantonly and are had 1 or 2 oxo substituting groups.

In another embodiment, Z is selected from the alkyl of hydrogen, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, heteroaryl and heteroaryl-(1-4C),

Wherein the substituent any heteroaryl of Z is selected from different  azoles base, furyl, thienyl, pyridyl, pyrazolyl, pyrryl and indyl,

Optional one or more halogens (for example fluorine or chlorine) or (1-4C) alkyl substituent or be selected from hydroxyl, cyano group, amino, (1-4C) alkoxyl group, the amino substituting group of (1-4C) alkylamino and two-[(1-4C) alkyl] of having of substituent any alkyl of Z or alkylidene group wherein

Wherein substituent any heteroaryl of Z or heterocyclic radical are chosen wantonly and are had one or more substituting groups, and this class substituting group is selected from for example dimethylamino of halogen (especially bromine, chlorine or fluorine), amino, nitro, cyano group, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group, [(1-4C) alkyl] amino and two-[(1-4C) alkyl] amino.

In another embodiment, Z is selected from hydrogen, (1-4C) alkyl, (2-4C) thiazolinyl and (2-4C) alkynyl,

Wherein substituent any alkyl of Z or alkylidene group are optional has one or more substituting groups, and this class substituting group is selected from fluorine and chlorine, or is selected from hydroxyl, cyano group, amino, (1-3C) alkoxyl group, the amino substituting group of (1-3C) alkylamino and two-[(1-3C) alkyl].

That Z is selected from alkyl and two-[(1-3C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of hydrogen, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C), cyano group-(1-4C), amino-(2-4C), (1-3C) alkylamino-(2-4C) in another embodiment is amino-(2-4C) alkyl.

Z is selected from the alkyl of the alkyl of the alkyl of hydrogen, (1-3C) alkyl, (2-3C) thiazolinyl, (2-3C) alkynyl, hydroxyl-(2-3C), (1-3C) alkoxyl group-(2-3C) and cyano group-(1-3C) in another embodiment.

Concrete, Z is selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl.

Z is selected from hydrogen, methyl, ethyl, sec.-propyl, allyl group, 2-propynyl and cyano methyl in another embodiment.

Z is selected from hydrogen, (1-3C) alkyl (for example Z is selected from hydrogen, methyl and ethyl) in embodiment further.

Preferred Z is a hydrogen atom.

In another embodiment of the invention, R ²⁰Be that hydrogen atom and Z are selected from hydrogen atom and (1-3C) alkyl.Preferred Z and R ²⁰It all is hydrogen atom.

In another embodiment of the invention-X ²NZR ²⁰Group is at Q ^aOn the ring ortho position of nitrogen-atoms (2-), the X of this nitrogen-atoms and formula I ¹Link to each other.More specifically ,-X ²NZR ²⁰Group is-C (O) ZR ²⁰And be at Q ^aOn the ring ortho position of nitrogen-atoms (2-), the X of this nitrogen-atoms and formula I ¹Link to each other, wherein Z and R ²⁰Has defined any value here.

The embodiment of aniline group in formula I

In embodiments of the invention, a is 1,2 or 3.

In a specific embodiment, work as R ³The aniline ring between when position, it is selected from halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkylamino and two-[(1-6C) alkyl] amino.

Suitable R ³Examples of groups be halogen, carbamyl, trifluoromethyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, N-(1-6C) alkylamino formyl radical or N, N-two-[(1-6C) alkyl] formamyls.In a concrete example, has a R at least ³, or all R that are fit to ³Group is a halogen, for example chlorine or fluorine.

The specific examples of secondary pole type (i) group:

Be (ii) group of secondary pole type in formula I:

R wherein ¹⁵Or R ¹⁷Have one to be hydrogen, another is for example chlorine or a fluorine of halogen, preferably fluorine, and R ¹⁶Be for example bromine, chlorine or fluorine of halogen, be in particular chlorine or bromine or be more particularly chlorine or bromine.R ¹⁶Chlorine preferably.

The specific examples of this class group is 3-chloro-2-fluorophenyl, 3-bromo-2-fluorophenyl or 3-chloro-4-fluorophenyl.

In a more particular embodiment, a is 1 or 2.A is 1 in another embodiment.A is 2, one R in a more particular embodiment ³Be fluorine another be chlorine or bromine.

A is 1 or 2 in another embodiment, each R ³, they can be identical or different, are selected from fluorine, chlorine, bromine and ethynyl.In this embodiment, preferred R ³It is position (3-) and be selected from chlorine, bromine and ethynyl (preferred chlorine or bromine) and when a is 2, another R between the aniline group of formula I ³At the ortho position (2-) and be fluorine.Preferably when a is 1, R ³Position (3-) and be bromine or ethynyl between the aniline group of formula I.

In another embodiment, aniline group is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido in the 4-position of the quinazoline ring of formula I.

Aniline group is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino in the 4-position of the quinazoline ring of formula I more specifically.More specifically, aniline group is a 3-bromo-2-fluoroanilino, or 3-chloro-2-fluoroanilino preferably.

X among the formula IA ⁸Embodiment

X in one embodiment ⁸Be selected from CH ₂, O or NR ¹³X wherein ⁸Be formula NR ¹³Group, wherein R ¹³Be hydrogen, carbamyl, amino-sulfonyl, formyl radical, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (1-6C) alkyl sulphonyl, N-(1-6C) alkylamino formyl radical, N, N-two-[(1-6C) alkyl] formamyls, N-(1-6C) alkylamino alkylsulfonyl and N, N-[(1-6C) alkyl] amino-sulfonyl, or be selected from the group of following formula:

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or CO and R ¹⁰As above definition, example is R ¹⁰Be (1-6C) alkyl, it optional by halogen, hydroxyl, (1-6C) alkoxyl group, amino, (1-4C) alkylamino and N, N-two-[(1-6C) alkyl] amino replacements.

X in one embodiment ⁸Be selected from CH ₂, O or NR ¹³X wherein ⁸Be formula NR ¹³Group, R ¹³The specific examples of group comprise hydrogen, carboxyl, carbamyl, N-(1-6C) alkylamino formyl radical, N, NThe group of-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl or following formula:

-X ⁷-R ¹⁰

X wherein ⁷And R ¹⁰As top definition.

Especially in this example, as X ⁷Be a connecting key or C (O) group.R ¹⁰Be selected from (1-6C) alkyl rightly, this group is optional to be replaced by one or more groups, for example 1 to 3, is selected from halogen, hydroxyl or (1-6C) alkoxyl group.This class-X ⁷-R ¹⁰Examples of groups comprises CH ₃COCH ₃COCH ₂OH; COCH ₂OCH ₃COCH (OH) CH ₂OH; COCH (OCH ₃) CH ₂(OCH ₃); COCH (OH) CH ₂OCH ₃COCH (OCH ₃) CH ₂OH; COCH ₂CH ₂OCH ₃COCH ₂CH ₃COCH (OH) CH ₃Or COCH (OCH ₃) CH ₃

X in one embodiment ⁸Be NR ¹³, R wherein ¹³Be selected from alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(2-4C) and (1-3C) alkyl of alkoxyl group-(2-4C).R for example ¹³Be selected from hydrogen, methyl, ethyl and 2-methoxy ethyl.

The R that is fit to ¹³Be hydrogen atom or methyl.

X in a specific embodiments Chinese style IA ⁸Be O or CH ₂

B is 0 in formula IA in a specific embodiments.

The specific embodiments of formula I

In a preferred embodiment, group-X in the quinazoline of formula I ²ZR ²⁰Be at Q ^aThe ortho position (2-) of theheterocyclic nitrogen atom, the X of nitrogen-atoms and formula I ¹Link to each other.

Provide in one embodiment of the invention formula I as top defined quinazoline derivant, wherein:

R ¹Be selected from alkoxyl group of hydrogen, hydroxyl, (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C) (R especially ¹Be selected from alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C));

X ¹Be C (R ⁹) ₂, one of them R ⁹Be hydrogen, another R ⁹Be selected from alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C) and (1-3C) alkyl of alkoxyl group-(1-3C) (R especially ⁹Be hydrogen atom or (1-3C) alkyl, more specifically R ⁹Be hydrogen atom).

Or two R ⁹Group forms (3-6C) cycloalkyl (example is a ring third ring) with the carbon atom that is connected with them;

Q ^aBe selected from azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only) 1,3-thiazoles alkane-3-base and morpholino;

Q is 0,1,2 or 3 (particularly 0,1 or 2);

Each W, they can be identical or different, are selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, hydroxyl-(1-4C) alkyl and (1-4C) alkyl of alkoxyl group-(1-4C),

Or the W group on two the adjacent ring carbon atom is at Q ^aLast formation (1-3C) alkylidene bridge should (1-3C) alkylidene bridge optionally has 1 or two substituting groups, and this class substituting group can be identical or different, is selected from hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group;

X ²Be selected from CH ₂C (O) and C (O) (preferred X ²Be C (O));

That Z is selected from alkyl and two-[(1-3C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of hydrogen, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C), cyano group-(1-4C), amino-(2-4C), (1-3C) alkylamino-(2-4C) is amino-(2-4C) alkyl;

R ²⁰It is hydrogen atom;

A is 1,2 or 3 (preferred a is 1 or 2);

Each R ³, they can be identical or different, are selected from fluorine, chlorine, bromine and ethynyl;

Or its pharmacy acceptable salt.

In this embodiment preferably-X ²ZR ²⁰At Q ^aThe ortho position (2-) of theheterocyclic nitrogen atom, the X of nitrogen-atoms and formula I ¹Link to each other.

The occurrence of Z is selected from hydrogen, (1-3C) alkyl, (2-3C) thiazolinyl and (2-3C) alkynyl in this embodiment.More specifically, Z is selected from hydrogen, methyl and ethyl.Preferred Z is a hydrogen atom.

In this embodiment the occurrence of q be 0 or 1 and W be selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C).

Preferred in this embodiment a is 1 or 2, and a R ³Position (3) this R simultaneously between aniline group ³Be selected from chlorine, bromine and ethynyl (preferred chlorine or bromine), another R ³At the ortho position of aniline group (2-) or contraposition (4-) this R simultaneously ³Be selected from fluorine or chlorine (preferred fluorine).

A concrete anilino on the quinazoline ring 4-position of formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido in this embodiment.More specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino.

In another specific embodiment of the present invention, provide the quinazoline derivant of formula I, its tool formula IB:

R wherein ¹, R ³, Z, W and q any value defined and formula I in relevant;

R ⁹Be selected from hydrogen and (1-3C) alkyl (example is R ⁹Be hydrogen or methyl, preferred R ⁹Be hydrogen);

A is 1,2 or 3 (preferred 1 or 2) each R simultaneously ³, they can be identical or different, are selected from fluorine, chlorine, a bromine and ethynyl (preferred R ³Be position (3-) and be selected from chlorine, bromine and ethynyl between the aniline group of formula IB, and when a is 2, another R ³Be fluorine);

Or its pharmacy acceptable salt.

R in the quinazoline derivant of formula IB ¹Occurrence be alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C).More specifically, R ¹Be for example methoxyl group, oxyethyl group or isopropoxy of (1-4C) alkoxyl group.

The occurrence of q is 0 or 1 and W is selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C) in the quinazoline derivant of formula IB.Concrete, W is selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C),

Or q be 2 and two W groups on the adjacent ring carbon atom of tetramethyleneimine-1-base form (1-3C) alkylidene bridge, this (1-3C) alkylidene bridge is chosen wantonly and is had 1 or two substituting groups, this class substituting group can be identical or different, is selected from hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group;

The occurrence of the Z of formula IB is selected from hydrogen and (1-3C) alkyl.But preferred Z is a hydrogen.

A concrete aniline group on the quinazoline ring 4-position of formula IB is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido in this embodiment.More specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino.

Correspondingly definition as described above, a concrete quinazoline derivant tool formula IB structure, wherein:

R ¹It is (1-4C) alkoxyl group;

R ⁹Be hydrogen or methyl (preferred hydrogen);

Q is 0,1 or 2 (preferred 0 or 1), and W have with front formula I in quinazoline derivant in the defined any value of corresponding W (especially W is selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C), and for example W is hydroxyl, methoxy or ethoxy);

Z is selected from hydrogen and (1-3C) alkyl (preferred Z be hydrogen); Anilino on the quinazoline ring 4-position is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, particularly 3-chloro-2-fluoroanilino simultaneously;

Or its pharmacy acceptable salt.

Another embodiment of the invention is the compound of formula IA, and wherein q is that 1 while W is in the 4-position of tetramethyleneimine-1-basic ring, so the quinazoline derivant of formula I is expressed as formula IC, or its pharmacy acceptable salt:

Wherein W, R ¹, R ³, X ¹, X ², R ²⁰With Z here definition and formula IA in corresponding.

In the quinazoline derivant of formula IC, X ²Be appropriate C (O).

In one embodiment of the invention, provide a kind of quinazoline derivant as previously defined formula IC, or its pharmacy acceptable salt, wherein:

R ¹It is (1-4C) alkoxyl group;

X ¹Be CH ₂Or CH (CH ₃) (preferred X ¹Be CH ₂);

X ²Be C (O);

R ²⁰Be hydrogen;

Z is hydrogen or (1-3C) alkyl;

W has with the front and is the defined any value of W in the quinazoline derivant of formula I accordingly; And

Anilino on the 4-position of formula IC is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido (more specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino).

Q is 0 or 1 and W is selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C) in this embodiment.Concrete, W is selected from the alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkoxyl group-(1-3C) alkyl, for example W are hydroxyl, methoxy or ethoxy.

The quinazoline derivant of the formula I of formula ID is provided in another embodiment of the invention:

R wherein ¹, R ³, Z and W here definition and formula I in corresponding.

R ⁹Be selected from hydrogen and (1-3C) alkyl (R for example ⁹Be hydrogen or methyl, preferred R ⁹Be hydrogen); Simultaneously

A is 1,2 or 3 (preferred 1 or 2) each R simultaneously ³, they can be identical or different, are selected from fluorine, chlorine, bromine or ethynyl;

Or its pharmacy acceptable salt.

In the quinazoline derivant of formula ID, R ¹Occurrence be alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C).R more specifically ¹Be (1-4C) alkoxyl group such as methoxyl group, oxyethyl group or isopropoxy.

In the quinazoline derivant of formula ID, the occurrence of q is 0 or 1, and W is selected from that hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, the alkyl of hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C).Concrete, W is selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C).

The occurrence of Z is selected from hydrogen and (1-3C) alkyl in formula ID.Preferred Z is a hydrogen.

In this embodiment, a concrete anilino on the quinazoline ring 4-position of formula ID is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido.More specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino.

Definition as described above accordingly, a concrete quinazoline derivant tool formula ID structure, wherein:

R ¹It is (1-4C) alkoxyl group;

R ⁹Be selected from hydrogen and methyl (preferable methyl);

Q is 0,1 or 2 (preferred 0 or 1), and W has the defined any value of corresponding W in the quinazoline derivant with front formula I (particularly W is selected from alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C), and for example W is hydroxyl, methoxy or ethoxy);

Z is selected from hydrogen and (1-3C) alkyl (preferred hydrogen); Simultaneously

Aniline group on the quinazoline ring 4-position is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino and particularly 3-chloro-2-fluoroaniline;

Or its pharmacy acceptable salt.

The quinazoline derivant of the formula I of formula IE is provided in another embodiment of the invention:

R wherein ¹, R ³, corresponding among the value of Z, W and q the definition here and the formula I;

Or its pharmacy acceptable salt.

In the quinazoline derivant of formula IE, R ¹Occurrence be alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C).More specifically, R ¹Be for example methoxyl group, oxyethyl group or isopropoxy of (1-4C) alkoxyl group.

In the quinazoline derivant of formula IE the occurrence of q be 0 or 1 and W be selected from alkyl of halogen, (1-4C) alkyl, hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C).Particularly W is selected from alkyl of (1-3C) alkyl, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C).

The occurrence of the Z of formula IE is selected from hydrogen and (1-3C) alkyl.Preferred Z is a hydrogen.

A concrete aniline group on the quinazoline ring 4-position of formula IE is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido in this embodiment.More specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino.

Definition as described above accordingly, a concrete quinazoline derivant tool formula IE structure, wherein:

R ¹It is (1-4C) alkoxyl group;

R ⁹Be selected from hydrogen and methyl (preferred hydrogen);

Q is 0,1 or 2 (preferred 0 or 1), and W has the defined any value of corresponding W in the quinazoline derivant with front formula I (being selected from alkyl of (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C) as W);

Aniline group on the quinazoline ring 4-position is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino and particularly 3-chloro-2-fluoroanilino;

Or its pharmacy acceptable salt.

The quinazoline derivant of the formula I of formula IF is provided in another embodiment of the invention:

R wherein ¹, R ³, corresponding among the definition of W, q and Z the value here and the formula I;

Or its pharmacy acceptable salt.

In the quinazoline derivant of formula IF, R ¹Occurrence be alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxyl group of alkoxyl group-(2-4C).More specifically, R ¹Be for example methoxyl group, oxyethyl group or isopropoxy of (1-4C) alkoxyl group.

In the quinazoline derivant of formula IF the occurrence of q be 0 or 1 and W be selected from alkyl of halogen, hydroxyl, (1-4C) alkyl, hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C).Concrete, W is selected from alkyl of hydroxyl, (1-3C) alkyl, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C).The value of preferred q is 0 or 1, and when W exists, is positioned at the 3-position of azetidine-1-base of formula IF.

The occurrence of Z among the formula IF is selected from hydrogen and (1-3C) alkyl.Preferred Z is a hydrogen.

A concrete aniline group on the quinazoline ring 4-position of formula IF is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido in this embodiment.More specifically, this aniline group is a 3-bromo-2-fluoroanilino, or preferred 3-chloro-2-fluoroanilino.

Definition as described above accordingly, a concrete quinazoline derivant tool formula IF structure, wherein:

R ¹It is (1-4C) alkoxyl group;

R ⁹Be selected from hydrogen or methyl (preferred hydrogen);

Q is 0,1 or 2 (preferred 0 or 1), W is in the 3-position of azetidine-1-basic ring, and and W have the defined any value of corresponding W in the quinazoline derivant with front formula I (being selected from the alkyl of hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl-(1-3C) and (1-3C) alkoxyl group-(1-3C) alkyl, for example W are hydroxyl, methoxy or ethoxy) as W;

Aniline group on the quinazoline ring 4-position is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, particularly 3-chloro-2-fluoroanilino;

Or its pharmacy acceptable salt.

A compound that special preferred secondary group is formula IG of the quinazoline derivant of formula I

R wherein ¹, R ³, R ²⁰, corresponding among the definition of a and Z the value here and the formula IA.

R ⁹Be hydrogen or methyl (preferred hydrogen); Simultaneously

R ²²Be selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (2-6C) alkyloyl and a R ¹⁰Group, wherein R ¹⁰Definition and front formula I in corresponding.

R ²²Specific examples comprise hydrogen, (1-6C) alkyl for example alkyl of the alkyl of methyl, ethyl, propyl group, sec.-propyl, normal-butyl, halogen-(1-6C), hydroxyl-(2-6C) or (1-6C) alkyl of alkoxyl group-(2-6C);

Or its pharmacy acceptable salt.

R ²²Example comprises alkyl of the alkyl of hydrogen, (1-4C) alkyl, halogen-(1-4C), hydroxyl-(2-4C) or (1-3C) alkyl of alkoxyl group-(2-4C) more specifically.

More specifically, R ²²Can be hydrogen or (1-6C) alkyl, R more specifically again ²²Be for example methyl or ethyl of (1-4C) alkyl.

In this embodiment of the present invention, the Z of formula IG and R ²⁰Be suitable hydrogen.

Definition as described above accordingly, a concrete quinazoline derivant tool formula IG, wherein:

R ¹It is (1-4C) alkoxyl group;

R ⁹Be hydrogen or methyl (preferable methyl);

R ²⁰Be hydrogen;

Z is selected from hydrogen and (1-3C) alkyl (preferred hydrogen);

R ²²Be that any value of definition is here arranged, as hydrogen or (1-3C) alkyl;

Or its pharmacy acceptable salt.

This point is appreciated that, promptly because some compound of previously defined formula I is owing to have the carbon atom and/or the sulphur atom of one or more asymmetric replacements, so they can optical activity or the form of raceme exist, simultaneously accordingly can optical purity, the form of non-enantiomer mixture or racemize salt mixture exists and with this class isolated in form.Present invention resides in the compound form any raceme, optically active, optically pure, non-enantiomer mixture, steric isomer of formula I in its range of definition, or have its active mixture above-mentioned.By the standard technique that organic chemistry filed is known, the synthetic of optical activity form can be realized, for example synthesize by optically active starting raw material, or to mesotomy.Similar, by using the hereinafter standard test chamber technology of indication, can detect activity above-mentioned.

The present invention relates to all isomeric forms with the formula I that suppresses proliferation activity.

This point also can understand be some compound of formula I can solvation and the form of non-solventization have hydrate forms for example.This point also can be understood and promptly the present invention includes all these classes and have the solvation form that suppresses proliferation activity.

This point also can understand be some compound of formula I can be polymorphous form exist, the present invention includes all these classes and have the polymorphous form that suppresses proliferation activity.

The suitable pharmacy acceptable salt of the compound of formula I is, the acid salt of the compound of formula I for example is for example with the organic or inorganic acid acid salt that forms of hydrogenchloride, hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid for example; Or the salt of acid enough formula I compound, for example for example calcium salt or magnesium salts of basic metal or alkaline earth salt, or ammonium salt, or with the organic bases salt that forms of methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine for example.

Preferred compounds of the invention are example is to be selected from the quinazoline derivant of the formula I of Table I and II:

Table I

Table II

The example of particular compound of the present invention is the quinazoline derivant of formula I, is selected from:

1) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the L-prolineamide;

2) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the D-prolineamide;

3) (4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-L-prolineamide;

4) (4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-L-prolineamide;

5) (4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide;

6) (4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide;

7) 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the L-prolineamide;

8) 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the D-prolineamide;

9) (4R)-1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide;

10) (4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide;

11) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the D-prolineamide; With

12) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)- N, N-dimethyl-L-prolineamide;

Or its pharmacy acceptable salt.

The example of the another kind of particular compound of the present invention is the quinazoline derivant of formula I, is selected from:

1) (4R)-3-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-1,3-thiazoles alkane-4-methane amide;

2) (3S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-hydroxyl-L-prolineamide;

3) (4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-oxyethyl group-D-prolineamide;

4) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-2-methyl prolineamide; With

5) (1S, 5R)-3-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-azabicyclo [3.1.0] hexane-2-methane amide;

Or its pharmacy acceptable salt.

The present invention also further provides the method for quinazoline derivant or its pharmacy acceptable salt of preparation formula I.It should be noted that some substituting group can need protection for fear of the reaction of not wishing to take place in some process below.When needing protection, those skilled in the art will know that how protecting group is placed the appropriate location and goes protecting group subsequently.

Book about this theme aspect of blocking group has a lot, for example the Protective Groups in Organic Synthesis (publisher: John Wiley ﹠amp that writes of Theodora Green; Sons).Protecting group can be removed by any easy method of describing in the document, or the method for the appropriate removal protecting group known to the chemist, the method that this class is selected when removing protecting group effectively to molecule in other group influence minimum.

If therefore reactant includes for example amino, carboxyl or this class group of hydroxyl, it can be protected this class group in some reaction of here mentioning.

For the protecting group that is fit to of amino or alkylamino is acyl group for example; such as alkyloyl ethanoyl for example; carbalkoxy is methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl for example, and fragrant methoxycarbonyl is rolled into a ball for example benzyloxy carbonyl, or aroyl is rolled into a ball for example benzoyl.Go protective condition according to selected protecting group and needs are done various variations to top protecting group.For example to the removal of acyl group such as alkyloyl or carbalkoxy or fragrant acyl carbonyl, can by with the alkali that is fit to for example alkali metal hydroxide such as lithium hydroxide or sodium hydroxide hydrolysis.The selectable another kind of method of removing acyl group is; removal such as tertbutyloxycarbonyl; adopt the acid that is fit to handle for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid; and the aryl methoxycarbonyl is rolled into a ball for example removal of benzene methoxycarbonyl; can adopt catalyzer for example palladium carbon come the method for catalytic hydrogenation, or with Lewis acid for example three (trifluoracetic acid) boron salt handle.For for example removal of phthalyl of primary amino group's protecting group, can for example handle by handling with alkanamine with dimethylaminopropylamine or with hydrazine.

Suitable protecting group for hydroxyl is, acyl group for example, and for example alkyloyl is such as ethanoyl, aroyl benzoyl or arylmethyl benzyl for example for example.Go protective condition according to selected protecting group and needs are done various variations to top protecting group.For example, can lead to suitable alkali and come hydrolysis, for example use alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or ammonium the removal of acyl group such as alkyloyl or aroyl.To for example removal of benzyl of arylmethyl, can come catalytic hydrogenation by using palladium-carbon catalyst.

The protecting group that is fit to for carboxyl is an esterified group; for example methyl or ethyl, they can by with alkali for example sodium hydroxide come hydrolysis to remove; or for the removal of the tertiary butyl, use sour; organic acid such as trifluoroacetic acid for example, or for example use for the removal of benzyl that the catalyzer of palladium carbon comes catalytic hydrogenation.

The mutual resin of ion also can use as protecting group.

In any stage in synthetic, can use the short-cut method of knowing at chemical field to remove blocking group.

The quinazoline derivant of formula I or its pharmacy acceptable salt, can by any known preparation chemically the method for similar compound prepare.These class methods when the quinazoline derivant that is used for preparation formula I or its pharmacy acceptable salt, as characteristics of the present invention, and are illustrated in the following example.Essential starting raw material can obtain (for example, Advanced Organic Chemistry (Wiley-Interscience), Jerry Mach) by the organic chemistry method of classics.The preparation of this class starting raw material is described in appended unrestricted embodiment.Or essential starting raw material prepares by similar process, and this class process can both be set forth in common organic chemist.For must starting raw material or the preparation information of related compound (they can be suitable for prepare must starting raw material) can be below patent and application find in open, the content of the correlated process in them is attached to herein by reference: WO 94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO97/38994, WO 01/66099, US 5,252,586, EP 520722, EP 566226, EP 602851 and EP 635507.

It is the quinazoline derivant of formula I that the present invention also provides this content, or its pharmacy acceptable salt can prepare (except other other explanation, variable wherein is according to top definition) by following method:

The present invention also provides the quinazoline derivant of preparation formula I, or the method for its pharmacy acceptable salt.

This point should be noted that promptly some substituting group can need protection to avoid taking place side reaction in below some process.When those skilled in the art needs to protect if should figuring out, how protecting group is placed correct position, and what happened, then is removed.

For the protecting group that is fit to of amino or alkylamino is acyl group for example, and such as alkyloyl for example methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl of ethanoyl, carbalkoxy for example, fragrant methoxycarbonyl is rolled into a ball for example benzyloxy carbonyl, or aroyl benzoyl for example.Go protective condition according to selected protecting group and needs are done various variations to top protecting group.For example to the removal of acyl group such as alkyloyl or carbalkoxy or fragrant acyl carbonyl, can by with the alkali that is fit to for example alkali metal hydroxide such as lithium hydroxide or sodium hydroxide hydrolysis.The selectable another kind of method of removing acyl group is; removal such as tertbutyloxycarbonyl; adopt the acid that is fit to handle for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid; and the aryl methoxycarbonyl is rolled into a ball for example removal of benzene methoxycarbonyl; can adopt catalyzer for example palladium carbon come the method for catalytic hydrogenation, or with Lewis acid for example three (trifluoracetic acid) boron salt handle.For for example removal of phthalyl of primary amino group's protecting group, can be by reacting, for example with dimethylaminopropylamine or hydrazine with alkanamine.

Suitable protecting group for hydroxyl is, acyl group for example, and for example for example benzoyl or arylmethyl are rolled into a ball for example benzyl to alkyloyl such as ethanoyl, aroyl.Go protective condition according to selected protecting group and needs are done various variations to top protecting group.For example, can lead to suitable alkali and come hydrolysis, for example use alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or ammonium the removal of acyl group such as alkyloyl or aroyl.To for example removal of benzyl of arylmethyl, can come catalytic hydrogenation by using palladium-carbon catalyst.

The protecting group that is fit to for carboxyl is an esterified group; for example methyl or ethyl, they can by with alkali for example sodium hydroxide come hydrolysis to remove; or for the removal of the tertiary butyl, use sour; the organic acid of trifluoroacetic acid for example, or for example use for the removal of benzyl that the catalyzer of palladium carbon comes the catalysis cyaniding.

The mutual resin of ion also can use as protecting group.

Method (a):

Compound with formula (II)

Wherein n, a, R ¹, R ³And R ⁹Such as claim 1 definition, when only needing any functional group is protected and the compound of formula (III) reaction:

X wherein ², W, R ²⁰B and Q ^aWhen only needing as described in claim 1, any functional group is protected; Or

Method (b):

Compound with formula (XX):

R wherein ¹, R ³, R ⁹, n and a as described in claim 1, when only needing any functional group is protected, L is a leavings group, with the compound reaction of defined formula (III) in the top method (a); Or

Method (c)

In order to prepare wherein X ²Be the quinazoline derivant of the formula I of C (O), can be easily in the presence of suitable alkali, with quinazoline or its reactive derivative of formula (XXI):

R wherein ¹, R ³, W, a, q, X ¹And Q ^aSuch as claim 1 definition, when only needing any functional group is protected and the compound or its salt of formula XXII:

HN(R ²⁰)Z

XXII

Carry out linked reaction and make,

R wherein ²⁰With Z such as claim 1 definition, when only needing any functional group is protected; Or

Method (d)

With suitable aldehyde the quinazoline derivant of the formula I that comprises the NH group accordingly being carried out reduction amination makes; Or

Method (e)

In order to prepare wherein R ¹Be the quinazoline derivant of the formula I of hydroxyl, by R wherein ¹For the cracking of the quinazoline derivant of the formula I of (1-6C) alkoxyl group makes; Or

Method (f)

In order to prepare wherein R ¹The quinazoline derivant of the formula I that links to each other with the quinazoline ring by Sauerstoffatom, with the compound of formula (XXIII):

R wherein ³, R ²⁰, Z, W, a, q, X ¹, X ²And Q ^aSuch as claim 1 definition, when only needing any functional group is protected, with formula R ^{1 '}The compound of OH carries out linked reaction and makes, wherein R ^{1 '}As in this paper claim 1 to R ¹Definition, be one of oxygen linking group, when only needing any functional group is protected;

(with any order) then, if desired

(i) quinazoline derivant of formula I is converted into the quinazoline derivant of another formula I;

(ii) remove any blocking group of existence by conventional methods; With

(iii) generate pharmaceutically acceptable salt.

The actual conditions of above-mentioned reaction is as follows:

The reaction conditions of method (a)

Under the corresponding reductive amination condition of described below and method (d), this reaction just takes place aptly.This is reflected at a kind of reductive agent, under the situation that for example a kind of boron compound of particularly a kind of Lewis acid or hydrogen exist, and just suitable generation.Concrete example is the sodium borohydride that sodium triacetoxy borohydride, sodium cyanoborohydride or polymer support are supported.Organic solvent is tetrahydrofuran (THF), ethylene dichloride, 1 for example, and 2-ethylene dichloride or alkyl alcohol be methyl alcohol or ethanol for example, and this reaction is had suitable influence.The optimal temperature of reaction is for example 0-60 ℃ or room temperature.Under the situation that siccative or dewatering agent exist, this reaction also can be carried out, particularly sal epsom or molecular sieve they can promote to react.

If desired, available compound optically active or that split the formula (III) of form prepares the compound of optically active formula I.

Method (a) is particularly suitable for the quinazoline derivant of preparation formula I, and wherein n is 1.

The preparation of method (a) starting raw material

Come the compound of suitable preparation formula (II) by the compound of a kind of formula of oxidation (IV)

R wherein ⁹, R ¹, R ³, corresponding among the definition of n and a and the formula I, but when needed wherein any functional group is protected.With oxygenant oxidizing reaction is suitably acted on, oxygenant for example manganese oxide, four-n-propyl is crossed ruthenic acid ammonium (TPAP)/N-methylmorpholine-N-oxide compound, or with the Swern condition (for example by add alkali for example triethylamine activate promoted oxidizing reaction by the oxalyl chloride of methyl-sulphoxide (DMSO)).For example methylene dichloride, methyl alcohol, dioxane, 1 in a kind of organic solvent, 2-methylene dichloride or THF.The temperature of reaction is 0-50 ℃ or room temperature for suitable temperature example.Reaction duration is wanted sufficiently long so that oxidizing reaction takes place.If desired, with column chromatography for example silicagel column come separated product.

Selectable another kind of method, the compound of formula (II) wherein n are 1 and R ⁹Be hydrogen, the compound hydroformylation by wushu (VII) prepares, and formula (VII) is defined as follows.In this example, compound by wushu (VII) and carbon monoxide and a kind of reductive agent be trioctylphosphine silane or triethyl silicane for example, under the condition that palladium catalyst exists, react, this reaction is exerted an influence, palladium catalyst palladium for example wherein, it and a kind of strong electron-donating group for example diphenylphosphino propane and a kind of alkali for example triethylamine combine.This for example is reflected at inert solvent N, NSuitably carry out in-the dimethyl formamide.This is reflected in the high temperature and suitably carries out, and for example 40 to 100 ℃, for example about 70 ℃.

The compound of formula (II) wherein n is 1 and R ⁹It is methyl, can be promptly as the compound of formula defined above (VII) and (1-6) alkyl vinyl acetate by the preparation of following method, normal-butyl vinyl acetate for example, in palladium catalyst prepared in reaction under the condition that exists of palladium for example, wherein palladium and a kind of strong electron-donating group for example diphenylphosphino propane and a kind of alkali for example triethylamine combine.Along with the carrying out of reaction, the ester that obtains obtains the compound of formula (II) with acid treatment.This reaction occurs in inert solvent or the thinner suitably to be carried out, the condition of reaction and hydroformylation conditional likelihood recited above.

R wherein ⁹Be the compound of the formula (IV) of hydrogen, the compound by suitable reduction formula V prepares

R wherein ¹, R ³, corresponding among the definition of n and a and the formula I, except when needed wherein any functional group being protected, R simultaneously ²⁵It is protecting group (1-6) alkyl for example of acid.Use reductive agent that reduction reaction is suitably taken place, for example use Lithium Aluminium Hydride (LiAlH ₄), diisobutyl aluminium hydride hydrogen (DIBAL-H), sodium borohydride (NaBH ₄) or BH ₃S (CH ₃) ₂A kind of special reductive agent that can need in this course to use is red aluminium, the compound of a kind of formula (VI)

([CH ₂OCH ₂OCH ₂) ₂AlH ₂]Na

(VI)

It obtains with the solution form, for example organic solvent for example in hexane or the toluene mass ratio be 65-75%.At a kind of organic solvent THF for example, for example carry out this reaction from-100 to 60 ℃ in low temperature or moderate temperature.With the reaction end of red aluminium, quencher reaction in the aqueous solution of sodium hydrotartrate.

The hydrocarboxylation of the compound of through type (VII) can prepare the compound that n wherein is 1 formula V

R wherein ¹, R ³Corresponding with among the definition of a and the formula I, except when needed wherein any functional group being protected, L represents leavings group simultaneously.Concrete, the compound of through type (VII) and carbon monoxide and formula R ²⁵The alcohol of OH reacts the generation that influences this class reaction, wherein R ²⁵Definition and the front formula V in corresponding, under the palladium catalyst condition that for example palladium exists, react, wherein palladium and a kind of strong electron-donating group for example diphenylphosphino propane and a kind of alkali for example triethylamine combine.At the inert solvent or the thinner that are fit to, for example N, NCarry out in-the dimethyl formamide.This is reflected at the high temperature example and carries out for example about 70 ℃ for from 40 to 100 ℃.

The specific examples of leaving group L comprises trifluoromethyl sulfonyloxy or halogen for example chlorine, bromine and iodine in formula V.

The preparation of the compound of formula (VII) is by the compound with formula (VIII)

R wherein ¹, R ³Corresponding with among the definition of a and the formula I is except protecting any functional group when needed, with the compound reaction of halide reagent or formula (IX)

Wherein L is the leavings group beyond the halogen.This reaction occurs in a kind of inert solvent for example ethylene dichloride, THF or 1, in the 2-ethylene dichloride, under the alkali condition that for example pyridine, triethylamine, di-isopropyl ethylamino or 4-dimethylaminopyridine (4-DMAP) exist.In low temperature, for example from-20 to 20 ℃, react under preferred 0 ℃ of condition.

The specific examples of the compound of formula (IX) is a trifluoromethyl sulfonic acid anhydride.

The compound of formula (VIII) is known, or the correlation technique that technology easy to use or this area were described in the past prepares.Patent that this class is concrete and application are listed in the above, for example WO96/15118, WO01/66099 and EP566226.For example, but according to the compound of reaction scheme 1 preparation formula (VIII):

Reaction scheme 1

R wherein ¹, X ¹, G ¹And G ²The same with the front definition, Pg is that hydroxyl protecting group, Lg are leavings groups, defines the same with L.

The note of reaction scheme 1

Step (i): reaction occurs in a kind of inertia protonic solvent (for example alkanol is such as Virahol) aptly, a kind of aprotic solvent (for example dioxane), or the bipolarity aprotic solvent is (for example N, N-N,N-DIMETHYLACETAMIDE) in, in the presence of acid, for example be dissolved in the hydrogen chloride gas in ether or the dioxane, or hydrochloric acid, in the above under the simulated condition of describing in the method (a).

Selectable another kind of method is, reaction can for example in the presence of the salt of wormwood, take place in the superincumbent inert solvent at alkali.The temperature range of reaction generation is 0 to 150 ℃ above, near the reflux temperature or reflux temperature of solvent.

Step is (ii): dissociating of Pg can be carried out under the standard conditions of this class reaction.For example when Pg be alkyloyl for example during ethanoyl, dissociate by in the presence of methanol ammonia, heating.

The compound of formula VIIIa is known or uses the method for preparing similar compound to prepare.If buy less than, the compound of formula (VIII) can prepare by the method that is selected from the classical chemical technology, this class technology is similar with close compound method on the synthetic known structure, or this class technology is similar with the top method of describing in example.For example, Jing Dian chemical technology has description in Houben Weyl.For example, the compound of formula VIII R wherein ¹Be that methoxyl group, Lg are that chlorine and Pg are ethanoyl, can prepare by the method for in reaction scheme 2, setting forth

Reaction scheme 2

Those skilled in the art can be applied to (for example introducing at the 7-of quinazoline ring is not the substituting group of methoxyl group) in other compound of specifically not setting forth in this specification sheets to reaction scheme 2.

Wherein n is 2 formula V compound, but the compound of through type (VII), wherein L is for example OTf of leaving group, Tf is a trifyl here, reacts with the compound of formula (X) to prepare

R wherein ⁹Definition with top the same, tms is a trimethyl silyl, is using the similar approach describe in J.Organic Chemistry 1991,56 (1) p261 in the presence of the palladium catalyst.

Selectable another kind of method, the compound of formula (IV) wherein n is 2, the compound by reduction-type (XI) prepares.

R wherein ¹, R ³Corresponding with among the definition of a and the formula I is except protecting wherein any functional group when needed.Suitable reductive condition is similar with the reductive condition of the compound of above-described formula V.

The preparation of the compound of formula (XI) can be by the compound to formula (XII)

R wherein ¹, R ³Corresponding with among the definition of a and the formula I except when needed wherein any functional group being protected, carried out the Arndt-Eistert homologation, and for example H.Meier etc. describes, Chem Int Ed.Engl., 1975,14,32.This reaction comprises:

I) formation of acyl chlorides (is for example used (COCl) ₂/ DMF/CH ₂CH ₂At 0 ℃ under room temperature;

The ii) formation of diazo ketone (for example with diazomethane or TMS diazomethane/Anaesthetie Ether/tetrahydrofuran (THF) at 0 ℃ under room temperature; With

Iii) use H ₂The Wolff of O resets, simultaneously at Ag ₂There is heating down in the O catalyzer.

By to the compound of formula V wherein n be the compound that 1 hydrolysis comes preparation formula (XII).Using for example methyl alcohol of alkyl alcohol, at alkali for example in the presence of sodium hydroxide or the lithium hydroxide, organic solvent for example among the THF hydrolysis reaction can take place.The reflux temperature of temperature range from the room temperature to the solvent of reaction.

The compound of formula VIII is known or uses the ordinary method of preparation similar compound to prepare.For example by aminoacylation X ²Become C (O) from corresponding carboxylic acid, simultaneously if desired, change functional group and obtain acid amides and/or W group.This class conversion is also here setting forth with example of knowing.

The reaction conditions of method (b)

Those skilled in the art know appropriate reaction conditions.Usually at inert organic solvents for example among methylene dichloride, ethylene dichloride, DMA, the DMF etc., at alkali for example in the presence of DIPEA, triethyl amino, salt of wormwood, the cesium carbonate etc., to reacting influential.The temperature range of reaction is from 0 ℃ to 200 ℃, or at the boiling temperature of solvent or near the ebullient temperature.

The preparation of method (b) starting raw material

But the compound of the method preparation formula (XX) by routine, for example the compound of through type (IV) and halide reagent or react with the compound of formula (IX) prepares, that describes in compound of its Chinese style (IV) and the top method (a) is corresponding, and that describes in the compound of formula (IX) and the preparation of top method (a) starting raw material is corresponding.At inert organic solvents for example methylene dichloride, THF or 1, in the 2-ethylene dichloride, at alkali for example in the presence of pyridine, triethyl amino, di-isopropyl ethylamino or the 4-DMAP, to reacting influential.Use low temperature, for example from-20 ℃ to 20 ℃, preferably about 0 ℃.

The reaction conditions of method (c)

Under the coupling agent that the is fit to condition that for example carbodiimide, I-hydroxybenzotriazole or urea  coupling reagent exist, the linked reaction of the acid of formula XXI takes place easily.The urea  coupling reagent that is fit to comprise as O-(7-azepine benzotriazole-1 base)- N, N, N ', N '-tetramethyl-phosphofluoric acid urea  (HATU) or O-(1H-benzotriazole-1-yl)- N, N, N ', N '-tetramethyl-Tetrafluoroboric acid urea  (TBTU).The carbodiimide that is fit to comprises bicyclohexane carbodiimide or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.For example react in the presence of dimethyl aminopyridine or the 4-pyrrolidyl pyridine at catalyzer and to carry out easily.

Linked reaction is carried out easily in the presence of the alkali that is fit to.The alkali that is fit to is, for example a kind of organic bases is such as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethyl amino, two-sec.-propyl ethylamino, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene, or basic metal or alkaline earth metal carbonate yellow soda ash for example for example, salt of wormwood, cesium carbonate or lime carbonate.

At the inert solvent or the thinner that are fit to, for example ester is such as ethyl acetate, and halogenated solvent is methylene dichloride, chloroform or tetracol phenixin for example, and ether is tetrahydrofuran (THF) or 1 for example, the 4-dioxane, and the aromaticity solvent is toluene for example, or the both sexes aprotic solvent is for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, in N-methylpyrrole alkyl-2-ketone or the dimethyl sulfoxide (DMSO), reaction is carried out easily.Reacting incidental temperature range is from-20 ℃ to 120 ℃, or reaction at room temperature easily.

" response derivative " of the acid of formula XXI, the meaning of term is meant the derivative of carboxylic acid, the amine reaction of it and formula XXII obtains corresponding amine.The response derivative that is fit to of the carboxylic acid of formula XXI is, as carboxylic acid halides, such as obtaining acyl chlorides by acid and inorganic acyl chloride reaction, such as thionyl chloride; Mixed acid anhydride is such as reacting the acid anhydrides that obtains by acid and Vinyl chloroformate or isobutyl chlorocarbonate; Active ester is such as the ester that obtains by acid and Pentafluorophenol or N-hydroxybenzotriazole; Or acyl azide, such as the trinitride that obtains by acid and the reaction of diphenylphosphine acylazide thing; Acyl cyanide is such as the acyl cyanide that obtains by acid and the reaction of diethyl phosphinylidyne prussiate.The reaction of this response derivative of carboxylic acid and amine (for example compound of formula XXII) is known in this area, and for example described in the above alkali exists down, and this reaction just can take place in the described in the above suitable solvent.The temperature of reaction is as described above.

The preparation of method (c) starting raw material

Formula (XXI) but the compound of preparation through type (II) and formula (IIIa) reaction of compound obtain:

Wherein W, Q ^aCorresponding with among the definition of q and the formula I is except protecting any functional group when needed.Similar in the reaction conditions of this reaction and the method (a).

The compound of formula (IIIa) and formula (XXII) is known, or prepares by easy technology and above-described similar process.

The reaction conditions of method (d)

The condition of the reductive amination reaction that is fit in this area is known, for example and describe in the method (a) corresponding.The quinazoline derivant of formula I, it contains a NH group and (for example works as Q ^aBe piperazine-1-yl), it and suitable aldehyde reaction obtain a group of taking up an official post and replacing at N (alkyl) ring.Suitable aldehyde is conspicuous, for example for the preparation of the quinazoline derivant that contains a N-methyl cyclic group among the formula I, is to obtain in reaction in appropriate reductant by respective compound and the formaldehyde that contains the N-H cyclic group.Similar, for the group that a N of preparation (alkyl) ring is taken up an official post and replaced, suitable aldehyde be corresponding optional substituted (2-6C) alkanal (acetaldehyde for example, propionic aldehyde or (1-4C) alcoxyl aldehyde such as methoxyl group acetaldehyde).

Appropriate reductant is a hydride reducer, and for example composite alkali aluminum hydride is such as Li-Al hydrogen, or alkali metal borohydride sodium borohydride for example, sodium cyanoborohydride, triethyl-boron sodium hydride, trimethyl-boron sodium hydride and sodium triacetoxy borohydride.This is reflected in suitable inert solvent or the thinner and carries out, for example to the strong reductive agent of this class of Li-Al hydrogen with tetrahydrofuran (THF) and ether, to the reductive agent a little less than sodium triacetoxy borohydride and this class of sodium cyanoborohydride with methylene dichloride or for example methyl alcohol and alcoholic acid protonic solvent.Carry out in the acidic conditions under being reflected at suitable acid for example hydrogenchloride or acetate existing, in reaction, can need damping fluid to keep the pH value in required scope.When reductive agent was formic acid, reaction was carried out in formic acid solution easily.The temperature range of reaction, for example-10 to 100 ℃, for example 0 to 50 ℃, or reaction at room temperature easily.

The reaction conditions of method (e)

Dissociation reaction can react in many processes any by present known this class to carry out.Concrete suitable dissociation reaction is the quinazoline derivant of formula I, wherein R ¹Be (1-6C) alkoxy grp and pyridine hydrochloride or alkali metal halide for example lithium iodide is 2,4, there is reaction down in 6-collidine (2).Reaction can be carried out in as previously defined suitable inert solvent or dilution property solvent.Reacting the suitable temperature range of carrying out is, for example 10 to 170 ℃, and preferably for example 120 to 170 ℃ of high temperature, for example general 130 ℃.

The reaction conditions of method (f)

Linked reaction is carried out under the Mitsunobu condition easily.Suitable Mitsunobu condition is known, for example being reflected at three valent phosphors and two-alkyl azodicarboxy hydrochlorate exists down, for example carry out among the THF at organic solvent, or in ethylene dichloride, in 0 to 100 ℃ temperature range, carry out, for example 0 to 60 ℃, but can under near the temperature of room temperature, carry out easily.Suitable three valent phosphors comprises for example three-normal-butyl phosphorus or preferred triphenyl phosphorus.Suitable two-alkyl azodicarboxy hydrochlorate comprises azoethane dicarboxylate (DETA), or two-tertiary butyl azodicarboxy hydrochlorate (DTAD).The detailed process of Mitsunobu reaction is consulted Tet.Letts., and 31,699, (1990); The Mitsunobu Reaction, D.L.Hughes, Organic Reactions, 1992, Vol.42,335-656 and Progress in the Mitsunobu Reaction, D.L.Hughes, Organic Preparations and Procedures international, 1996, Vol.28,127-164.

But the dissociating of quinazoline derivant as the compound through type I of the formula XXIII of starting raw material prepares R in formula I ¹Be methoxyl group for example, (e) prepares by method recited above.

By top method, the quinazoline derivant of formula I can obtain with the form of free alkali, or with salt, a kind of form of acid salt obtains.In the time need from the salt of the compound of formula I, obtaining free alkali, this salt can with suitable alkali reaction, for example a kind of alkali or alkaline earth metal carbonate or oxyhydroxide, yellow soda ash for example, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide, or by and ammonia react, the methanol solution that for example uses ammonia is the methanol solution of 7N ammonia for example.

In compound of the present invention, the various substituting groups on the ring can be introduced by classical aromatic ring substitution reaction, or the conversion by functional group, and this mentions in front, and this class all is a part of the present invention.This class reaction and conversion comprise, for example, introduce substituting group by the aryl substitution reaction, reduction substituting group, substituent alkylation and oxidizing reaction.The reagent and the condition of this class reaction are known in chemical field.The specific examples of aryl substitution reaction comprises by concentrated nitric acid introduces nitro; Under the Friedel-Crafts reaction condition, introduce acyl group by carboxylic acid halides and Louis acid (such as aluminum chloride); Introduce halogen group.

When the pharmacy acceptable salt of the quinazoline derivant that needs formula I, during for example a kind of acid salt, it can react acquisition by simple method by quinazoline derivant and the acid that is fit to.

Already mentioned just as the front, some compound of the present invention can contain a plurality of chiral centres, therefore simultaneously can have multiple steric isomer.By the separable steric isomer of easy method, for example column chromatography or fractional crystallization.Enantiomorph can separate by separating racemic mixture, for example by fractional crystallization, splits or HPLC.Diastereoisomer can separate by the difference on the diastereoisomer physical property, for example by fractional crystallization, and HPLC or rapid column chromatography.Selectable other method is, the part steric isomer can adopt the starting raw material of chirality and chiral reagent to synthesize by chirality under the condition that can not cause racemization to prepare.When separation obtained a kind of concrete steric isomer, appropriate separation was not contain other steric isomer, for example is less than 20%, as is less than 10%, and more the weight as other steric isomer is less than 5%.

In the quinazoline derivant of part about preparation formula I, this expression of inert solvent is meant a kind of solvent in front, this kind solvent discord starting raw material, and reaction reagent, intermediate or product react.

Those skilled in the art can notice, in order to obtain compound of the present invention, can be by other method and some easier methods, carry out the single reaction mentioned among the present invention in differing order, or carry out single reaction (for example chemical conversion can be undertaken by different intermediates, and this class intermediate is relevant with aforementioned certain the concrete reaction of the present invention) in the different steps of whole route.

Used in the present invention some new intermediate and their preparation method are as an additional features of the present invention.Therefore the present invention additionally provides formula (II), and (IV), (V), (VII), (XX) and compound (XXI), their definition as mentioned above.In this compounds specifically, the group of secondary pole type (i)

Be 3-chloro-2-fluorophenyl or 3-bromo-2-fluorophenyl.

Formula (VI), (VIII) and compound (IX) are known or utilize easy method to prepare by compound known.

Biological detection

Following detection can be used to measure compound of the present invention as the erb-tyrosine kinase inhibitor, as KB cell (KB cell) in-vitro multiplication inhibitor with as the effect that is implanted in the growth inhibitor of the intravital Lo Vo of nude mice tumour cell (large intestine gland cancer).

A) the protein tyrosine kinase phosphorylation detects

This test is to analyze test compound to suppress EGFR, erbB2 or the erB4 Tyrosylprotein kinase ability to the peptide substrate phosphorylation that contains tyrosine.

Segment is cloned in baculovirus/Sf21 system and is expressed in the reorganization born of the same parents of EGFR, erbB2 and erbB4 (numbering is respectively X00588, X03363 and L07868).This class cell is by freezing molten born of the same parents' damping fluid (20mM N-2-hydroxyethyl piperazinyl-N '-2-ethylsulfuric acid (HEPES), pH7.5,150mM NaCl, 10% glycerol, 1%Triton X-100,1.5mM MgCl ₂, 1mM ethylene glycol-two (beta-aminoethyl ether) N ', N ', N ', N '-triethyl acid (EGTA) adds proteinase inhibitor, then by centrifugal removal) handle the preparation solute.

The composing type kinase activity of recombinant protein is to detect by the ability that the synthetic peptide of its phosphorylation (by L-glutamic acid, the polymer that L-Ala and tyrosine constitute at random with 6: 3: 1 ratio) constitutes.Concrete, Maxisorb ^TM96-hole immunity plate bag is by last synthetic peptide (polypeptide of 0.2 μ g in phosphate-buffered salt (PBS) solution of 100 μ l, 4 ℃ of incubated overnight).Wash plate with PBS-T (phosphate buffered saline(PBS) that contains 0.5%Tween), then at the synthetic polypeptide of removing under the 50mM HEPES pH7.4 room temperature condition in the excessive not combination.It is that at 100mM HEPES pH7.4, adenosine triphosphate (ATP) was respectively under the condition of every kind of enzyme Km concentration, at 10mM MnCl the plate insulation of 22 ℃ of polypeptide bag quilts 20 minutes that the activity of EGFR, ErbB2 and ErbB4 Tyrosylprotein kinase detects ₂, 0.1mM Na ₃VO ₄, 0.2mM DL-dithiothreitol (DTT) (DTT), 0.1%Triton X-100 and the testing compound (final concentration is 2.5%) that is dissolved in DMSO.By the liquid removing composition, wash plate with PBS-T then and come termination reaction.

Phosphoric acid-polypeptide product that the fixed reaction obtains detects by immunological method.Beginning, plate at room temperature and shouldered Tyrosine O-phosphate first antibody insulation 90 minutes, this first antibody obtains in mouse (4G10 is from Upstate Biotechnology).After the flushing, plate is used in conjunction with Horseradish Peroxidase (HRP) second antibody (NXA931 is from Amersham) of last sheep anti mouse and was at room temperature handled 60 minutes.After further washing, the activity of the HBP of each groove is by using 22 '-azino-two-[3-ethyl benzo thiazole phenanthroline sulfonic acid (6)] di-ammonium salts crystal (ABTS onboard ^TMFrom Roche) as substrate, measure by colorimetry.

The quantitative analysis of colour developing, and enzymic activity subsequently obtains in the absorption detecting of 405nm by Molecular DevicesThermoMax microplate reader.Kinase inhibition for given compound is expressed as IC ₅₀Value.The needed compound concentrations of inhibition 50% phosphorylation decides this value in this detection by calculating.The scope of phosphorylation is according to (carrier+ATP) and negative (carrier-ATP) control value calculates just.

B) EGFR drives the detection of KB cell proliferation

This detects the ability that testing compound suppresses KB cell (from the KB cell of American type culture collection (American Type Culture Collection (ATCC))) propagation of measuring.

KB cell (from the KB cell of ATCC) is containing 10% foetal calf serum, in 2mM glutamine and nonessential amino acid whose Dulbecco ' s improvement Eagle ' the s substratum (DMEM), at 37 ℃ at 7.5%CO ₂The incubator heat insulating culture.Use trypsinase/EDTA to come harvested cell.Use hematimeter to measure cell density, the mensuration of cytoactive be to use trypan blue solution before inoculation in the plate in one 96 hole the cell concn in each hole be 1.25 * 10 ³In DMEM, contain 2.5% charcoal absorption serum, 1mM glutamine and nonessential amino acid at 37 ℃ at 7.5%CO ₂Placed 4 hours under the condition.

After the cell absorption onboard, be incubated after 4 days with being with or without EGF (final concentration is 1ng/ml) and being with or without concentration range (final concentration 0.1%) processing in dimethyl sulfoxide (DMSO) (DMSO) under the situation of compound.After the insulation, the number of cell is by adding the 3-(4,5-dimethylthiazole-2-yl)-2 of 50 μ l, and 5-phenylbenzene tetrazolium  bromide (MTT) (liquid storage 5mg/ml) detected after 2 hours.Bleed off MTT solution then, plate gently falls to do, with the DMSO dissolving of cell by adding 100 μ l.

The absorption value of reading dissolved cell in the absorption of 540nm by Molecular Devices ThermoMax microplate reader.With IC ₅₀Value is represented inhibition of proliferation power.Reaching 50% proliferation suppressive by calculating needs drug concentrations to decide this value.The scope of propagation is according to (carrier+EGF) and negative (carrier-EGF) control value calculates just.

C) clone's 24 phosphoric acid-erbB2 cell detection

The immunofluorescence end point analysis detects the ability that testing compound is suppressed at the phosphorylation activity of the erbB2 in MCF7 (mammary cancer) the derived cell system, the preparation of this clone is by obtaining a clone with classic methods with total length erbB2 gene transfection MCF7 cell, this expression of cell lines total length wild-type erbB2 albumen (hereinafter ' clone's 24 ' cell).

Clone 24 cells in growth medium (Growth Medium) (do not have phenol red Dulbecco ' s improvement Eagle ' s substratum (DNEF), contain 10% foetal calf serum, 2mM glutamine and 1.2mg/ml G418), at 7.5%CO ₂Cultivate down at 37 ℃ in the incubator.By once, with the trypsin 1.25mg/ml of 2ml with PBS (phosphate-buffered salt, pH7.4, Gibco No.10010-015) flushing)/EDTA (0.8mg/ml) solution comes harvested cell.Cell is suspended in the growth medium again.The density of cell is measured with cell counter, and the mensuration of cytoactive is to use trypan blue solution, before this with growth medium dilution then with the density in every hole 1 * 104 be inoculated in the 96 clean orifice plates (Packard, No.6005182).

After 3 days, growth medium removed from the hole change 100 μ l simultaneously and detect substratum (not having phenol red DMEM, 2mM glutamine, 1.2mg/ml G418) or be with or without the erbB inhibitor compound.Plate was put back to thermostat container 4 hours, and 20% formaldehyde solution of 20 μ l in PBS joins in each hole then, at room temperature places 30 minutes.Remove stationary liquid with the porous suction pipe, the PBS that adds 100 μ l removes with the porous suction pipe in each hole then, and the PBS that adds 50 μ l then is in each hole.Plate is sealed then, preserves down at 4 ℃ to be up to for 2 weeks.

Immune labeledly at room temperature carry out.(preparation is by adding the PBS/Tween dry powder (Sigma of a pouch with 200 μ l PBS/Tween 20 in the hole, No.P3563) in the distilled water of 1L) wash once, add the confining liquid (5%Marvel dried skimmedmilk (Nestle) in PBS/Tween 20) of 200 μ l then, be incubated 10 minutes.Remove the 0.5%Triton X-100/PBS that confining liquid adds 200 μ l simultaneously.After 10 minutes, wash plate, the 200 μ l confining liquids of adding are arranged then in each hole, be incubated 15 minutes with 200 μ l PBS/Tween 20.After removing confining liquid, (epitope phosphoric acid-tyrosine 1248, SantaCruz No.SC-1235-R), diluted in confining liquid 1: 250 the anti-phosphoric acid ErbB2IgG of the rabbit polyclonal of 30 μ l antibody, joined in each hole, were incubated 2 hours.This first antibody solution is removed then, then washes twice with 200 μ l PBS/Tween 20.(molecular probe No.A-11008), diluted in confining liquid 1: 750 the Alexa-Fluor488 goat anti-rabbit igg second antibody of 30 μ l, joined in each hole then.After this, under the possible situation, plate will be protected and not be exposed under the light, uses backing strip (backing tape) sealing of black in this course.Plate insulation 45 minutes, second antibody solution is removed from the hole then, washes twice with 200 μ lPBS/Tween 20 then.Add 100 μ l PBS then to each plate, be incubated 10 minutes and get rid of again then.Add 100 μ l PBS then again to each plate, need not be incubated, get rid of then.Add 50 μ l PBS then to each hole, plate was preserved 2 days down at 4 ℃ before analysis with the backing strip sealing of black simultaneously.

By Acumen Explorer Instrument (Acumen Bioscience Ltd.), a kind ofly can be used to the plate readout instrument of fast quantification image characteristics by laser scanning, can measure the fluorescent signal in each hole.This instrument is measured the number of fluorescent object by preset value, and a kind of measurement means of erbB2 phosphorylation state of protein is provided simultaneously.The fluorescence data that every kind of compound obtains obtains suitable curve fitting analysis by suitable software package analysis (for example Origin).ErbB2 phosphorylation inhibition passes through IC ₅₀Value is represented.Determine this value by calculating inhibition 50%erbB2 phosphorylation signal required compound concentration.

D) transplant detection in the body

This analytical test testing compound is in the activity of LoVo tumour (colorectal adenomas the derives from ATCC) growth that suppresses female Swiss nude mice (Alderley Park, nu/nu genotype).

Female Swiss nude mice (nu/nu genotype) is cultivated in the negative pressure shield retaining (PFI Systems Ltd.) of Alderley Park.Mouse was placed on for 12 little time/dark round-robin retaining device in, infinitely provide aseptic food and water to it.This all class processes proceeds to all sizes of mouse to 8 at least.The foundation that LoVo tumour cell (colorectal adenomas derives from ATCC) is transplanted is the back flank subcutaneous injection 1 * 10 every donor mouse ⁷Fresh culturing cell at 100 μ l serum free mediums.After the implantation the 5th day is divided into 7 groups at random with mouse, before this through every day the 0.1ml/10g body weight give compound or vehicle Control treatment.Tumor size measures twice weekly by vernier callipers, calculates with formula (long * wide) * √ (long * wide) * (π/6), and the length here is the longest diameter of tumour, and width is its corresponding vertical line.Research beginning growth-inhibiting is to calculate by the mean change of contrast control group and treatment group gross tumor volume, and the statistical significance between two groups is by the t experimental evaluation.

E) potassium channel of hERG-coding suppresses to detect

This analysis has determined that testing compound suppresses the ability of tail current by hERG-coding potassium channel.

The HEK cell of expressing the hERG-coding pass is grown in (EMEM in the Eaglel minimal medium; Sigma-Aldrich catalog number (Cat.No.) M2279), replenish 10% foetal calf serum (Labtech International; Production code member 4-101-500), 10%M1 serum-free additive (Egg Technologies; Production code member 70916) and 0.4mg/ml GeneticinG418 (Sigma-Aldrich; Catalog number (Cat.No.) G7043).A couple of days before each experiment, by the tissue culture method of standard cell is separated from tissue culture flasks with Accutase (TCS Biologicals).Be placed on the cover glass according to each hole on 12 orifice plates then, and add the 2ml growth medium.

For writing down each cell, the cover glass that contains cell is put into the bottom, Perspex chamber that tank liquor (as follows) is housed, room temperature preservation (～20 ℃).This chamber is fixed on the microscopical platform of paraphase.After immediately cover glass being put into the chamber, from gravity-charging storehouse, tank liquor being filled in the chamber, continue 2 minutes with the speed of about 2ml/min.After time arrives, stop perfusion.

With P-97 microtubule tensilometer (Sutter Instrument CO.) borosilicate glass tube system batch methode dropper, filled with fluid (seeing below).The top of dropper and patch clamp amplifier (Axopatch200B, Axon instruments) connects through silver/silver chloride line.The place, top is connected with ground wire.This is to be embedded in 3% the agar that contains 0.85% sodium-chlor by silver/silver chloride line to constitute.

Cell is noted with the full cell structure of patch clamp technique.In " insertion " afterwards, this is to keep current potential (by the amplifier setting) to finish by-80mV, suitable adjusting resistance and control capacitance, electrophysiology software (Clampex, Axon instruments) are used for being provided with and keep current potential (80mV) with the transfer overvoltage scheme.Per 15 seconds of this scheme is used once, and then step of 1 second-50mV moved and forms by 1 second+40mV for it.Low with 1KHz for the electric current reflection that applies voltage schemes by filtering by amplifier.The filtering signal of online then acquisition is by a similar similar digitizer digitizing of signal process from amplifier.During the sustaining voltage during to+40mV electric current take a sample with 1KHz.To the remaining part of voltage schemes, sampling frequency is set to 5kHz then.

It is as follows that the mole osmotic pressure of composition, pH and tank liquor and dropper liquid is made form.

Salt	Dropper (mM)	Groove (mM)
Salt	Dropper (mM)	Groove (mM)	NaCl	-	137
KCl	130	4	NaCl	-	137
KCl	130	4	MgCl ₂	1	1
CaCl ₂	-	1.8	MgCl ₂	1	1
CaCl ₂	-	1.8	HEPES	10	10
Glucose	-	10	HEPES	10	10
Glucose	-	10	Na ₂ATP	5	-
EGTA	5	-	Na ₂ATP	5	-

Parameter	Dropper	Tank liquor
Parameter	Dropper	Tank liquor	pH	7.18-7.22	7.40
PH regulator is used	1M KOH	1M NaOH	pH	7.18-7.22	7.40
PH regulator is used	1M KOH	1M NaOH	Mole osmotic pressure (mOsm)	275-285	285-295

By Clampex software when voltage from+40mV to-50mV, the amplitude online record of the potassium-channel afterbody electric current of hERG-coding gets off.After the afterbody current amplitude was stable, the tank liquor that contains substrate carrier to be measured was added on cell.Suppose that used carrier to the not obviously influence of afterbody current amplitude, just can construct the cumulative concentration response curve to compound.

Afterbody current amplitude under the medicine to be measured of given concentration exists dissolves the influence of every kind of concentration of medicine to be measured than last afterbody current amplitude in the presence of carrier with it as percentage.

Validity (the IC of medicine to be measured ₅₀) use the data fitting bag of standard that the Hill equation of 4 parameters is set up concentration-response by match percentage inhibiting value to determine.If the inhibition level of high drug level to be measured is no more than 50%, just can not get the validity value, just quote the percentage inhibiting value under that concentration.

Though along with the variation of structure changes, the activity that compound had of formula I generally speaking can be by following concentration or the superincumbent test of dosage (a) as predicting for the pharmacological property of the compound of formula I, (b) with (c) in obtain explaining :-

Test (a) :-IC ₅₀The scope of (for EGFR), for example, 0.001-10 μ M;

Test (b) :-IC ₅₀Scope, for example, 0.001-10 μ M;

Test (c) :-IC ₅₀Scope, for example, 0.01-10 μ M;

Test (d) :-active scope, for example 1-200mg/kg/day;

Explanation by way of example with test (a) (to inhibition of EGFR Tyrosylprotein kinase protein phosphorylation) and test (b) and KB cell detection described above, has provided IC to the representation compound of describing in an embodiment here ₅₀As a result, the A that is listed in the table below:

Table A

The embodiment compound	IC ₅₀(nM) test (a) (to inhibition of EGFR Tyrosylprotein kinase protein phosphorylation)	IC ₅₀(nM) the KB cell proliferation test of test (b) EGFR driving)
The embodiment compound			20	64	143
24	20	50	20	64	143
24	20	50	37	67	160
41	52	290	37	67	160

According to other part of the present invention, medicinal compositions is provided, comprise the quinazoline derivant of formula I, or its pharmacy acceptable salt, define associated pharmaceutically acceptable diluent or carrier as described above.

Composition of the present invention can be to be fit to oral form (tablet for example, lozenge, hard or soft capsule, water or the agent of oiliness DL, emulsion, powder or granule, syrup or elixir), local form (the example emulsion that uses, ointment, gel, or the solution of oiliness or water-based or suspension), the form of inhalation (for example thin powder or the liquid aerosol that looses), be blown into the form (for example thin powder that looses) of administration, or the form of drug administration by injection (for example, intravenous injection, subcutaneous injection, intramuscular injection is with aseptic water-based or oily solution, or rectal administration suppository).

Composition of the present invention can prepare by easy method by using pharmaceutical excipient commonly used, and this class is known in this area.Therefore, can contain just like one or more tinting materials, sweeting agent, correctives and/or sanitas for liquid preparations for oral administration.

Combine the activeconstituents that forms one-pack type with one or more excipient, the different and corresponding variation of their amount according to the approach of the people of medication and administration.For example, prescription for people's oral administration contains usually, for example, (what be more suitable for is to 100mg from 0.5 to activeconstituents from 0.5mg to 0.5g, for example from 1 to 30mg), activeconstituents and an amount of excipient mix, the shared ratio of excipient from whole composition weight about 5% to about 98% variation.

For being used for the treatment of or preventing purpose, the dosage size of the compound of formula I changes according to the principle of medication of knowing according to patient's physique and disease serious degree, age, sex and route of administration.

When the compound of wushu I is used for the treatment of or during prophylactic, gives usually so that the scope of medication of every day exists, for example, supposing need be in the dosage that separates, by the 0.1mg/kg of body weight to 75mg/kg.When drug administration by injection, dosage will reduce usually.Therefore, for example, for intravenous injection, the common use range of dose exists, and for example, the 0.1mg/kg that presses body weight is to 30mg/kg.Similar, for inhalation, the scope of dose exists, and for example presses the 0.05mg/kg of body weight to 25mg/kg.But oral administration is preferred, especially for tablet.Concrete, unit dosage form contains the The compounds of this invention of about 0.5mg to 0.5g.

We find that compound of the present invention has antiproliferative character, cancer resistance for example, and the inhibition activity that this is considered to from erbB family receptors Tyrosylprotein kinase has particularly suppressed the activity of EGF acceptor (erbB1) Tyrosylprotein kinase.Further, according to the present invention, some compound is to the inhibition effect of ERG receptor tyrosine kinase, and for example the inhibition effect of erbB2, VEGF or KDR receptor tyrosine kinase is far better than other Tyrosylprotein kinase.This compounds has effect of sufficient for the EGF receptor tyrosine kinase, to such an extent as to they can significant quantity suppress the EGF receptor tyrosine kinase, but for example the activity of erbB2 is very little or very low to other Tyrosylprotein kinase.This compounds may may cause effective medicine of tumour simultaneously as EGF as the selective depressant of EGF receptor tyrosine kinase.

Accordingly, compound of the present invention wish to be used for by erbB receptor tyrosine kinase (particularly EGF receptor tyrosine kinase) separately or part cause disease, for example, when a warm-blooded animal needed such treatment, this compounds can be used to produce the effect that suppresses the erbB receptor tyrosine kinase activity.Therefore compound of the present invention provides by suppressing one or more receptor tyrosine kinases erbB family to be characteristics, to treat the method for malignant cell.Concrete, compound of the present invention is used for the treatment of antiproliferative and/or apoptosis and/or anti-invasion by suppressing the erbB receptor tyrosine kinase separately or partly.Concrete, compound of the present invention is used to prevent or treats suppressing the tumour of erbB receptor tyrosine kinase sensitivity, for example EGF and/or erbB2 and/or erbB4 receptor tyrosine kinase (particularly EGF receptor tyrosine kinase), they participate in the signal conduction step of impelling tumor cell proliferation and survival.Accordingly, present compound of the present invention is hopeful to be used for the treatment of psoriasis, benign prostatic hyperplasia (BPH), arteriosclerosis and restenosis and/or cancer, it is by antiproliferative curative effect, particularly on the cancer to treatment erbB receptor tyrosine kinase sensitivity.Optimum or the virulent tumour of this class can influence any tissue, comprises for example leukemia of non-solid tumor, and multiple myeloma or lymphoma and solid tumor be cholangiocarcinoma for example, osteocarcinoma, bladder cancer, brain/CNS cancer, mammary cancer, colorectal carcinoma, carcinoma of endometrium, cancer of the stomach, head and neck cancer, liver cancer, lung cancer, neural cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, kidney, skin carcinoma, carcinoma of testis, Tiroidina, uterus carcinoma and carcinoma vulvae.

According to this part of the present invention, the quinazoline derivant of formula I is provided, or its pharmacy acceptable salt, as drug use.

According to further aspect of the present invention, the quinazoline derivant of formula I is provided, or its pharmacy acceptable salt, for example use as antiproliferative agents on the mankind warm-blooded animal.

Therefore according to this part of the present invention, provide the quinazoline derivant of formula I, or its pharmacy acceptable salt, the same with aforementioned definitions, be prepared into medicine, for example use as antiproliferative agents on the mankind warm-blooded animal.

The further characteristics of this part according to the present invention, the warm-blooded animal that provides in this treatment of needs for example suppress a kind of method of propagation among the mankind, and this method comprises quinazoline derivant or its pharmacy acceptable salt that gives as previously defined formula I.

According to another part of the present invention, provide formula I quinazoline derivant or as previously defined its pharmacy acceptable salt be used for preventing or treating the purposes of the medicine of tumour in preparation, this class tumour is responsive to suppressing the erbB receptor tyrosine kinase, for example for EGFR and/or erbB2/ or erbB4 (particularly EGFR) receptor tyrosine kinase, they participate in the signal conduction step of impelling tumor cell proliferation and survival.

The further characteristics of this part according to the present invention, provide in warm-blooded animal a kind of method of prevention or treatment tumour among the mankind for example, this class tumour is responsive to the erbB family that suppresses one or more receptor tyrosine kinases, for example to EGFR and/or erbB2/ or erbB4 (particularly EGFR) receptor tyrosine kinase, they participate in the signal conduction step of impelling tumor cell proliferation and survival, use the quinazoline derivant of formula I in this course, or defined its pharmacy acceptable salt as described above.

The further characteristics of this part according to the present invention, the derivative of formula I is provided, or its pharmacy acceptable salt, warm-blooded animal for example on the mankind as a kind of method of prevention or treatment tumor disease, this class tumour is responsive to the erbB family that suppresses receptor tyrosine kinase, for example to EGFR and/or erbB2/ or erbB4 (particularly EGFR) receptor tyrosine kinase, they participate in impels in the tumor cell proliferation signal conduction step.

The further characteristics of this part according to the present invention, the quinazoline derivant of wushu I is provided, or as previously defined its pharmacy acceptable salt, be prepared into medicine, for example on the mankind, be used to suppress EGFR and/or erbB2/ or erbB4 (particularly EGFR) receptor tyrosine kinase warm-blooded animal.

The further characteristics of this part according to the present invention, provide warm-blooded animal for example on the mankind, with the quinazoline derivant of formula I, or, suppress EGFR and/or erbB2/ or erbB4 (particularly EGFR) receptor tyrosine kinase as previously defined its pharmacy acceptable salt.

The further characteristics of this part according to the present invention provide the quinazoline derivant of wushu I, or as previously defined its pharmacy acceptable salt, be prepared into medicine,, be used for selectivity and suppress the EGFR receptor tyrosine kinase for example on the mankind warm-blooded animal.

The further characteristics of this part according to the present invention provide warm-blooded animal for example on the mankind, with the quinazoline derivant of formula I, or as previously defined its pharmacy acceptable salt, come selectivity to suppress the EGFR receptor tyrosine kinase.

" optionally EGFR kinase inhibitory activity " is meant that the quinazoline derivant of formula I is stronger to other kinase whose effect than it to the restraining effect of EGFR receptor tyrosine kinase.Concrete some drugs according to the present invention to the restraining effect of EGFR receptor kinase than other Tyrosylprotein kinase for example other erbB receptor tyrosine kinase for example the effect of erbB2 is stronger.For example, in suitable detection, pass through relative IC according to the present invention ₅₀Value judges that the kinase whose inhibitor of selectivity EGFR is stronger at least 5 times to the restraining effect of erbB2 Tyrosylprotein kinase than it to the effect that the EGFR receptor tyrosine kinase suppresses, preferably at least 10 times.For example, for a given testing compound as previously described, by the IC from KB cell detection (detect EGFR tyrosine-kinase enzyme inhibition activity) relatively ₅₀Value and the IC from clone 24 phosphoric acid-erbB2 cell detection (detecting erb-B2 tyrosine-kinase enzyme inhibition activity) ₅₀Value.

The further characteristics of this part according to the present invention, the quinazoline derivant of wushu I is provided, or as previously defined its pharmacy acceptable salt, be prepared into medicine, for example on the mankind, (for example this cancer is selected from leukemia to be used for the treatment of cancer warm-blooded animal, multiple myeloma, lymphoma, cholangiocarcinoma, osteocarcinoma, bladder cancer, brain/CNS cancer, mammary cancer, colorectal carcinoma, carcinoma of endometrium, cancer of the stomach, head and neck cancer, liver cancer, lung cancer, neural cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, kidney, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma and carcinoma vulvae).

The further characteristics of this part according to the present invention, provide warm-blooded animal for example on the mankind, in treatment, when needs are used for the treatment of, comprise the quinazoline derivant of having used formula I, or as previously defined its pharmacy acceptable salt, (for example this cancer is selected from leukemia to treat cancer, multiple myeloma, lymphoma, cholangiocarcinoma, osteocarcinoma, bladder cancer, brain/CNS cancer, mammary cancer, colorectal carcinoma, carcinoma of endometrium, cancer of the stomach, head and neck cancer, liver cancer, lung cancer, neural cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, kidney, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma and carcinoma vulvae).

The further characteristics of this part according to the present invention, provide warm-blooded animal for example on the mankind, quinazoline derivant with formula I, or, treat cancer (for example this cancer is selected from leukemia, multiple myeloma, lymphoma, cholangiocarcinoma, osteocarcinoma, bladder cancer, brain/CNS cancer, mammary cancer, colorectal carcinoma, carcinoma of endometrium, cancer of the stomach, head and neck cancer, liver cancer, lung cancer, neural cancer, the esophageal carcinoma, ovarian cancer, carcinoma of the pancreas, kidney, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma and carcinoma vulvae) as previously defined its pharmacy acceptable salt.

The front is mentioned, and for the treatment or the prevention of certain disease specific, the size of dosage needs according to the medication main body, and the severity of treatment plan and disease changes.

According to aforementioned definitions, antiproliferative treatment/Tyrosylprotein kinase inhibition/antineoplaston can adopt monotherapy treatment or multiple therapy for treating, except compound of the present invention, operation or radiotherapy or chemotherapy is arranged.This class chemotherapy can comprise one or more in the following antitumour drug classification:

(i) antiproliferative/antitumor drug and its compound, this class is used in the medicine oncology, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Metabolic antagonist (for example anti-folic acid is fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, Methotrexate, oxygen Aminometradine Arabinoside and hydroxyurea for example); Anti-tumour antibody (for example the anthracene nucleus class is as Zorubicin, bleomycin, adriamycin, daunorubicin, pidorubicin, Mitomycin-C, gengshengmeisu and mithramycin); Antimitotic agent (biological example alkali is as vincristine(VCR), vinealeucoblastine(VLB), vindesine, taxol and docetaxel); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin is as Etoposide, teniposide, amsacrine and camptothecine);

(ii) cytostatic medicine is estrogen antagonist (tamoxifen for example for example, toremifene, raloxifene, droloxifene and iodoxyfene), conditioning agent under the estrogen receptor (for example fulvestrant), androgen antagonist (bicalutamide for example, Sch-13521, Nilutamide and Cyproterone acetic ester), lhrh antagonist (for example megestrol acetic ester), arimedex (anastrozole for example, letrozole, vorazole and exemestane) and 5 alpha reductase inhibitors finasteride for example;

(iii) anticancer is invaded agent (for example the substratum inhibitors of metalloproteinase is as marimastat and urokinase profibr(in)olysin catalyst receptor depressant of functions);

(iv) somatomedin depressant of functions, for example inhibitor comprise growth factor antibodies, growth factor receptor antibody (anti-erbB 2 antibody trastuzumab [Herceptin for example ^TM] and anti-erbb1 antibody trastuzumab [C225], farnesyl tranfering enzyme inhibitor, other epidermal growth factor family inhibitor (other EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (erlotinib for example for example, OSI-774) and 6-amide group-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033), for example platelet derived growth factor man group inhibitor and for example pHGF man group inhibitor.

(v) for example vascular endothelial growth factor inhibitor, (anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin for example of anti-angiogenic agent ^TM], disclosed compound for example as in International Patent Application WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354) and the compound by other mechanism effect;

(vi) the blood vessel injury agent is for example examined his spit of fland A4 of step and disclosed compound in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/9224, WO02/04434 and WO 02/08213;

(vii) antisense therapy, for example inverted defined gene of those listed target spots above direct attack such as ISIS 2503, a kind of anti-ras inverted defined gene;

(viii) gene therapy scheme, comprise for example replace aberrant gene such as unusual p53 or unusual BRCA1, BRCA2, GDEPT (treatment of gene targeting enzyme prodrug) scheme for example use Isocytosine deaminase, thymidine kinase or bacterium nitroreductase and improve patient to the tolerance of chemotherapy and radiation for example the multiple medicines thing resist gene therapy; With

(ix) immunotherapy scheme, comprise in the body for example and external scheme improve the immunogenicity of patient's tumour cell, for example with cytokine such as interleukin 2, interleukin 4 or granulocyte-macrophage mono-clonal stimulating factor transduce, reduce the T-cellular energy scheme, use transfection immunocyte for example cytokine transfection dendritic cell scheme, usefulness cytokine transfection tumor cell line scheme and use the antiidiotypic antibody scheme;

(x) the cell cycle supressor comprises for example CDK supressor (for example flavopiridol) and other cell cycle monitoring point supressor (for example check point kinases); Sudden change interval kinases and other participate in the supressor of the enzyme (for example mitotic kinase) in mitotic division and the division of cytoplasm; With the histone deacetylase supressor.

By to the treatment single component the time, priority or respectively the use, can realize combination therapy.In the dosage range of Miao Shuing, The compounds of this invention and other pharmaceutically acceptable promoting agent are united use in the dosage range that they allow in front.

According to this some of the present invention, medicinal product is provided, it includes as the quinazoline derivant of the defined formula I in front with as the antitumour drug of front definition for the combination therapy cancer.

Warm-blooded animal (comprising the people) though in the compound of formula I be the principal component of curative, at any time when needs were used for suppressing the erbB receptor tyrosine protein kinase, they also were effective.Therefore, for being used for the development of new biological detection and seeking new drug, they are useful as the pharmacology standard.

Except special statement,, set forth the present invention from now on by following limiting examples:

(i) with degree centigrade (℃) expression temperature; Under room temperature or envrionment temperature, promptly in 18-25 ℃ of scope, react;

(ii) organic solution is passed through anhydrous magnesium sulfate drying; Use Rotary Evaporators at decompression (600-4000Pascals; 4.5-30mmHg) in 60 ℃ water-bath, steam solvent;

(iii) column chromatography is meant quick silica gel column chromatography; Thin-layer chromatography (TLC) carries out with silica-gel plate;

(iv) common, the process of reaction is followed the tracks of with TLC and/or analysis LCMS, and the reaction times of being given only illustrates usefulness;

(v) final product has satisfied proton magnetic resonance (PMR) (NMR) collection of illustrative plates and/or mass-spectrometric data;

(vi) the productive rate of being given only illustrates usefulness, not necessarily the productive rate that obtains by method exploitation diligently; More raw materials just repeats preparation feedback if desired;

(vii) ought provide nuclear-magnetism ( ¹H NMR (spectrum)) data the time, what it detected mainly that the proton chemical shifts data use is the delta value, and target ppm value in promptly doing with respect to TMS except specifying, all is to make solvent with DMSO-d6 to scan at 300MHz or 400MHz; Abbreviation below using: s, single; D, two; T, three; Q, four; M is many; B, wide;

(viii) chemical symbol has their common meanings; Use SI units and symbol;

(ix) ratio of solvent is with volume: the form of volume is represented;

(x) under the plus or minus ion source, make mass spectrum (Mass spectrum) with Waters or Micromass electron spray(ES) LC-MS; The m/z value provides; Usually, only provide the molion quality; Unless otherwise indicated, mass ion is designated as (MH) ⁺

(xi) unless otherwise indicated, containing the carbon of asymmetric replacement and/or the compound of sulphur atom does not split;

(xii) when the experimentation of describing in a described building-up process and the previous examples was similar, used amount was the mmole ratio with respect to aforementioned usage quantity;

(xiii) when using Mass-Triggered to prepare type LCMS to come purifying compounds, use following conditions:

Pillar: ThermoHypersil Keystone B-Basic 5 μ 21mm * 100mm

Elutriant: the acetonitrile solution ((NH of damping fluid 2g/l of 7.5 minutes gradients from 20% to 90% ₄) ₂CO ₃, pH8.9).

Elution speed: 25ml/min;

(xiv) use following abbreviation:

The DMSO dimethyl sulfoxide (DMSO);

DMF N, N-dimethyl formamide;

DMA N, N-N,N-DIMETHYLACETAMIDE;

HATU O-(7-azepine benzo triazol-1-yl)- N, N, N ', N ' ,-tetramethyl-urea ion six

Fluorophosphate

The THF tetrahydrofuran (THF)

(xv) when described synthetic be (for example HCl salt) when being used for synthetic acid salt, the concrete chemical equivalent of this salt is not confirmed.

Embodiment 1

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6 base } methyl)-L-prolineamide (the compound N o2 in table 1)

(method (a))

Under room temperature and protection of nitrogen gas, the 624mg sodium triacetoxy borohydride is joined in tetrahydrofuran (THF) (50ml) solution of L-prolineamide (246mg) and 4-(3-chloro-2-fluoroanilino)-6-formaldehyde-7-methoxyl group quinazoline 650mg.React that mixture filters reduction vaporization then after 18 hours.Residue is assigned between saturated sodium bicarbonate and the methylene dichloride.The organic layer dried over mgso is filtered, evaporation.Crude product is purified by column chromatography, and elutriant is the methylene chloride (100/0 to 90/10) that polarity increases gradually.Merge the flow point that comprises required product, reduction vaporization obtains white foam, grinds with ether and obtains white solid, collects this solid by filtering, and drying obtains title product (224.6mg, 27%); ¹HNMR Spectrum:(DMSO d ₆) 1.60-1.85 (m, 3H), 2.0-2.25 (m, 1H), 2.25-2.45 (m, 1H), and 2.90-3.00 (m, 1H), 3.00-3.15 (m, 1H), 3.60 (d, 1H), 3.85-4.05 (m, 4H), 7.17 (bs, 1H), 7.20 (s, 1H), 7.27 (m, 1H), 7.39 (bs, 1H), 7.42-7.61 (m, 2H), 8.37 (s, 1H), 8.42 (s, 1H), 9.78 (s, 1H); Mass Spectrum: (M+H) ⁺430.08.

4-(3-chloro-2-fluoroanilino)-6-formaldehyde-7-methoxyl group quinazoline as starting raw material prepares in order to the below method:

The 150ml methylene dichloride suspension of 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (800mg) is cooled to 0 ℃ and add pyridine 1.5ml.Drip trifluoromethanesulfanhydride anhydride 507 microlitres then, the gained solution stirring is to room temperature.Mixture water and salt water washing after 18 hours, dried over mgso is filtered reduction vaporization.Residue grinds in methylene dichloride and obtains white solid, and by solid collected by filtration, drying obtains 4-(3-chloro-2-fluoroanilino)-6-trifluoromethyl sulfonyl oxygen base-7-methoxyl group quinazoline (880mg, 79%);

¹HNMR Spectrum：(DMSOd ₆)4.13(s，3H)，7.37(m，1H)，7.56(m，1H)，7.64(m，1H)，7.66(s，1H)，8.86(s，1H)，9.06(s，1H)，11.7(bs，1H). Mass Spectrum：(M+H) ⁺452.

With 4-(3-chloro-2-fluoroanilino)-6-trifyl oxygen base-7-methoxyl group quinazoline (883mg); palladium (14mg); 1; 3 dibiphenylyl phosphine propane (25mg) and triethylamine (543 microlitre) are heated to 70 ℃ with (10Bar) under the carbon monoxide and stirred 2 hours in the mixture of 120ml methyl alcohol and 6mlDMF.The reaction mixture reduction vaporization, residue is purified with the fast silica gel chromatogram method, and elutriant is methylene chloride/saturated ammoniacal liquor 100/8/1.After merging required flow point, vacuum decompression obtains the solid shape 4-(3-chloro-2-fluoroanilino) of white-7-methoxyl group-6-quinazolinecarboxylic acid methyl esters

(630mg，89％)； ¹ H NMR Spectrum：(DMSO d ₆)3.89(s，3H)，3.98(s，3H)，7.29(m，1H)，7.32(s，1H)7.51(m，2H)，8.51(s，1H)，8.85(s，1H)，10.15(s，1H)； Mass Spectrum：(M+H) ⁺362.

In tetrahydrofuran (THF) (5ml) solution of-70 ℃ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-quinazolinecarboxylic acid methyl esters (200mg), drip red-aluminium (Red-Al) (65% cyclohexane solution) 245 microlitres.Use red-aluminium (65% cyclohexane solution) 245 microlitre reaction mixture after 2 hours again, be heated to stirring at room then 18 hours.Drip the 20ml aqueous solution quencher reaction mixture of 1g sodium hydrotartrate.By filter collecting the gained solid, and water and washing with acetone obtain white powder 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-quinazoline methyl alcohol 220mg, Mass Spectrum:(M+H) ⁺334.

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-quinazoline methyl alcohol 180mg and the mixture of manganese oxide (IV) 405mg in the methylene dichloride of 15ml stirring at room 18 hours.Reactant is directly gone up silicagel column then, and elutriant is 5% ethanol/methylene.Merge the flow point that contains required product, vacuum decompression obtains the solid shape 4-(3-chloro-2-fluoroanilino) of white-6-formaldehyde-7-methoxyl group quinazoline 40mg, ¹HNMR Spetrum: (DMSO d ₆) 4.07 (s, 3H), 7.29 (t, 1H), 7.35 (s, 1H), 7.45-7.60 (m, 2H), 8.50 (s, 1H), 8.96 (s, 1H), 10.35 (s, 1H), 10.43 (s, 1H); Mass Spectrum: (M+H) ⁺332.

4-(3-chloro-2-the fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline that is used as starting raw material in above-mentioned reaction can prepare with ordinary method, for example utilize the similar approach of preparation 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline of describing among the patent WO97/30034 (example 32), replace 3-chloro-4-fluoroaniline with 3-chloro-2-fluoroaniline, as described below: that 6-acetoxyl group-4-chloro-7-methoxyl group quinazoline (is prepared with the described method of patent WO01/66099 embodiment 25-5,6.00g, 23.8mmol) and 3-chloro-2-fluoroanilino (3.46g 23.8mmol) is suspended in the 200ml Virahol.Reaction mixture is heated to 80 ℃ and refluxed 3 hours.Steaming desolventizes; Residue obtains rose pink crystalline solid 6-acetoxyl group-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline hydrochloride (8.16g, 92%) with second cyanogen recrystallization;

¹ H NMB：2.37(s，3H)，4.00(s，3H)，7.34(ddd，1H)，7.48(s，1H)，7.52(ddd，1H)，7.61(ddd，1H)，8.62(s，1H)，8.86(s，1H)； Mass Spectrum：362.4，364.4.

(8.72g 21.9mmol) is dissolved in the 200ml methyl alcohol, adds strong aqua (15ml) then, this solution is heated to 50 ℃ stirred 2 hours down, obtains cream-colored solid precipitation with 6-acetoxyl group-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline hydrochloric acid.Solid collected by filtration is used ether then, and (3 * 200ml) washings are used Vanadium Pentoxide in FLAKES vacuum-drying down at 60 ℃ then, obtain the solid shape 4-(3-chloro-2-fluoroanilino) of white-6-hydroxyl-7-methoxyl group quinazoline (5.40g, 77%);

¹ H NMR：3.95(s，3H)，7.19(s，1H)，7.23(dd，1H)，7.42(dd，1H)，7.50(dd，1H)，7.64(s，1H)，8.32(s，1H)，9.43(s，1H)，9.67(br.s，1H)； Mass Spectrum：320.4，322.4.

Embodiment 2

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-prolineamide (the compound N o1 in table 1)

(method (a))

Under room temperature and protection of nitrogen gas, the 480mg sodium triacetoxy borohydride is joined in tetrahydrofuran (THF) (50ml) suspension of the D-prolineamide (190mg) of stirring and 4-(3-chloro-2-fluoroanilino)-6-formaldehyde-7-methoxyl group quinazoline (500mg).React mixture filtration after 18 hours, reduction vaporization.Residue is distributed between saturated sodium bicarbonate and the methylene dichloride.The organic layer dried over mgso is filtered, evaporation.Crude product is purified by column chromatography, and elutriant is methylene chloride (100/0 to the 90/10) mixture that polarity increases gradually.Merge the flow point that comprises required product, reduction vaporization obtains jelly.And then purify with column chromatography, elutriant is methylene chloride (100/0 to the 90/10) mixture that polarity increases gradually, merges the flow point that comprises required product, reduction vaporization obtains white foam, grinds with ether then and obtains the solid shape title mixture of white.Solid collected by filtration, drying obtains product (214.3mg, 33%);

¹ H NMR Spectrum：(DMSO d ₆)1.60-1.85(m，3H)，2.0-2.20(m，1H)，2.20-2.41(m，1H)，2.90-3.01(m，1H)，3.01-3.10(m，1H)，3.60(d，1H)，3.85-4.05(m，4H)，7.15(m，1H)，7.21(s，1H)，7.29(m，1H)，7.39(m，1H)，7.42-7.60(m，2H)，8.38(s，1H)，8.42(s，1H)，9.78(s，1H)； Mass Spectrum：(M+H) ⁺429.96.

Embodiment 3

(4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-L-prolineamide (the compound N o4 in table 1)

Method (a)

With 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde (50mg, 0.75mmol) and 4R-4-hydroxyl-L-prolineamide (147mg, 1.13mmol) in containing the 15ml methylene dichloride of 5% acetate, stir, (240mg 1.13mmol) adds in half an hour sodium triacetoxy borohydride in batches.After adding finishes, reactant restir one hour, with the washing of 2N sodium hydroxide, water layer transfers to pH7-8, and uses ethyl acetate extraction, merges organic layer, dried over mgso, concentrating under reduced pressure then.Residue is purified with column chromatography (methanol solution/methylene dichloride that contains 5%7N ammoniacal liquor) and is obtained white powder title product (216mg, 64%);

¹ H NMR Sprctrum：(DMSOd ₆)1.88(m，1H)，2.01(m，1H)，2.33(dd，1H)，3.18(dd，1H)，3.32(t，1H)，3.69(d，1H)，3.96(m，4H)，4.19(m，1H)，4.86(d，1H)，7.16(d，1H)，7.21(s，1H)，7.29(dt，1H)，7.36(d，1H)，7.50(dt，1H)，7.56(dt，1H)，8.39(s，1H)，8.44(s，1H)，9.79(s，1H)； Mass Spectrum：(M+H) ⁺446.

As the 4-[(3-chloro-2-fluorophenyl of starting raw material) amino]-7-methoxyl group quinazoline-6-formaldehyde prepares by the following method:

The 4-[(3-chloro-2-fluorophenyl of packing in high pressure pipe the inside) amino]-7-methoxyl group quinazoline-6-base triflate (in embodiment 1, describing) (10g, 22.1mmol), palladium (II) (700mg, 3.12mmol), triethylamine (7.6ml, 54.5mmol), 1, and 3-dibiphenylyl phosphine propane (1.46g, 3.54mmol), trioctylphosphine silane (13.2ml, 29.4mmol) and 110mlDMF.Reaction mixture is heated to 70 ℃ and stirred 3 hours under the situation of logical carbon monoxide (13Bar).Thing cooling to be mixed, the DMF layer below separating filters concentrating under reduced pressure.Residue is suspended in methyl alcohol, filters, and with the isohexane washing, drying obtains greenish orange look solid shape 4-[(3-chloro-2-fluorophenyl on filter) amino]-7-methoxyl group quinazoline-6-formaldehyde (3.0g, 41%);

¹ H NMR spectrum：(DMSO d ₆)4.07(s，3H)，7.29(t，1H)，7.36(s，1H)，7.51(t，2H)，8.52(s，1H)，8.95(s，1H)，10.36(s，1H)，10.45(s，1H)； Mass Spectrum：(M+H) ⁺332.

The 4R-4 hydroxyl-L-prolineamide as starting raw material among the embodiment 3 prepares in order to the below method:

With (4R)-1-(tertbutyloxycarbonyl)-4-hydroxyl-L-proline(Pro) (1.0g, 4.32mmol) and triethylamine (0.66ml, 15mlTHF solution 4.76mmol) are cooled to-15 ℃.(0.45ml 4.76mmol), adds strong aqua 1.5ml then to drip Vinyl chloroformate.Mixture stirred 2 hours at 0～5 ℃.Add saturated ammonium chloride solution, separate each layer.Water layer extracts with THF again, merges the organic layer dried over mgso, concentrating under reduced pressure.Grind residue with ether and obtain white solid 610mg.Solid stirred 1 hour in the 10ml of 4M HCl dioxane, then concentrating under reduced pressure.Residue is dissolved in methyl alcohol, uses Isolute ^Methanol wash is used in the absorption of SCX post then, and the methanol solution wash-out with 7N ammoniacal liquor obtains being white crystal shape solid (4R)-4-hydroxyl-L-prolineamide (320mg, 55%):

H NMR spectrum：(DMSO d ₆)1.67(ddd，1H)1.90(qt，1H)，2.70(dt，1H)，2.86(dd，1H)，3.63(t，1H)，4.16(m，1H)，4.63(brs，1H)，6.94(brs，1H)，7.34(brs，1H).

Embodiment 4

(4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-L-prolineamide (compound 5 in table 1)

With the similar approach of describing among the embodiment 3, by 4-[(3-chloro-2-fluorophenyl) amino]-linked reaction of 7-methoxyl group quinazoline-6-formaldehyde and (4S)-4-hydroxyl-L-prolineamide prepares described compound.

¹ H NMR spectrum：(DMSO d ₆)1.69(ddd，1H)，2.40(ddd，1H)，2.53(m，1H)，2.84(d，1H)，3.06(dd，1H)，3.57(d，1H)，3.97(m，4H)，4.19(m，1H)，4.69(d，1H)，7.14(d，1H)，7.22(s，1H)，7.29(dt，1H)，7.44(d，1H)，7.50(dt，H)，7.57(dt，1H)，8.37(s，1H)，8.45(s，1H)，9.77(s，1H)； Mass spectrum：(M+H) ⁺446.

(4S)-4-hydroxyl-L-prolineamide starting raw material prepares in order to the below method:

With (4R)-1-(tertbutyloxycarbonyl)-4-hydroxyl-L-proline(Pro) (1.00g, 4.32mmol) and triphenylphosphine (1.36g 5.19mmol) stirs in the 50ml methylene dichloride and is cooled to 0 ℃.(0.8ml, 5.19mmol), the gained compound is in stirred overnight at room temperature slowly to add DEAD.With this mixture concentrating under reduced pressure, residue with column chromatography purify (methylene dichloride/acetone=20: 1) obtain the white crystalline solid tertiary butyl (1S, 4S)-3-oxo-2-oxa--5-azabicyclic [2.2.1] heptane-5-manthanoate (615mg, 67%);

¹ H NMR spectrum：(CDCl ₃)1.48(s，9H)，2.01(d，1H)，2.20(m，1H)，3.46(d，1H)，3.53(dd，1H)，4.55(brs，1H)，5.07(s，1H).

With the tertiary butyl (1S, 4S)-(610mg 2.86mmol) is dissolved in 50mlTHF and 30ml Virahol and be cooled to 0 ℃ to 3-oxo-2-oxa--5-azabicyclic [2.2.1] heptane-5-manthanoate.With ammonia solution is charged to saturatedly, rose to stirring at room 48 hours.Obtain oily matter behind the mixture concentrating under reduced pressure.Obtain white crystal shape solid (4S)-1-(tertbutyloxycarbonyl)-4-hydroxyl-L-prolineamide (495mg, 75%) with the ether grinding;

¹ H NMR spectrum：(DMSO d ₆ 100℃)1.40(s，9H)，1.80(m，1H)，2.30(ddd，1H)，3.24(m，1H)，3.50(dd，1H)，4.08(dd，1H)，4.18(m，1H)，4.90(d，1H)，6.85(brs，2H).

(490mg 2.13mmol) stirred 1 hour in the 10ml of 4M HCl dioxane, then concentrating under reduced pressure with (4S)-1-(tertbutyloxycarbonyl)-4-hydroxyl-L-prolineamide.Residue is dissolved in methyl alcohol, with the absorption of Isolute  SCX post, uses methanol wash then, uses the methanol solution wash-out of 7N ammoniacal liquor, obtains white crystal shape solid (4S)-4-hydroxyl-L-prolineamide (270mg, 98%) and is: ¹H NMR spectrum:(DMSO d ₆) 1.57 (ddd, 1H), 2.12 (ddd, 1H), 2.65 (dd, 1H), 2.83 (dd, 1H), 3.40 (dd, 1H), 4.09 (m, 1H), 4.59 (brs, 1H), 6.92 (brs, 1H), 7.35 (brs, 1H).

Embodiment 5

(4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide (compound 6 in table 1)

Method (a)

With the similar approach of describing among the embodiment 3, title compound is by 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (4S)-4-hydroxyl-D-prolineamide carries out linked reaction and prepares;

¹ H NMR spectrum：(DMSO d ₆)1.88(m，1H)，2.01(m，1H)，2.33(dd，1H)，3.18(dd，1H)，3.32(t，1H)，3.69(d，1H)，3.96(m，4H)，4.19(m，1H)，4.86(d，1H)，7.16(d，1H)，7.21(s，1H)，7.29(dt，1H)，7.36(d，1H)，7.50(dt，1H)，7.56(dt，1H)，8.39(s，1H)，8.44(s，1H)，9.79(s，1H)； Mass Spectrum：(M+H) ⁺446.

As (4S)-4-hydroxyl-D-prolineamide (4S)-1-(tertbutyloxycarbonyl)-4-hydroxyl-D-proline(Pro) of starting raw material, by the same method preparation of describing among the embodiment 3.

¹ H NMR spectrum：(DMSO d ₆)1.67(ddd，1H)，1.90(qt，1H)，2.70(dt，1H)，2.86((dd，1H)，3.63(t，1H)，4.16(m，1H)，4.63(brs，1H)，6.94(brs，1H)，7.34(brs，1H).

Embodiment 6

(4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide (compound 7 in table 1)

Method (a)

With the similar approach of describing among the embodiment 3, title compound is by 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (4R)-4-hydroxyl-D-prolineamide carries out linked reaction and prepares;

¹ H NMR spectrum：(DMSO d ₆)1.69(ddd，1H)，2.40(ddd，1H)，2.53(m，1H)，2.84(d，1H)，3.06(dd，1H)，3.57(d，1H)，3.97(m，4H)，4.19(m，1H)，4.69(d，1H)，7.14(d，1H)，7.22(s，1H)，7.29(dt，1H)，7.44(d，1H)，7.50(dt，1H)，7.57(dt，1H)，8.37(s，1H)，8.45(s，1H)，9.77(s，1H)， Mass Spectrum：(M+H) ⁺446

(the 4R)-4-hydroxyl-D-prolineamide that is used as starting raw material makes from (4S)-1-(tertbutyloxycarbonyl)-4-hydroxyl-D-proline(Pro) with the same method of describing in the embodiment 5 suitable steps.

(1R, 4R)-the same method preparation of 3-oxo-2 oxa-s-5-azabicyclic [2.2.1] heptane-5-manthanoate by describing in the embodiment 5 suitable steps.

¹ H NMR sectrum：(CDCl ₃)1.48(s，9H)，2.01(d，1H)，2.20(m，1H)，3.46(d，1H)，3.53(dd，1H)，4.55(brs，1H)，5.07(s，1H).

(4R)-the same method preparation of 1-(tertbutyloxycarbonyl)-4-hydroxyl-D-prolineamide by describing in the embodiment 5 suitable steps;

(4R)-the same method preparation of 4-hydroxyl-D-prolineamide by describing in the embodiment 5 suitable steps.

¹ H NMR spectrum：(DMSO d ₆)1.57(ddd，1H)，2.12(ddd，1H)，2.65(dd，1H)，2.83(dd，1H)，3.40(dd，1H)，4.09(m，1H)，4.59(brs，1H)，6.92(brs，1H)，7.35(brs，1H).

Embodiment 7

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-L-prolineamide (the compound N o3 in table 1)

Method (a)

Carry out linked reaction with the similar methods of describing among the embodiment 1 and 4-(3-chloro-4-fluoroanilino)-7-methoxyl group quinazoline-6-formaldehyde and L-prolineamide and obtain title product;

¹ H NMR Spectrum：(DMSO d ₆)1.55-1.85(m，3H)，2.05-2.20(m，1H)，2.30-2.50(m，1H)，2.85-2.98(m，1H)，2.98-3.15(m，1H)，3.60(d，1H)，3.85-4.10(m，4H)，7.14(bs，1H)，7.23(s，1H)，7.38(bs，1H)，7.39(m，1H)，7.73-7.88(m，1H)，8.05-8.20(m，1H)，8.41(s，1H)，8.55(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺430.02.

4-[(3-chloro-4-fluorophenyl as starting raw material) amino]-7-methoxyl group quinazoline-6-base-triflate, with the similar approach of describing among the embodiment 1, by 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-alcohol (among the WO97/30034 embodiment 32) and trifluoromethanesulfanhydride anhydride prepared in reaction.

NMR Spectrum：(DMSO d ₆)4.14(s，3H)，7.51(s，1H)，7.57(m，1H)，7.68(m，1H)，8.00(m，1H)，8.82(s，1H)，8.93(s，1H)，11.13(bs，1H)； Mass Spectrum：(M+H) ⁺452；(M-H) ^-450.

4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde is with the similar approach of describing in the embodiment 3 suitable steps, from 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-triflate preparation.

NMR Spectrum：(DMSO d ₆)4.03(s，3H)，7.30(s，1H)，7.43(m，1H)，7.73-7.90(m，1H)，8.08-8.22(m，1H)，8.59(s，1H)，8.95(s，1H)，10.21(s，1H)，10.42(s，1H)； Mass Spectrum：

Embodiment 8

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-prolineamide (the compound N o8 in table 1)

Method (a)

With embodiment 1 similar methods and 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (4R)-4-hydroxyl-D-prolineamide carries out linked reaction and obtains title product;

¹ H NMR Spectrum：(DMSO d ₆)1.55-1.85(m，3H)，2.00-2.25(m，1H)，2.28-2.50(m，1H)，2.82-2.98(m，1H)，2.98-3.11(m，1H)，3.58(d，1H)，3.85-4.10(m，4H)，7.15(bs，1H)，7.20(s，1H)，7.38(bs，1H)，7.42(m，1H)，7.70-7.90(m，1H)，8.05-8.20(m，1H)，8.39(s，1H)，8.52(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺430.16.

Embodiment 9

(4R)-1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxyl-D-prolineamide (the compound N o9 in table 1)

Method (a)

With the similar approach of embodiment 1, title product is by 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (4R)-4-hydroxyl-D-prolineamide (embodiment 7) carries out the linked reaction preparation.

¹ H NMR Spectrum：(DMSO d ₆+CD ₃COOD)1.65-1.80(m，1H)，2.3-2.55(m，1H)，2.60-2.72(m，1H)，2.92(d，1H)，3.25(m，1H)，3.72(d，1H)，3.93(s，3H)，4.05(d，1H)，4.18(m，1H)，7.23(s，1H)， 7.38(m，1H)，7.70-7.83(m，1H)，8.09(dd，1H)，8.39(s，1H)，8.55(s，1H)； Mass Spectrum：(M+H) ⁺446.02.

Embodiment 10

(4R)-1-(4-[3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-methoxyl group-D-prolineamide (the compound N o13 in table 1)

Method (a)

With the similar approach of describing among the embodiment 3, title product is by 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (4R)-4-methoxyl group-D-prolineamide carries out linked reaction and prepares.

¹ H NMR spectrum：(DMSO d ₆)1.81(ddd，1H)，2.41(ddd，1H)，2.47(m；1H)，2.98(d，1H)，3.09(m，4H)，3.58(d，1H)，3.88(m，1H)，3.97(m，4H)，7.14(d，1H)，7.23(s，1H)，7.30(t，1H)7.37(d，1H)，7.50(t，1H)，7.57(t，1H)，8.38(s，1H)，8.45(s，1H)9.81(s，1H)； Mass Spectrum：(M+H) ⁺460.0

(4R)-4-methoxyl group-D-prolineamide as starting raw material prepares by the following method:

With (4R)-1-(tertbutyloxycarbonyl)-4-hydroxyl-D-proline(Pro) (5.0g 21.6mmol) is dissolved in the 35ml acetone, and add silver suboxide (16.5g, 71.2mmol).And then add acetone (adding 100ml altogether) and allow solution is convenient to be stirred, adding the 4.7ml methyl iodide then, compound of reaction also stirs and spends the night.With reacting liquid filtering, concentrating under reduced pressure.Starting raw material also has residue, therefore repeats said procedure again.(2R, 4R)-4-methoxyl group tetramethyleneimine-1,2-dicarboxylic acid esters (3.0g, 54%) is an oily matter to obtain clarifying the oily 1-tertiary butyl-2-methyl by column chromatography (ether/acetone=1: 1).

¹ H NMR spectrum：(DMSO d ₆ 100℃)1.38(s，9H)，2.00(dt，1H)，2.38(m，1H)，3.19(s，3H)，3.23(dd，1H)，3.57(dd，1H)，3.63(s，3H)，3.94(m，1H)，4.25(dd，1H).

(1.42g, (2R, 4R)-4-methoxyl group tetramethyleneimine-1, (1.75g in the solution of THF 6.75mmol) (40ml) and water (20ml), stirred 5 hours under the room temperature 2-dicarboxylic acid esters 33.7mmol) to join the 1-tertiary butyl-2-methyl with lithium hydroxide monohydrate.(the 4M hydrogenchloride dioxane solution of 8.5ml 34.0mmol) concentrates this solution decompression then, removes most of tetrahydrofuran (THF) to add hydrogenchloride then.Remaining aqueous solution dichloromethane extraction is used anhydrous magnesium sulfate drying, and concentrating under reduced pressure obtains white crystalline solid (4R)-1-(tertbutyloxycarbonyl)-4-methoxyl group-D-proline(Pro) (1.45g, 88%).

¹ H NMR spectrum：(DMSO d ₆ 100℃)1.39(s，9H)，1.99(dt，1H)，2.38(m，1H)，3.20(m，4H)，3.58(t，1H)，3.93(m，1H)，4.15(dd，1H).

With the similar approach in the embodiment 4 suitable steps, (4R)-4-methoxyl group-D-prolineamide removes the BOC protecting group and makes from 4R-1-(tertbutyloxycarbonyl)-4-methoxyl group-D-proline(Pro).

¹ H NMR spectrum：(DMSO d ₆)1.75(m，1H)，2.10(m，1H)，2.82(m，3H)，3.13(s，3H)，3.96(m，1H)，3.78(m，1H)，6.91(brs，1H)，7.28(brs，1H).

Embodiment 11

(2S)-1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) preparation of piperidines-2-methane amide (the compound N o15 in table 1)

Method (a)

With 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde (250mg, 0.75mmol) and (2S)-(145mg 1.13mmol) stirs in 15ml contains the methylene dichloride of 5% acetate piperidines-2-methane amide.The 240mg sodium triacetoxy borohydride added in half hour in batches.After adding finishes, compound of reaction was stirred 1 hour, the sodium hydroxide with 2N washs then.It is 7～8 that water layer is transferred pH, uses ethyl acetate extraction then, uses anhydrous magnesium sulfate drying, concentrating under reduced pressure behind the merging organic layer.Residue is purified by column chromatography, with the ethanol/methylene mixture wash-out (1～2%) that polarity increases gradually, obtains the white powder title product and is (106mg, 32%).

¹ H NMR spectrum：(DMSO d ₆)1.31(m，1H)，1.47-1.72(m，4H)，1.86(m，1H) 2.01(dt，1H)，2.76(dd，1H)，2.88(m，1H)，3.42(d，1H)，3.77(d，1H)，3.95(s，3H)，7.12(s，1H)，7.20(m，2H)，7.30(dt，1H)，7.51(dt，1H)，7.60(m，1H)，8.42(s，1H)，8.44(s，1H)，9.73(s，1H)； Mass Spectrum：(M+H) ⁺444.6.

(2S)-piperidines-2-methane amide prepares by the following method:

With (S)-1-(tertbutyloxycarbonyl)-piperidines-2-formic acid (1.0g, 4.36mmol) and N-methylmorpholine (0.53ml, 15mlTHF solution 4.79mmol) are cooled to-15 ℃.(0.44ml 4.79mmol), adds the 1.5ml strong aqua then to drip isobutyl chlorocarbonate.Reaction mixture stirred 2 hours at 0～5 ℃, and with this mixture concentrating under reduced pressure, residue is distributed between the citric acid of ethyl acetate and 10%.Organic layer washs with saturated sodium bicarbonate solution, dried over mgso, and concentrating under reduced pressure obtains oily matter, separates out crystal (550mg, 55%) after leaving standstill.Need not purify and be directly used in later reaction.This solid is joined 10ml to be contained in the dioxane of 4M HCL and stirred concentrating under reduced pressure one hour.Residue is dissolved in methyl alcohol, uses Isolute then ^Methanol wash is used in the absorption of SCX post, and the methanol solution wash-out with containing 7N ammoniacal liquor obtains white crystalline solid (2S)-piperidines-2-methane amide (291mg, 96%).

¹ H NMR spectrum：(DMSO d ₆)1.31(m，3H)，1.45(m，1H)，1.71(m，2H)，2.12(s，1H)，2.45(m，1H)，2.93(m，2H)，6.86(brs，1H)，7.04(brs，1H).

Embodiment 12

(2R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperidines-2-methane amide (the compound N o10 in Table II)

Method (a)

With the similar approach of embodiment 1,4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (2R)-piperidines-2-methane amide carries out linked reaction and obtains title product.

¹ H NMR spectrum：(DMSO d ₆)1.31(m，1H)，1.47-1.72(m，4H)，1.86(m，1H)，2.01(dt，1H)，2.76(dd，1H)，2.88(m，1H)，3.42(d，1H)，3.77(d，1H)，3.95(s，3H)，7.12(s，1H)，7.20(m，2H)，7.30(dt，1H) 7.51(dt，1H)，7.60(m，1H)，8.42(s，1H)，8.44(s，1H)，9.73(s，1H)； Mass Spectrum：(M+H) ⁺444.6.

With the similar approach in the embodiment 11 suitable steps, begin preparation from (2R)-2-(aminocarboxyl) piperidines-1-formic acid tertiary butyl ester as (2R)-piperidines-2-methane amide of starting raw material.

Embodiment 13

4-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) morpholine-3-methane amide (compound 11 in Table II)

Method (a)

With the similar approach of embodiment 1,4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and morpholine-3-methane amide carry out linked reaction and obtain title product.

¹ H NMR spectrum：(DMSO d ₆)2.20(m，1H)，2.77(d，1H)，2.95(dd，1H)，3.48(m，3H)，3.72(d，1H)，3.86(m，2H)，3.95(s，3H)，7.21(s，1H)，7.31(m，3H)，7.52(m，2H)，8.39(s，1H)，8.43(s，1H)，9.75(s，1H)； Mass Spectrum：(M+H) ⁺446.5.

With the similar approach of embodiment 3 suitable steps, be feedstock production morpholine-3-methane amide with 4-(tertbutyloxycarbonyl) morpholine-3-formic acid.

¹H NMR(spectrum)：(DMSO d ₆)2.71(m，2H)，2.89(brs，1H)，3.21(dd，1H)，3.35(m，2H)，3.58(dt，1H)，3.73(dd，1H)，7.07(brs，1H)，7.21(brs，1H).

Embodiment 14

2R-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperidines-2-methane amide (compound 12 in Table II)

Method (a)

With the similar approach of describing among the embodiment 1,4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (2R)-piperidines-2-methane amide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)1.17-1.75(m，4H)，1.75-1.90(m，1H)，1.90-2.10(m，1H)，2.65-2.80(m，1H)，2.80-2.90(m，1H)，3.25-3.33(m，1H)，3.33-3.42(m，1H)，3.85(d，1H)，3.95(s，3H)，7.12(s，1H)，7.20(s，2H)，7.45(m，1H)，7.70-7.82(m，1H)，8.05-8.15(m，1H)，8.37(s，1H)，8.55(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺444.16，(M-H) ^-446.20.

Embodiment 15

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-N, N-diethyl-L-prolineamide (compound 14 in Table I)

Method (a)

With the similar approach of describing among the embodiment 1,4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and N, N-dimethyl-L-prolineamide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)1.60-1.90(m，3H)，1.93-2.12(m，1H)，2.35-2.60(m，1H+DMSO)，2.75(s，3H)，2.95(s，3H)，3.00-3.15(m，1H)，3.53(dd，1H)，3.80(ABq，2H)，3.92(s，3H)，7.15(s，1H)，7.25(m，1H)，7.40-7.60(m，2H)，8.25(s，1H)，8.40(s，1H)，9.80(bs，1H)； Mass Spectrum：(M+H) ⁺458.0，(M-H) ^-455.97.

Embodiment 16

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-ethyl-D-prolineamide

Method (c)

67mg 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride is joined 100mg 1-({ the 4-[(3-chloro-4-fluorophenyl) amino of stirring]-7-methoxyl group quinazoline-6-yl } methyl)-the D-proline(Pro), 21.8mg I-hydroxybenzotriazole is in the 5ml DMF solution of ethylamine hydrochloride and 127 microlitre N-methylmorpholines.Reaction mixture was stirred 18 hours, be evaporated to dried then.Residue is allocated in saturated 25ml sodium carbonate solution and ethyl acetate (between 2 * 10ml).Merge organic layer,, filter evaporation with 10ml water and the water washing of 10ml salt, dried over mgso.Crude product is used methylene chloride: (100/0～90/10) wash-out by fast silica gel chromatogram method purifying.Merge the flow point that comprises required product, be evaporated to dried.The gained foam grinds with ether/hexanaphthene (1/1), and by solid collected by filtration, vacuum-drying obtains title product (54.2mg) then;

¹ H NMR Spectrum：(DMSO d ₆)0.93(t，3H)，1.50-1.83(m，3H)，2.00-2.20(m，1H)，2.35-2.60(m，1H+DMSO)，2.85-3.00(m，1H)，3.00-3.17(m，3H) 3.63(d，1H)，3.93(d，1H)，3.98(s，3H)，7.22(s，1H)，7.43(dd 1H)，7.65-7.75(m，1H)，7.75-7.89(m，1H)8.15(m，1H)，8.39(s，1H)，8.55(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺458.

1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) starting raw material prepares by following method:

With the similar approach of describing among the embodiment 1,4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde (preparation by the starting raw material of describing among the embodiment 7 makes) and D-proline(Pro) carry out linked reaction and obtain 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the D-proline(Pro).

¹ H NMR Spectrum：(DMSO d ₆)1.60-2.00(m，3H)，2.00-2.25(m，1H)，2.60-2.80(m，1H)，3.10-3.30(m，1H)，3.50(q，1H)，3.95(s，3H)，4.10(ABq，2H)，7.20(s，1H)，7.40(dd，1H).7.70-7.90(m，1H)，8.15(dd，1H)，8.50(s，1H)，8.55(s，1H)，9.90(s，1H)； Mass Spectrum：(M+H) ⁺431.

Embodiment 17

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-methyl D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, carry out linked reaction with 1-({ 4-(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and methylamine hydrochloride and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.50-1.85(m，3H)，2.00-2.20(m，1H)，2.35-2.55(m，1H+DMSO)，2.63(d，3H)，2.82-3.00(m，1H)，3.00-3.20(m.1H).3.62(d，1H)3.95(d，1H)，3.97(s，3H)，7.22(s，1H)，7.44(dd，1H)，7.65-7.76(m，1H)，7.76-7.85(m，1H)，8.15(dd，1H)，8.39(s，1H)，8.57(s，1H)，9.68(s，1H)； Mass Spectrurn：(M+H) ⁺444.

Embodiment 18

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-cyclopentyl-D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, with 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and cyclopentamine carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.00-1.90(m，7H)，2.00-2.20(m，1H)，2.40-2.70(m，1H+DMSO)，2.95-3.08(m，1H)，3.08-3.20(m，1H)，3.65-4.10(m，7R)，3.97(s，3H)，7.20(s，1H)，7.32-7.55(m，2H)，7.70-7.90(m，1H)，8.05-8.22(m，1H)，8.40(s，1H)，8.55(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺498.

Embodiment 19

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-third-2-alkynes-1-base-D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, with 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and propargyl amine carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)1.50-1.85(m，3H)，2.00-2.20(m，1H)，2.35-2.60(m，1H+DMSO)，2.80-2.98(m，1H)，3.07(s，1H)，3.12-3.23(m，1H)，3.61(d，1H)，3.85-4.1(m，3H)，4.02(s，3H)，7.23(s，1H)，7.44(dd，1H)，7.75-7.90(m，1H)，8.00-8.11(m，1H)，8.11-8.22(m，1H)，8.40(s，1H)，8.57(s，1H)，9.70(s，1H)； Mass Spectrum：(M+H) ⁺468.

Embodiment 20

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-cyano methyl-D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, with 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and aminoacetonitriles carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.55-1.85(m，3H)，2.03-2.25(m，1H)，2.35-2.60(m，1H+DMSO)，2.85-3.02(m，1H)，3.15-3.35(m，1H+H ₂O)，3.68(d，1H)，3.93(d，1H)，4.00(s，3H)，4.16(d，2H)，7.21(s，1H)，7.44(dd，1H)，7.75-7.90(m，1H)，8.10-8.23(m，1H)，8.33(dd，1H)，8.37(s，1H)，8.54(s，1H)，9.68(s，1H)； Mass Spectrum：(M+H) ⁺469.

Embodiment 21

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) N-[2-(dimethylamino) ethyl]-the D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, with 1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl methyl)-the D-proline(Pro) and N, N-dimethyl-ethylenediamine carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆+CD ₃COOD)1.60-2.00(m，3H+CHD ₂COOD)，2.00-2.20(m，1H)，2.30-2.60(m，1H+DMSO)，2.65(s，6H)，2.85-3.12(m，3H)，3.12-3.22(m，1H)，3.22-3.35(m，1H)，3.35-3.60(m，1H)，3.70(d，1H)，3.89(d，1H)，3.96(s，3H)，7.23(s，1H)，7.35(dd，1H)，7.70-7.90(m，1H)，8.10(dd，1H)，8.50(s，1H)，8.54(s，1H)； Mass Spectrum：(M+H) ⁺501.

Embodiment 22

1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) the different  azoles of N-[(5-methyl-3-yl) methyl]-the D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16, usefulness 1-(4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and N-[(5-methyl-3- Different The azoles base) methyl] amine carries out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.55-1.90(m，3H)，2.00-2.25(m，1H)，2.28(s，3H)，2.35-2.65(m，1H+DMSO)，2.83-3.02(m，1H).3.10-3.35(m，1H+H ₂O).3.66(d，1H)，3.90(s，3H)，3.96(d，1H)，4.30(d，2H)，5.91(s，1H)，7.17(s，1H)，7.43(dd，1H)，7.70-7.90(m，1H)，8.05-8.20(m，1H)，8.20-8.33(m，1H)，8.39(s，1H)，8.55(s，1H)，9.65(s，1H)； Mass Spectrum：(M+H) ⁺525.

Embodiment 23

2-[(2S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) tetramethyleneimine-2-yl] ethanamide

Method (a)

With the similar approach of describing in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde (as preparation among the embodiment 3) and 2-[(2S)-tetramethyleneimine-2-yl] ethanamide carries out linked reaction and obtains title product.

¹ H NMR spectrum：(DMSO d ₆)1.53(m，1H)；1.67(m，2H)；1.95(m，1H)；2.21(m，2H)；2.47(m，1H)；2.82(m，1H)；2.95(m，1H)；3.42(d，1H)；3.95(s，3H)；4.10(d，1H)；6.79(brs，1H)；7.20(s，1H)；7.29(t，1H)；7.42(brs，1H)；7.51(m，2H)；8.30(s，1H)；8.43(s，1H)；9.79(s，1H)； Mass Spectrum：(M+H) ⁺444.

With the same method of describing in the embodiment 3 suitable steps, make 2-[(2S from [(2S)-1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl] acetate)-tetramethyleneimine-2-yl] the ethanamide starting raw material.

¹ H NMR spectrum：(DMSOd ₆)1.22(m，1H)；1.62(m，2H)；1.76(m，1H)；2.13(dd，2H)；2.71(m，1H)；2.81(m，1H)；3.20(m，1H)；6.71(brs，1H)；7.34(brs，1H).

Embodiment 24

(4R)-3-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-1,3-thiazoles alkane-4-methane amide

Method (a)

With the similar approach of describing in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (4R)-1,3 thiazolidine-4-methane amide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)3.06(dd，1H)；3.46(dd，1H)；3.79(d，1H)；3.84(d，1H)；3.97(s，3H)；4.08(m，3H)；7.24(s，1H)；7.30(t，1H)；7.40(brd，2H)；7.52(t，1H)；7.57(t，1H)；8.46(s，1H)；8.55(s，1H)；9.82(s，1H). Mass Spectrum：(M+H) ⁺448.

Same method with describing in the embodiment 3 suitable steps makes (4R)-1,3 thiazolidine-4-methane amide starting raw material from (4R)-3-(tertbutyloxycarbonyl)-1,3 thiazolidine-4-formic acid.

¹ H NMR Spectrum：(DMSO d ₆)2.85(dd，1H)；2.93(dd，1H)；3.73(t，1H)；4.03(d，1H)；4.12(d，1H)；7.13(brs，1H)；7.44(brs，1H).

Embodiment 25

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-N-methyl D-prolineamide

Method (c)

With 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) (150mg, 0.35mmol), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (100mg, 0.52mmol) and I-hydroxybenzotriazole (70mg 0.52mmol) stirs in 5mlDMF.Add triethylamine (170 microlitres, 1.22mmol), add then methylamine hydrochloride (28mg, 0.42mmol), the reaction mixture stirred overnight at room temperature.Gained solution is heated to 50 ℃, and adds 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride, I-hydroxybenzotriazole, triethylamine and the methylamine hydrochloride of above-mentioned amount once more.After 1 hour, reaction mixture with the ethyl acetate dilution, is used the saturated aqueous common salt washed twice then, and dried over mgso is filtered concentrating under reduced pressure.Residue is purified with quick SiO2 column chromatography, and elutriant is ethanol/methylene=2/98.Obtain white foam shape title product (100mg, 65%).

¹ H NMR Spectrum：(DMSO d ₆)1.72(m，3H)；2.12(m，1H)；2.41(m，1H)；2.64(d，3H)；2.97(m，1H)；3.12(dd，1H)；3.62(d，1H)；3.93(d，1H)；4.00(s，3H)；7.24(s，1H)；7.30(t，1H)；7.53(m，2H)；7.77(q，1H)；8.38(s，1H)；8.45(s，1H)；9.80(s，1H)； Mass Spectrum：(M+H) ⁺444.

1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) starting raw material prepares by the following method:

With the similar approach of describing among the embodiment 16, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and D-proline(Pro) carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.77(m，2H)；1.91(m，1H)；2.10(m，1H)；2.60(m，1H)；3.19(m，1H)；3.42(m，1H)；3.96(m，4H)；4.15(d，1H)；7.20(s，1H)；7.26(t，1H)；7.46(t，1H)；7.52(brt，1H)；8.42(s，2H)；10.0(brs，1H)； Mass Spectrum：(M+H) ⁺431.

Embodiment 26

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-N-ethyl-D-prolineamide

Method (c)

With the other method of describing among the embodiment 16,1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and ethylamine hydrochloride carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)0.97(t，3H)；1.72(m，3H)；2.12(m，1H)；2.42(m，1H)；2.98(m，1H)；3.10(m，3H)；3.65(d，1H)；3.92(d，1H)；3.99(s，3H)；7.23(s，1H)；7.30(t，1H)；7.53(m，2H)；7.76(brt，1H)；8.38(s，1H)；8.45(s，1H)；9.81(s，1H)； Mass Spectrum：(M+H) ⁺458.

Embodiment 27

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-N, N-dimethyl-D-prolineamide

Method (c)

With the similar approach of describing among the embodiment 16,1-({ 4-[(3-chloro-4-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-D-proline(Pro) and diethylamine hydrochloride carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSO d ₆)1.75(m，3H)；2.09(m，1H)；2.45(q，1H)；2.77(s，3H)；2.97(s，3H)；3.07(m，1H)；3.55(m，1H)；3.77(d，1H)；3.86(d，1H)；3.93(s，3H)；7.19(s，1H)；7.28(t，1H)；7.51(m，2H)；8.28(s，1H)；8.43(s，1H)；9.86(s，1H)； Mass Spectrum：(M+H) ⁺458.

Embodiment 28

(3S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-hydroxyl-D-prolineamide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (3S)-3-hydroxyl-L-proline(Pro) carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)1.64(dd，1H)；1.76(m，1H)；2.67(m，1H)；2.91(t，1H)；3.02(d，1H)；3.75(d，1H)；3.96(s，3H)；4.01(d，1H)；4.15(brs，1H)；5.11(d，1H)；7.19(d，1H)；7.22(s，1H)；7.30(t，1H)；7.46(d，1H)；7.50(t，1H)；7.56(t，1H)；8.40(s，1H)；8.45(s，1H)；9.77(s，1H)； Mass Spectrum：(M+H) ⁺446

(3S)-3-hydroxyl-L-proline(Pro) starting raw material prepares with following method:

With the similar approach in the embodiment 3 suitable steps, with (3S)-1-tertbutyloxycarbonyl-3 hydroxyls-L-proline(Pro) carry out linked reaction then deprotection obtain 3S-3-hydroxyl-L-prolineamide.

¹ H NMR Spectrum：(DMSO d ₆)1.57(m，2H)；2.90(m，3H)；4.14(m，1H)；4.84(brs，1H)；7.00(brs，1H)；7.30(brs，1H).

Embodiment 29

(3R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) tetramethyleneimine-3-methane amide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (3R)-tetramethyleneimine-3-methane amide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSO d ₆)1.93(q，2H)；2.50(m，2H)；2.75(m，1H)；2.87(m，2H)；3.71(d，1H)；3.76(d，1H)；3.96(s，3H)；6.74(brs，1H)；7.21(s，1H)；7.24(brs，1H)；7.28(dt，1H)；7.51(m，2H)；8.35(s，1H)；8.43(s，1H)；9.83(s，1H)； Mass Spectrum：(M+H) ⁺430.

(3R)-tetramethyleneimine-3-methane amide starting raw material prepares in order to the below method:

With pulverous sodium cyanide (550mg, 1.3mmol) and (3S)-3-[(methyl sulphonyl) oxygen] (2g, 10mlDMSO solution 7.54mmol) are heated to 80 ℃ and stirred 4 hours tetramethyleneimine-1-formic acid tertiary butyl ester.Gained yellow mixture cooling back adds 4ml salt solution and 4.5ml water.Mixture extracted with diethyl ether (* 3), dried over mgso is filtered, and concentrating under reduced pressure is purified by quick SiO2 column chromatography, and elutriant is ether/isohexane=50/50, obtains colorless oil (3R)-3-Cyanopyrolidine-1-formic acid tertiary butyl ester (579mg, 39%).

¹ H NMR Spectrum：(DMSOd ₆)1.39(s，9H)；2.08(m，1H)；2.18(m，1H)；3.34(m，4H)；3.53(m，1H).

(575mg 2.93mmol) was dissolved in 15ml and contains in the dioxane solution of 4MHCl, stirring at room 2 hours with (3R)-3-Cyanopyrolidine-1-formic acid tertiary butyl ester.Restir is 5 hours behind the adding 0.5ml water, and concentrating under reduced pressure, residue are dissolved in the methyl alcohol, gained solution Isolute ^Methanol wash is used in the absorption of SCX post, obtains hemicrystalline solid (3R)-tetramethyleneimine-3-manthanoate (285mg, 85%) with the methanol solution wash-out that contains 7N ammoniacal liquor

¹ H NMR Spectrum：(DMSO d ₆ 1.75(m，2H)；2.70(m，4H)；2.90(m，1H)；6.65(brs，1H)；7.25(brs，1H).

Embodiment 30

(3S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) tetramethyleneimine-3-methane amide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (3S)-tetramethyleneimine-3-methane amide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSOd ₆)1.93(q，2H)；2.50(m，2H)；2.75(m，1H)；2.87(m，2H)；3.71(d，1H)；3.76(d，1H)；3.96(s，3H)；6.74(brs，1H)；7.21(s，1H)；7.24(brs，1H)；7.28(dt，1H)；7.51(m，2H)；8.35(s，1H)；8.43(s，1H)；9.83(s，1H)； Mass Spectrum：(M+H) ⁺430.

(3S)-tetramethyleneimine-3-methane amide prepares in order to the below method:

With same method in the suitable step of previous embodiment, from (3R)-3-[(methyl sulphonyl) oxygen] tetramethyleneimine-1-formic acid tertiary butyl preparation (3S)-3-Cyanopyrolidine-1-formic acid tertiary butyl ester.

¹ H NMR Spectrum：(DMSO d ₆)1.39(s，9H)；2.08(m，1H)；2.18(m，1H)；3.34(m，4H)；3.53(m，1H).

With the same method of describing in the embodiment 29 suitable steps, from (3S)-3-Cyanopyrolidine-1-manthanoate preparation (3S)-tetramethyleneimine-3-methane amide.

¹ H NMR Spectrum：(DMSO d ₆)1.75(m，2H)；2.70(m，4H)；2.90(m，1H)；6.65(brs，1H)；7.25(brs，1H).

Embodiment 31

(4R)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-oxyethyl group-D-prolineamide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (4R)-4-oxyethyl group-D-prolineamide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSOd ₆)1.03(t，3H)；1.79(m，1H)；2.41(m，1H)；2.54(d，1H)；2.96(d，1H)；3.08(t，1H)；3.31(m，2H)；3.58(d，1H)；3.96(m，5H)；7.14(d，1H)；7.23(s，1H)；7.30(t，1H)；7.36(d，1H)；7.50(t.1H)；7.57(t，1H)；8.38(s，1H)；8.45(s，1H)；9.80(s，1H)； Mass Spectrum：(M+H) ⁺474.

(4R)-4-oxyethyl group D-prolineamide starting raw material prepares in order to the below method:

Under the same condition of in embodiment 10 suitable steps, describing, with (4R)-1-(tert-butoxycarbonyl)-4-hydroxyl-D-proline(Pro) and iodoethane reaction, preparation 1-tertiary butyl 2-ethyl (2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-dicarboxylic acid esters.

H NMR Spectrum：(DMSOd ₆，100℃)1.06(t，3H)；1.20(t，3H)；1.38(6，9H)；1.98(m，1H)；2.36(m，1H)；3.21(dd，1H)；3.39(q，2H)；3.58(dd，1H)；4.09(m，3H)；4.21(dd，1H).

With the same method of describing in the embodiment 10 suitable steps, (2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the hydrolysis of 2-dicarboxylic acid esters obtains (4R)-1-(tert-butoxycarbonyl)-4-oxyethyl group-D-proline(Pro) with the 2-ethyl.

¹ H NMR Spectrum：(DMSOd ₆，100℃)1.08(t，3H)；1.39(s，9H)；1.93(m，1H)；2.38(m，1H)3.18(dd，1H)；3.41(q，2H)；3.60(dd，1H)；4.04(dd，1H)；4.13(dd，1H).

With the same method of describing in the embodiment 3 suitable steps, with (4R)-1-(tert-butoxycarbonyl)-the 4-oxyethyl group-the D-proline(Pro) carries out linked reaction and deprotection obtains (4R)-4-oxyethyl group-D-prolineamide.

¹ H NMR Spectrum：(DMSOd ₆)1.05(t，3H)；1.69(m，1H)；2.13(m，1H)；2.75(dd，1H)；2.86(m，2H)；3.33(q，2H)；3.39(dd，1H)；3.88(m，1H)；6.91(brs，1H)；7.28(brs，1H).

Embodiment 32

(4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-(dimethylamino)-L-prolineamide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde with (4S)-4-(dimethylamino)-L-prolineamide carries out linked reaction and obtains title product.

¹ H NMR Spectrum：(DMSOd ₆)1.66(m，1H)；2.06(s，6H)；2.26(m，1H)；2.54(m，1H)；2.81(m，1H)；2.92(dd，1H)；3.17(dd 1H)；3.61(d，1H)；3.88(d，1H)；3.96(s，3H)；7.20(d，1H)；7.22(s，1H)；7.30(t，1H)；7.41(d，1H)；7.51(t，1H)；7.58(t，1H)；8.40(s，1H)；8.45(s，1H)；9.78(s，1H). Mass Spectrum：(M+H) ⁺473.

(4S)-4-(dimethylamino)-L-prolineamide prepares in order to the below method:

With sodium cyanoborohydride (1.0g, 17.4mmol) join stirring (4S)-4-amino-1-(tert-butoxycarbonyl)-L-proline(Pro) (1.0g, 4.34mmol), sal epsom (1.0g, 8.69mmol) and paraformaldehyde (260mg is in 30ml methyl alcohol suspension 8.68mmol).The gained reactant was 45 ℃ of heated and stirred 2 hours, and concentrating under reduced pressure is filtered in cooling.This dissolving crude product in methyl alcohol, is used Isolute then ^Methanol wash is used in the absorption of SCX post, with the methanol solution wash-out that contains 7N ammoniacal liquor.Filtrate is evaporated to dried, and residue is dissolved in 15mlTHF again and (0.59ml is 4.26mmol) in the triethylamine.The gained mixture is cooled to-15 ℃, slowly adds Vinyl chloroformate (0.41ml, tetrahydrofuran (THF) 4.26mmol) (3ml) solution then.After 10 minutes, add concentrated ammonia solution (8ml) in this mixture, mixture stirred 2 hours at 0 ℃.Add saturated ammonium chloride solution, layering.The water layer ethyl acetate extraction merges the organic layer dried over mgso then, filters concentrating under reduced pressure.Residue is purified with quick SiO2 column chromatography, and elutriant is the ethanol/methylene (7.5/92.5～15/85) that polarity increases gradually.Merge the flow point that comprises required product, obtain white solid 200mg.This solid is dissolved in the dioxane solution that contains 4MHCl, stirred 2 hours, concentrating under reduced pressure, residue are dissolved in the methyl alcohol, use Isolute then ^Methanol wash is used in the absorption of SCX post, with the methanol solution wash-out that contains 7N ammoniacal liquor, obtains the solid shape (4S) of white-4-(dimethylamino)-L-prolineamide 93mg.

¹ H NMR Spectrum：(DMSOd ₆)1.41(m，1H)；2.09(s，6H)；2.16(m，1H)；2.44(m，2H)；2.96(m，1H)；3.49(t，1H)；6.93(brs，1H)；7.31(brs，1H).

Embodiment 33

(2S, 4S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-hydroxy piperidine-2-methane amide

Method (a)

With the similar approach of describing among the embodiment 3, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (2S, 4S)-4-hydroxy piperidine-2-methane amide carries out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSOd ₆)1.51(m，1H)；1.63(m，1H)；1.74(m，1H)；1.86(m，1H)；2.47(m，1H)；2.70(m，1H)；3.16(dd，1H)；3.54(d，1H)；3.79(m，2H)；3.96(s，3H)；4.61(d，1H)；7.14(d，1H)；7.21(s，1H)；7.27(d，1H)；7.30(t，1H)；7.51(t，1H)；7.58(t，1H)；8.42(s，1H)；8.44(s，1H)；9.77(s，1H)； Mass Spectrum：(M+H) ⁺460.

(2S, 4S)-4-hydroxy piperidine-2-methane amide starting raw material prepares in order to the below method:

The same method of describing in the embodiment 3 suitable steps, with (2S, 4S)-1-(tert-butoxycarbonyl)-the 4-hydroxy piperidine-2-formic acid carries out linked reaction and deprotection obtain (2S, 4S)-4-hydroxy piperidine-2-methane amide.

¹ H NMR Spectrum：(DMSOd ₆)1.32(m，1H)；1.52(m，2H)；1.67(m，1H)；2.61(m，1H)；2.75(brs，1H)；2.83(m，1H)；3.37(dd，1H)；3.76(m，1H)；4.48(s，1H)；6.88(brs，1H)；7.13(brs，1H).

Embodiment 34

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-5-methyl-L-prolineamide

Method (c)

With 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-5-methyl-L-proline(Pro) (585mg, 1.31mmol this 5-methyl mixture of isomers of 4: 1) and (0.202ml, 1.45mmol) the THF solution of 5ml of triethylamine be cooled to-15 ℃, drip the 3mlTHF solution that contains Vinyl chloroformate (0.138ml 1.45mmol) then.Add the 3ml strong aqua after 10 minutes, stirred this mixture 2 hours at 0 ℃.Add the protection ammonium chloride solution, layering, the water layer ethyl acetate extraction merges the organic layer dried over mgso, filters evaporation.The quick SiO of residue ₂Column chromatography with ethanol/methylene (3/97) wash-out, obtains 4: 1 5-methyl isomer mixture (340mg, 58%) of title product.

¹ H NMR Spectrum：(DMSOd ₆)0.95 ^*(d，3H)；1.08(d，3H)；1.34(m，1H)；1.45 ^*(m，1H)；1.72(m，1H)；1.88(m，1H)；2.01(m，1H)；2.26 ^*(m，1H)；2.88(m，1H)；3.18(dd，1H)；3.31 ^*(m，1H)；3.73(m，1H)；3.96(m，4H)；6.92(d，1H)；7.02 ^*(d，1H)；7.19-7.36(m，3H)；7.49(m，1H)；7.57(m，1H)；8.36-8.44(m，2H)；9.74(m，1H)( ^*＝minor isomer peaks)； Mass Spectrum：(M+H) ⁺444.

^*=less isomer peak

1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-5-methyl-L-proline(Pro) starting raw material prepares in order to the below method:

With the same method of describing in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and 5-methyl-L-proline(Pro) carry out linked reaction and obtain 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-5-methyl-L-proline(Pro) (4: 1 5-methyl mixture of isomers).

¹ H NMR Spectrum：(DMSOd ₆+D ₂O)1.11 ^*(d，3H)；1.33(d，3H)；1.48(m，1H)；1.51 ^*(m，1H)；1.78 ^*(m，1H)；2.04(m，1H)；2.18(m，1H)；3.41(m，1H)；3.66(m，1H)；3.94-4.17(m，4H)；4.49(d，1H)；7.26(m，1H)；7.52(m，2H)；8.42(m，2H)( ^*＝minor isomer peaks)；Mass Spectrum：(M+H) ⁺445.

^*=less isomer peak

Embodiment 35

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperazine-2-methane amide

Method (a)

With 3-(aminocarboxyl)-4-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperazine-1-formic acid tertiary butyl ester (400mg, the 20ml dioxane solution stirring of 4MHCL 0.73mmol) 3 hours.With the reaction mixture evaporation, residue is dissolved in the methyl alcohol again, uses Isolute then then ^Methanol wash is used in the absorption of SCX post, with the methanol solution wash-out that contains 7N ammoniacal liquor, obtains the solid shape title product (325mg, 100%) of white.

¹ H NMR Spectrum：(DMSOd ₆)2.04(m，1H)；2.40(brs，1H)；2.73(m，5H)；3.01(d，1H)；3.41(d，1H)；3.79(d，1H)；3.96(s，3H)；7.23(m，3H)；7.30(t，1H)；7.51(t，1H)；7.59(t，1H)；8.41(s，1H)；8.44(s，1H)；9.74(s，1H)； Mass Speptrum：(M+H) ⁺445.

3-(aminocarboxyl)-4-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperazine-1-formic acid tertiary butyl ester starting raw material prepares in order to the below method:

With the 1-[(benzyloxy) carbonyl]-4-(tertiary butyl oxygen carbonyl) piperazine-2-formic acid (2.0g, 5.49mmol) and triethylamine (0.842ml, 6.04mmol) 20mlTHF solution be cooled to-15 ℃, drip Vinyl chloroformate (0.577ml, 5mlTHF solution 6.04mmol).Add the 10ml strong aqua after 10 minutes, mixture stirred 2 hours at 0 ℃.Add saturated ammonium chloride solution then, layering, the water layer ethyl acetate extraction merges the organic layer dried over mgso, filters, evaporation, residue is dissolved in 50ml methyl alcohol again, uses the nitrogen purge system then, adds 10% palladium carbon (0.18g, 10%by mass of residue), then mixture was stirred 3 hours.Mixture filters, and concentrating under reduced pressure obtains solid shape 3-(aminocarboxyl) piperazine of white-1-formic acid tertiary butyl ester (700mg, 56%)

¹ H NMR Spectrum：(DMSOd ₆)1.40(s，9H)；2.54(d，1H)；2.83(m，3H)；3.05(dd，1H)；3.62(d，1H)；3.85(m，1H)；7.08(brs，1H)；7.24(brs，1H).

With the same method of describing in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and 3-(aminocarboxyl) piperazine-1-formic acid tertiary butyl ester carry out linked reaction and obtain 3-(aminocarboxyl)-4-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl) methyl) piperazine-1-formic acid tertiary butyl ester.

¹ H NMR Spectrum：(DMSOd ₆)1.41(s，9H)；2.13(t，1H)；2.90(dd，2H)；3.08(t，1H)；3.18(m，1H)；3.49(d，1H)；3.65(d，1H)；3.86(d，2H)；3.95(s，3H)；7.22(s，1H)；7.32(m，3H)；7.51(t，1H)；7.58(t，1H)；8.39(s，1H)；8.45(s，1H)；9.74(s，1H)； Mass Spectrum：(M+H)+545.

Embodiment 36

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-methylpiperazine-2-methane amide

Method (d)

With sal epsom (73mg, 0.61mmol), paraformaldehyde (76mg, 0.61mmol) and sodium cyanoborohydride (18mg, 1.21mmol) join 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) piperazine-2-methane amide (135mg, 0.30mmol embodiment 35) the 5ml methanol solution in.Mixture was 50 ℃ of heating 1.5 hours, and cooling is filtered, and uses Isolute ^Methanol wash is used in the absorption of SCX post, with the methanol solution wash-out that contains 7N ammoniacal liquor.Merging filtrate, evaporation.The quick SiO of residue ₂Column chromatography is purified, and with ethanol/methylene (5/95～10/90) the mixture wash-out that polarity increases gradually, obtains the solid shape title product (105mg, 76%) of white.

¹ H NMR Spectrum：(DMSOd ₆)2.18(m，6H)；2.57(s，1H)；2.79(m，2H)；2.92(dd，1H)；3.44(d，1H)；3.84(d，1H)；3.96(s，3H)；7.22(s，1H)；7.30(m，3H)；7.51(t，1H)；7.58(t，1H)；8.40(s，1H)；8.44(s，1H)；9.75(s，1H)； Mass Spectrum(M+H) ⁺459.

Embodiment 37

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-(2-methoxyethyl) piperazine-2-methane amide

Method (d)

With sodium triacetoxy borohydride (79mg, 0.37mmol) join 1-({ the 4-[(3-chloro-2-fluorophenyl) amino of stirring]-7-methoxyl group quinazoline-6-yl } methyl) piperazine-2-methane amide (110mg, 0.25mmol, embodiment 35), (24mg contains the solution of 17% water to methoxyl group acetaldehyde, 0.37mmol) and in the suspension of the 5% acetate/methylene dichloride (10ml) of 3A molecular sieve (250mg).After 1 hour, do not observe product and generate, therefore add 10 normal methoxyl group acetaldehyde and sodium triacetoxy borohydride again.Stirred this mixture two hours, and filtered then, concentrating under reduced pressure, residue are dissolved in the methyl alcohol again, use Isolute then ^Methanol wash is used in the absorption of SCX post, with the methyl alcohol elution that contains 7N ammoniacal liquor, merges the flow point that comprises required product, evaporation.The quick SiO of residue ₂Column chromatography is purified (ethanol/methylene=5/95), obtains the solid shape title product (30mg, 24%) of white.

¹ H NMR Spectrum：(DMSOd ₆+d ₄ AcOH)2.30-2.41(m，3H)；2.66(m，2H)；2.82(d，2H)；3.04(m，2H)；3.24(s，3H)；3.49(m，3H)；3.84(d，1H)；3.95(s，3H)；7.22(s，1H)；7.28(t，1H)7.48(t，1H)；7.56(t，1H)；8.38(s，1H)；8.43(s，1H)； Mass Spectrum：(M+H) ⁺503.

Embodiment 38

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-4-(dimethylamino) piperidines-4-methane amide

Method (a)

With the same method in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and 4-(dimethylamino) piperidines-4-methane amide (commercial product, or the method by describing among the Japanese Patent JP03188030 embodiment 2, prepare with the debenzylating reaction of 1-benzyl-4-(dimethylamino) piperidines-4-methane amide) carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSOd ₆)1.65(t，2H)；2.03(d，2H)；2.16(m，8H)：2.69(m，2H)；3.58(s，2H)；3.95(s，3H)；6.96(d，2H)；7.20(s，1H)；7.28(t，1H)；7.49(t，1H)；7.54(t，1H)；8.32(s，1H)；8.43(s，1H)；9.83(s，1H)； Mass Spectrum：487.

Embodiment 39

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-2-methyl prolineamide

Method (a)

With the same method of describing in the embodiment 3 suitable steps, with 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and 2-methyl prolineamide carry out linked reaction and obtain title product.

¹ H NMR Spectrum：(DMSOd ₆)1.22(s，3H)；1.73(m，3H)；2.06(m，1H)；2.49(s，1H)；2.87(m，1H)；3.48(d，1H)；3.86(d，1H)；3.95(s，3H)；7.12(s，1H)；7.21(s，1H)；7.28(t，1H)；7.52(m，2H)；7.61(s，1H)；8.37(s，1H)；8.42(s，1H)；9.77(s，1H)； Mass Spectrum：(M+H) ⁺444.

2-methyl prolineamide starting raw material prepares in order to the below method:

With the same method of describing in the embodiment 3 suitable steps, with 1-(tertbutyloxycarbonyl)-the 2-methylproline carries out coupling method and deprotection obtains title product.

¹ H NMR(spectrum)：(DMSOd ₆)1.22(s，3H)；1.40(m，1H)；1.58(m，2H)；2.02(m，1H)；2.70(m，1H)；2.92(m，1H)；6.86(s，1H)；7.41(s，1H).

Embodiment 40

(3S)-1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-methyl-L-prolineamide (method (c)

With (3S)-1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-methyl-L-proline(Pro) carries out linked reaction with the same method of describing in the suitable step of embodiment 34, obtains title product.

¹ H NMR Spectrum：(DMSOd ₆)1.09(d，3H)；1.93(m，1H)；2.12(m，1H)；2.40(m，1H)；2.49(m，1H)；2.59(d，1H)；2.96(m，1H)；3.56(d，1H)；3.92(m，4H)；7.15(s，1H)；7.19(s，1H)；7.28(m，2H)；7.52(m，2H)；8.37(s，1H)；8.42(s，1H)；9.76(s，1H)； Mass Spectrum：(M+H) ⁺444.

As (the 3S)-1-of starting raw material ({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-methyl-L-proline(Pro) prepares with following method:

With 4-[(3-chloro-2-fluorophenyl) amino]-the same method described in 7-methoxyl group quinazoline-6-formaldehyde (carbaldehyde) and (the 3S)-suitable step of 3-methyl-L-proline(Pro) with embodiment 3 carries out linked reaction, obtains (3S)-1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-methyl-L-proline(Pro);

¹ H NMR Spectrum：(DMSOd ₆)1.08(d，3H)；1.41(m，1H)；1.99(m，1H)；2.25(m，1H)；2.63(q，1H)；2.92(d，1H)；3.14(m，1H)；3.91(m，4H)；4.06(d，1H)；7.18(s，1H)；7.25(m，1H)；7.48(m，2H)；8.39(m，2H)； Mass Spectrum：(M+H) ⁺445.

Embodiment 41

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-3-methane amide

(method (c)

At 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-3-formic acid (200mg, 0.48mmol) DMF (2ml) solution in add diisopropylethylamine (0.42ml, 2.40mmol), add then HATU (274mg, 0.72mmol).After 10 minutes, (39mg, 0.72mmol), stirred reaction mixture spends the night under the room temperature to add ammonium chloride.Crude product obtains Powdered title compound (11mg, 5%) with preparation HPLC (the mass triggered preparative HPLC) purifying that mass spectrum triggers;

¹ H NMR Spectrum：(DMSO d ₆)3.16(m，1H)，3.22(brs，2H)，3.60(brs，2H)，3.81(brs，2H)，3.96(s，3H)，6.94(brs，1H)，7.20(s，1H)，7.28(t，1H)，7.36(brs，1H)，7.48-7.53(m，2H)，8.28(s，1H)，8.43(s，1H)+NH； Mass Spectrum：(M+H) ⁺416.

As the 1-of starting raw material ({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-3-formic acid prepares with following method:

With 4-[(3-chloro-2-fluorophenyl) amino]-the same method described in 7-methoxyl group quinazoline-6-formaldehyde and the suitable step of 3-carboxyl azetidine with embodiment 3 carries out linked reaction, obtain 1-({ the 4-[(3-chloro-2-fluorophenyl) amino of white powder]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-3-formic acid (120mg, 65%);

¹ H NMR Spectrum：(DMSO d ₆)3.17(m，1H)，3.26(m，2H)，3.52(m，2H)，3.67(s，2H)，3.94(s，3H)，7.17(s，1H)，7.25(t，1H)，7.46(m，2H)，8.24(s，1H)，8.41(s，1H)； Mass Spectrum：(M+N) ⁺417.

Embodiment 42

1-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-2-methane amide

(method (c)

With 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl methyl) azetidine-2-formic acid (200mg, 0.48mmol) and triethylamine (74 microlitres, tetrahydrofuran (THF) 0.53mmol) (9ml) solution is chilled to-15 ℃.(51ul 0.53mmol), after 10 minutes, adds strong aqua (0.84ml) dropwise to add Vinyl chloroformate.Stirred this compound 2 hours at 0 ℃.Add saturated ammonium chloride solution, separate each layer.The water layer ethyl acetate extraction merges organic layer, uses dried over mgso, filters concentrating under reduced pressure.Crude product obtains Powdered title product (28mg, 14%) with the preparation HPLC purifying that mass spectrum triggers;

¹ H NMR Spectrum:(CDCl ₃) 2.01 (m, 1H), 2.26 (m, 1H), 2.92 (m, 1H), 3.31 (signal hiding under solvent, 1H),

3.60-3.67(m，2H)，3.80(d，1H)，3.95(s，3H)，7.20-7.30(m，4H)，7.48-7.55(m，2H)，8.32(s，1H)，8.43(s，1H)，9.82(brs，1H)； Mass Spectrum：(M+H) ⁺416.

As the 1-of starting raw material ({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-2-formic acid prepares with following method:

With 4-[(3-chloro-2-fluorophenyl) amino]-the same method described in 7-methoxyl group quinazoline-6-formaldehyde and the suitable step of azetidine-2-formic acid with embodiment 3 carries out linked reaction and obtains 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl) azetidine-2-formic acid;

¹ H NMR Spectrum：(DMSO d ₆)2.14(m，2H)，2.85(m，1H)，3.59(t，1H)，3.72(d，1H)，3.79(s，1H)，3.87(d，1H)，3.93(s，3H)，7.14(s，1H)，7.25(t，1H)，7.45(t，1H)，7.53(t，1H)，8.40(s，1H)，8.65(s，1H)； Mass Spectrum：(M+H) ⁺417.

Embodiment 43

1-(1-{4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } ethyl)-the L-prolineamide

With 1-{4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } ethyl ketone (ethanone) and (2S)-prolineamide carries out the isomer mixture that linked reaction obtains title compound with being similar to the method for describing among the embodiment 3, and isomer ratio is 6: 1.

¹ H NMR(spectrum)：(DMSOd ₆+D ₂O)1.31(d，3H)；1.44 ^*(d，3H)；1.72(m，3H)；2.08(m，1H)；2.21m，1H)；2.79 ^*(m，1H)；2.98(m，1H)；3.21(m，1H)；3.95(s，3H)；3.96 ^*(s，3H)；4.20(m，1H)；4.39 ^*(m，1H)；7.19 ^*(s，1H)；7.20(s，1H)；7.31(dt，1H)；7.55(m，2H)；8.41(s，1H)；8.42 ^*(s，1H)；8.43 ^*(s，1H)；8.46(s，1H)( ^*＝minor isomer peaks)； Mass spectrum：(M-H) ^-442.

^*=less isomer peak

As the 1-{4-[(3-chloro-2-fluorophenyl of starting raw material) amino]-7-methoxyl group quinazoline-6-yl } ethyl ketone prepares with following method:

With 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-base triflate (3g, 6.64mmol, embodiment 1, the preparation of starting raw material) is dissolved among the DMF (21ml), add normal-butyl Vinyl Ether (4.3ml, 33.2mmol), triethylamine (2.3ml, 16.6mmol), two (diphenylphosphino) propane of 3-(438mg, 1.06mmol) and acid chloride (223mg, 1mmol).Compound of reaction is chilled to stirred overnight at room temperature then 80 ℃ of heating 2 hours.Add 2M hydrochloric acid (24ml), stirred this compound 0.5 hour.This compound is alkalized with saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic extract liquid salt water washing, dry (MgSO ₄), concentrating under reduced pressure.The gained solid suspension filters in methyl alcohol, obtains faint yellow 1-{4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } and ethyl ketone (1.7g, 74%) 7.49 (t, 2H); 8.48 (s, 1H); 8.72 (s, 1H); 10.19 (s, 1H); Mass Spectrum:(MH)

Embodiment 44

(1S, 5R)-3-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazolyl-6-yl } methyl)-3-azabicyclo [3.1.0] hexane-2-methane amide

(1S, 5R)-3-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazolyl-6-yl methyl)-the same method described in 3-azabicyclo [3.1.0] hexane-suitable step of 2-methane amide with embodiment 41 from (1S, 5R)-3-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazolyl-6-yl methyl)-3-azabicyclo [3.1.0] hexane-2-formic acid is synthetic to be obtained;

¹ H NMR Spectrum:(DMSOd ₆) 0.34 (m, 1H); 0.78 (q, 1H); 1.45 (m, 1H); 1.67 (m, 1H); 2.52 (m, 1H); 2.87 (d, 1H); 3.15 (d, 1H); 3.50 (d, 1H); 3.88 (d, 1H); 3.95 (s, 1H); 7.15 (d, 1H); 7.22 (s, 1H); 7.29 (m, 2H); 7.51 (m, 1H); 7.58 (m, 1H); 8.29 (s, 1H); 8.45 (s, 1H); 9.75 (s, 1H); Mass Spectrum: (M+H) ⁺442. as starting raw material (1S, 5R)-3-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazolyl-6-yl methyl)-3-azabicyclo [3.1.0] hexane-2-formic acid prepares with following method:

With 4-[(3-chloro-2-fluorophenyl) amino]-the same method described in 7-methoxyl group quinazoline-6-formaldehyde and cis-3-azabicyclo [3.1.0] hexane-suitable step of 2-formic acid (Aldrich) with embodiment 3 carry out linked reaction obtain (1S, 5R)-3-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazolyl-6-yl methyl)-3-azabicyclo [3.1.0] hexane-2-formic acid;

¹ H NMR Spectrum：(DMSO d ₆)0.30(m，1H)；0.89(q，1H)；1.37(m，1H)；1.63(m，1H)；2.59(dd，1H)；3.02(d，1H)；3.24(d，1H)；3.79(d，1H)；3.91(m，4H)；7.19(s，1H)；7.27(t，1H)；7.48(t，1H)；7.54(t，1H)；8.24(s，1H)；8.43(s，1H)；9.87(brs，1H)； Mass Spectrum：(M+H) ⁺443.

Embodiment 45

(1R, 5S, 6r)-3-(4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-3-azabicyclo [3.1.0] hexane-6-methane amide

With 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-formaldehyde and (1R, 5S, 6r)-3-azabicyclo [3.1.0] hexane-6-methane amide with the same method of describing in the embodiment 3 suitable steps carry out linked reaction obtain (1R, 5S)-3-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl methyl)-3-azabicyclo [3.1.0] hexane-6-methane amide;

¹ H NMR Spectrum: (DMSO d ₆) 1.72 (m, 2H); 1.91 (m, 1H); 2.52 (m, 2H); 3.00 (d, 2H); 3.75 (s, 2H); 3.96 (s, 3H); 6.66 (s, 1H); 7.21 (s, 1H); 7.29 (t, 1H); 7.37 (s, 1H); 7.52 (m, 2H); 8.24 (s, 1H); 8.43 (s, 1H); 9.79 (s, 1H). as starting raw material (1R, 5S, 6r)-3-azabicyclo [3.1.0] hexane-6-methane amide prepares with following method:

With (1R, 5S)-and the 3-[(benzyloxy) carbonyl]-3-azabicyclo [3.1.0] hexane-6-formic acid carries out coupling and deprotection reaction with the same method of describing in the embodiment 35 suitable steps, obtain (1R, 5S, 6r)-3-azabicyclo [3.1.0] hexane-6-methane amide;

¹ H NMR Spectrum：(DMSO d ₆)1.39(m，1H)；1.65(m，2H)；2.72(d，2H)；2.87(d，2H)；6.65(bra，1H)；7.25(brs，1H).

Embodiment 46

Medicinal compositions

Following example preparation be used for the representational pharmaceutical dosage form of the present invention of human treatment or prevention, so place definition (active ingredient is known as " compounds X "):

(a) tablet I mg/ sheet

Compounds X ... ... ... ... ... ... ... ... ... ... 100

Lactose Ph.Eur.................................................. ... .182.75

Croscarmellose sodium ... ... ... ... ... ... ... ... .12.0

Corn starch paste (5%w/v paste) ... ... ... ... ... ... ... ... ..2.25

Magnesium Stearate ... ... ... ... ... ... ... ... ... ... ..3.0

(b) injection I (50mg/ml)

Compounds X ... ... ... ... ... ... ... ... ... ... 5.0%w/v

The 1M sodium hydroxide solution ... ... ... ... ... ... ... ... ... ..15.0%v/v

0.1M hydrochloric acid (regulating pH to 7.6)

Poly(oxyethylene glycol) 400 ... ... ... ... ... ... ... ... ... ..4.5%w/v

Water for injection adds to 100%.

Above-mentioned composition can prepare with well-known conventional procedure in the pharmaceutical field.Can be by component be mixed as tablet I, and compacting makes in flakes.

Claims

1. the quinazoline derivant of a formula I or its pharmaceutically acceptable salt:

Wherein:

Q ¹-X ³-

-Q ²-X ⁴-

-X ⁵-Q ³

Wherein at R ¹Any heterocyclic group base in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; described substituting group can be identical or different, they be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl amido of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfonamido of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ⁷

Wherein at R ¹Any heterocyclic group base in the last substituting group is optional to have 1 or 2 oxos or sulfo-substituting group;

X ¹Be (C (R ⁹) ₂) _n, each R wherein ⁹Can be identical or different, be selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, (1-4C) alkyl, halogen (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (3-7C) cycloalkyl and (3-7C) cycloalkyl-(1-4C) alkyl, or two R ⁹Group forms (3-7C) cycloalkyl ring with the carbon that connects them, and n is 1 or 2, and condition is to work as R ⁹Group is a hydroxyl or (1-4C) during alkoxyl group, n is 2, connect hydroxyl or (1-4C) carbon atom of alkoxyl group no longer be connected with other oxygen or nitrogen-atoms;

Q ^aBe the undersaturated heterocyclic radical of saturated or part of non-aromaticity, this heterocyclic radical contains a nitrogen heteroatom and optional 1,2 or 3 other heteroatoms that is selected from O, S and N, and described group passes through Q ^aIn nitrogen heteroatom and the X among the formula I ¹Link to each other;

Q is 0,1,2,3 or 4;

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, R ¹⁰Be selected from (1-6C) alkyl, its optional by one or more be selected from halogen, hydroxyl, (1-6C) alkoxyl group, cyano group, amino, N-(1-6C) alkylamino, N, N-two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl and (2-6C) the group replacement of alkanoyloxy,

Or two W groups form (1-4C) alkylidene bridges, should (1-4C) alkylidene bridge is optional have 1,2 or 3 substituting group, and described substituting group can be identical or different, they be selected from halogen, hydroxyl, oxo, (1-6C) alkyl, (1-6C) alkoxyl group, amino, N-(1-6C) alkylamino and N, N-two-[(1-6C) alkyl] amino;

X ²Be selected from CH ₂C (O), CH ₂SO ₂, C (O) and SO ₂

Wherein Z is selected from the alkyl of the alkyl of hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), heterocyclic radical, heterocyclic radical-(1-4C) alkyl, aryl and aryl-(1-4C),

Any CH in the Z substituting group wherein ₂=CH-or HC ≡ C-group are chosen wantonly at CH ₂=or HC ≡ end have substituting group, this substituting group is selected from halogen, carboxyl, formamyl,

Wherein optionally on any aryl in the Z substituting group or the heterocyclic radical have one or more substituting groups, described substituting group be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (1-3C) alkoxyl group, (1-4C) alkylthio, (1-4C) alkyl sulphinyl, (1-4C) alkyl sulphonyl, (2-6C) alkyloyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, (1-4C) carbalkoxy, N-(1-6C) alkyl-carbamoyl and N, N-two-[(1-6C) alkyl] formamyls,

Optional one or two oxo or the sulfo-substituting group of having on any heterocyclic radical in the Z substituting group wherein, condition be any described oxo substituting group not with heterocyclic radical in the adjacent carbon atom of epoxy atom on;

A is 1,2,3,4 or 5;

Each R ³Can be identical or different, be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, N-(1-6C) alkyl amino sulfonyl and N, N-two-[(1-6C) alkyl] amino-sulfonyls.

2. the quinazoline derivant of the formula I of claim 1 or its pharmaceutically acceptable salt, it has formula IA:

Wherein:

R ¹Be selected from the group of hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group or following formula:

Q ¹-X ³-

R wherein ¹The optional group that is inserted in the chain of C atom adjacent in any (2-6C) alkylidene chain in the substituting group is separated, and this group is selected from O, S, SO, SO ₂, N (R ⁴), CO, CH (OR ⁴), CON (R ⁴), N (R ⁴) CO, SO ₂N (R ⁴), N (R ⁴) SO ₂, CH=CH and C ≡ C, wherein R ⁴Be hydrogen or (1-6C) alkyl,

Wherein at R ¹Any CH in the substituting group ₂=CH-or HC ≡ C-group are at CH ₂=or the optional substituting group that has of HC ≡ end, this substituting group be selected from halogen, carboxyl, formamyl, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or be selected from the group of following formula:

Q ²-X ⁴-

Wherein at R ¹Any alkyl in the substituting group or alkylidene group be optional have one or more halogens, (1-6C) alkyl, hydroxyl, cyano group, amino, carboxyl, formamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkyl amido, N-(1-6C) alkyl amido of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, NThe alkane sulfuryl amino of-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C), or be selected from the group of following formula:

-X ⁵-Q ³

Wherein at R ¹Any heterocyclic radical in the substituting group is chosen wantonly and is had 1,2 or 3 substituting group; they can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, formyl radical, sulfydryl, (1-6C) alkyl, (2-8C) thiazolinyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkene oxygen base, (2-6C) alkynyloxy group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) carbalkoxy, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfonamido and N-(1-6C) the alkane sulfonamido of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ⁷

X wherein ⁶Be connecting key or be selected from O, N (R ⁸) and C (O), wherein R ⁸Be selected from hydrogen or (1-6C) alkyl, R ⁷Be selected from alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), carboxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of the alkyl of the alkyl of alkyl, (2-6C) alkyl amido-(1-6C), (1-6C) alkoxycarbonyl amido-(1-6C), formamyl-(1-6C), N-(1-6C) alkyl of alkyl-carbamoyl-(1-6C), N, NAlkyl of the alkyl of-two-[(1-6C) alkyl] formamyls-(1-6C), (2-6C) alkyloyl-(1-6C) or (1-6C) alkyl of carbalkoxy-(1-6C),

X ¹Be (C (R ⁹) ₂) _n, each R wherein ⁹Can be identical or different, being selected from hydrogen, hydroxyl, (1-4C) alkyl, halogen (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, n is 1 or 2, or two R ⁹Group forms (3-7C) cycloalkyl ring together with the carbon atom that is connected them, and condition is to work as R ⁹When being hydroxyl, n is 2, connect hydroxyl or (1-4C) carbon atom of alkoxyl group no longer link to each other with another oxygen or nitrogen-atoms;

-X ⁷-R ¹⁰

X wherein ⁷Be connecting key or be selected from O, CO and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, R ¹⁰Be (1-6C) alkyl, its optional by one or more be selected from halogen, hydroxyl, (1-6C) alkoxyl group, cyano group, amino, N-(1-6C) alkylamino, N, N-two-[(1-6C) alkyl] amino, (2-6C) alkyl amido, formamyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl and (2-6C) the substituting group replacement of alkanoyloxy,

X ²Be selected from C (O) and SO ₂

Z is selected from hydrogen, (1-6C) alkyl, (2-6C) thiazolinyl, (2-6C) alkynyl,

The optional group that is inserted in the chain of carbon atom adjacent in any (2-6C) alkylidene chain in the Z substituting group is separated, and described group is selected from O, S, SO, SO ₂, N (R ¹²) and CO, wherein R ¹²Be selected from hydrogen and (1-6C) alkyl,

Wherein any alkyl in the Z substituting group or alkylidene group are optional has one or more halogens or (1-6C) alkyl substituent, or be selected from hydroxyl, cyano group, amino, carboxyl, formamyl, amino-sulfonyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkyl amino sulfonyl, N, N-two-[(1-6C) alkyl] amino-sulfonyls, (1-6C) alkane sulfuryl amino and N-(1-6C) substituting group or (3-8C) cycloalkyl or the heterocyclic radical of the alkane sulfuryl amino of alkyl-(1-6C), wherein any one can be chosen wantonly by one or more groups and replace, and described group is selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, amino-sulfonyl, trifluoromethyl, (1-4C) alkyl, (2-4C) thiazolinyl, (2-4C) alkynyl, (1-3C) alkoxyl group, (2-4C) alkene oxygen base, (2-4C) alkynyloxy group, (1-4C) alkylthio, (1-4C) alkyl sulphinyl, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, (1-4C) carbalkoxy;

-X ⁷-R ¹⁰

X wherein ⁷And R ¹⁰As defined above;

A is 1,2,3,4 or 5;

B is 0 or 1;

Q is 0,1,2,3 or 4; And

R ²⁰Be hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group (2-6C) alkyl.

3. the quinazoline derivant of claim 1 or its pharmaceutically acceptable salt, wherein Q ^aBe selected from azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only) 1,3-thiazoles alkane-3-base, morpholino and piperazine-1-base.

4. the quinazoline derivant among the claim 1-3 or its pharmaceutically acceptable salt, wherein-X ²NZR ²⁰Group with X ¹The Q that links to each other ^aNeighbour (2-) position of theheterocyclic nitrogen atom.

5. the quinazoline derivant of claim 2 or its pharmaceutically acceptable salt, wherein b is 0.

6. each quinazoline derivant or its pharmaceutically acceptable salt, wherein R in the aforementioned claim ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group.

7. each quinazoline derivant or its pharmaceutically acceptable salt, wherein R in the aforementioned claim ¹Be (1-3C) alkoxyl group.

8. each quinazoline derivant or its pharmaceutically acceptable salt, wherein X in the aforementioned claim ¹Be CHR ⁹, R wherein ⁹Be selected from hydrogen and (1-4C) alkyl.

9. each quinazoline derivant or its pharmaceutically acceptable salt, wherein X in the aforementioned claim ¹Be CH ₂

10. each quinazoline derivant or its pharmaceutically acceptable salt in the aforementioned claim, wherein q is 0,1 or 2, each W can be identical or different, and they are selected from, and hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] are amino, hydroxyl-(1-4C) alkyl and (1-4C) alkyl of alkoxyl group-(1-4C).

11. each quinazoline derivant or its pharmaceutically acceptable salt, wherein X in the aforementioned claim ²Be C (O).

12. each quinazoline derivant or its pharmaceutically acceptable salt, wherein R in the aforementioned claim ²⁰Be hydrogen.

13. each quinazoline derivant or its pharmaceutically acceptable salt in the aforementioned claim, wherein Z is selected from the alkyl of the alkyl of the alkyl of hydrogen, (1-3C) alkyl, (2-3C) thiazolinyl, (2-3C) alkynyl, hydroxyl-(2-3C), (1-3C) alkoxyl group-(2-3C) and cyano group-(1-3C).

14. each quinazoline derivant or its pharmaceutically acceptable salt, wherein Z and R in the aforementioned claim ²⁰All be hydrogen.

15. each quinazoline derivant or its pharmaceutically acceptable salt in the aforementioned claim, wherein the anilino in the 4-position of the quinazoline ring of formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido.

16. each quinazoline derivant or its pharmaceutically acceptable salt in the aforementioned claim, wherein the anilino in the 4-position of the quinazoline ring of formula I is a 3-chloro-2-fluoroanilino.

17. the quinazoline derivant of the formula I of claim 1 or its pharmaceutically acceptable salt, it has formula IB:

R ¹Be (1-4C) alkoxyl group;

R ⁹Be hydrogen or methyl;

Q is 0,1 or 2;

Each W can be identical or different, as defined in claim 1;

Z is selected from hydrogen and (1-3C) alkyl;

A is 1 or 2; With

Each R ³Can be identical or different, they are selected from fluorine, chlorine, bromine and ethynyl.

18. the quinazoline derivant of the formula I of claim 17 or its pharmaceutically acceptable salt, wherein the anilino on the quinazoline ring 4-position is selected from 3-chloro-4-fluoroanilino and 3-bromo-2-fluoroanilino.

19. the quinazoline derivant of claim 1 is selected from:

11) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-the D-proline(Pro); With

12) 1-({ 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group quinazoline-6-yl } methyl)-N, N-dimethyl-L-prolineamide;

Or its pharmaceutically acceptable salt.

20. the quinazoline derivant of claim 1 is selected from:

Or its pharmaceutically acceptable salt.

21. comprising the quinazoline derivant of each formula I in the aforementioned claim or its pharmaceutically acceptable salt and pharmacy, a medicinal compositions, described medicinal compositions can accept diluent or carrier.

22. the quinazoline derivant of each formula I or its pharmaceutically acceptable salt among the claim 1-20, it is as drug use.

23. the quinazoline derivant of the formula I of each definition or its pharmaceutically acceptable salt are used for producing purposes in the medicine of antiproliferative effect warm-blooded animal such as the mankind in production among the claim 1-20.

24. the quinazoline derivant of the formula I of each definition or its pharmaceutically acceptable salt are used for the treatment of purposes in the warm-blooded animal such as the mankind's the medicine of cancer in production among the claim 1-20.

25. a method that produces antiproliferative effect in the warm-blooded animal of this treatment of needs such as the mankind, described method comprises quinazoline derivant or its pharmaceutically acceptable salt of the formula I of each definition among the claim 1-20 that gives described animal effective dose.

26. treat the warm-blooded animal of this treatment of needs such as the mankind's method for cancer for one kind, described method comprises quinazoline derivant or its pharmaceutically acceptable salt of the formula I of each definition among the claim 1-20 that gives described animal effective dose.

27. a method for preparing the formula I quinazoline derivant of definition in the claim 1, described method comprises:

Method (a):

Compound with formula (II)

X wherein ², W, Z, R ²⁰B and Q ^aSuch as claim 1 definition, when only needing any functional group is protected; Or

Method (b):

Compound with formula (XX):

R wherein ¹, R ³, R ⁹, n and a such as claim 1 definition, when only needing any functional group is protected, L is a leavings group, with the compound reaction of defined formula (III) in the top method (a); Or

Method (c)

HN(R ²⁰)Z

XXII

Carry out linked reaction,

Method (d)

With suitable aldehyde the quinazoline derivant of the formula I that comprises the NH group is accordingly carried out reduction amination; Or

Method (e)

In order to prepare wherein R ¹Be the quinazoline derivant of the formula I of hydroxyl, cracking is R wherein ¹Quinazoline derivant for the formula I of (1-6C) alkoxyl group; Or

Method (f)

R wherein ³, R ²⁰, Z, W, a, q, X ¹, X ²And Q ^aSuch as claim 1 definition, when only needing any functional group is protected, with formula R ^{1 '}The compound of OH carries out linked reaction, wherein R ^{1 '}As in this paper claim 1 to R ¹Definition, be one of oxygen linking group, when only needing any functional group is protected;

(with any order) then, if desired

(ii) remove any blocking group of existence by conventional methods; With

(iii) generate pharmaceutically acceptable salt.