CN101003515A

CN101003515A - 4-anilino quinazoline derivatives as antiproliferative agents

Info

Publication number: CN101003515A
Application number: CN 200710004468
Authority: CN
Inventors: R·H·布拉博里; L·F·A·亨内奎恩; J·G·凯特尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2002-03-28
Filing date: 2003-03-26
Publication date: 2007-07-25
Also published as: GB0207323D0; ZA200407416B; ZA200610455B

Abstract

The invention concerns quinazoline derivatives of Formula (I) wherein each of Q<1>, Z, R<1> and Q<2> have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases.

Description

4-anilinoquinazoline derivatives as antiproliferative

The application is to be invention and created name the dividing an application for the Chinese patent application of " as the 4-anilinoquinazoline derivatives of antiproliferative " (national applications number be No.03811739.8, international application no is PCT/GB03/01306) on March 26th, 2003 applying date.

Technical field

The present invention relates to some new quinazoline derivant or its pharmacy acceptable salt, these compounds have anti-tumor activity, therefore can be used for the methods of treatment of human or animal body.The invention still further relates to method, the pharmaceutical composition that contains these derivatives and their purposes in methods of treatment of the described quinazoline derivant of preparation, as the purposes of medicine of the noumenal tumour disease that is used for prevention or treatment warm-blooded animal (as the people) in preparation.

Background technology

All adopt the compound that suppresses the synthetic and cell proliferation of DNA by the unusual multiple existing treatment plan of regulating the disease (as psoriasis and cancer) that causes of cell proliferation.Up to now, the general pair cell of compound that adopts in these treatments all has toxicity, but they may be useful for the enhanced toxic action of the cell (as tumour cell) of quick differentiation.Developing at present other approach of these cell toxicant antineoplastic agents, for example the selective depressant of cell signal approach.Therefore the inhibitor of these types may present selectivity enhanced potential to the effect of tumour cell, may reduce the possibility of the unwanted side effect that described therapy has.

The multiple different extracellular signal of communication continues response to eukaryotic cell between the organ inner cell to making.These Signal Regulation various cells physiological reactions comprise propagation, differentiation, apoptosis and migration.These extracellular signals adopt the form of multiple different dissolution factor (comprising somatomedin and paracrine and endocrine factor).By combining with specific transmembrane receptor, these parts are integrated into the intracellular signal approach with these extracellular signals, therefore, with the signal conduction by plasma membrane and make individual cells respond its extracellular signal.Many these signal conductive processes all utilize the reversing process that relates to the protein phosphorylation that promotes these different cellular response.The phosphorylation situation of targeting proteins is subjected to the adjusting of specific kinases and phosphoesterase, and these kinases and phosphoesterase are responsible for the regulating effect of all albumen about 1/3rd of mammalian genes group coding.Because phosphorylation is regulation mechanism important in the signal conductive process, thereby so pathway unusual can cause cell growth and differentiation in these born of the same parents unusual promote cell transformation unusual and not at all surprising (see Cohen etc., Curr Opin Chem Biol, 1999,3, the summary of 459-465).

Show extensively that now many these Tyrosylprotein kinases can cause the somatic conversion of various human in the time of suddenling change structural activity form of generation and/or overexpression.Described kinase whose these sudden changes and overexpression form be present in most of human body tumour (see Kolibaba etc., Biochimica etBiophysica Acta, 1997, 133, the summary of F217-F248).Because Tyrosylprotein kinase plays basic effect in the propagation of multiple tissue and differentiation, therefore in the new anti-cancer therapies of exploitation, most of attention has concentrated on these enzymes.The family of this enzyme can be divided into two classes-acceptor and nonreceptor tyrosine kinase, for example be respectively EGF acceptor and SRC family.As seen, differentiated about 90 kinds of Tyrosylprotein kinases in human genome from the big quantity research result of (comprising the Human genome project), wherein 58 kinds is acceptor type, and 32 kinds is non-acceptor type.They 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).

Described receptor tyrosine kinase has special importance in the conduction of the mitogenesis signal that trigger cell duplicates.These big glycoprotein of crossing over cytoplasmic membrane have outside the born of the same parents in conjunction with the territory its ligands specific (as the endothelial cell growth factor (ECGF) (EGF) of EGF acceptor).The bound energy of part causes the activation of receptor kinase enzymic activity, and described enzymic activity is by the inner coding that divides of the born of the same parents of acceptor.This activity is the crucial tyrosine amino acid phosphorylated in the targeting proteins, thereby with the plasma membrane of proliferation signal conduction by cell.

The erbB family of known receptor Tyrosylprotein kinase comprises EGFR, erbB2, erbB3 and erbB4, they relate generally to order about the propagation of tumour cell and survival (Olayioye etc., EMBO J, 2000, 19, 3159 summary).An attainable mechanism is by the described acceptor of overexpression on protein level, and this generally is because the amplification of gene causes.In many common human cancers, observed at present it (see Klapper etc., Adv.Cancer Res., summary in 2000,77,25), as mammary cancer (Sainsbury etc., Brit.J.Cancer, 1988, 58, 458; Guerin etc., Oncogene Res, 1988,3,21; Slamon etc., Science, 1989, 244, 707; Klijin etc., Breast Cancer Res.Treat., 1994, 29, 73; With Salomon etc., Crit.Rev.Oncol.Hematol, 1995, 19, 183), nonsmall-cell lung cancer (NSCLCs), comprise 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 such as colon, rectum or cancer of the stomach (Bolen etc., Oncoeene Res, 1987, 1, 149; Kapitanovic etc., Gastroenterology, 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 Genet Cytogenet, 2001, 127, 174), ovarian cancer (Hellstrom etc., Cancer Res, 2001, 61, 2420), head and neck cancer (Shiga etc., Head Neck, 2000, 22, 599) or carcinoma of the pancreas (Ovotny etc., Neoplasma, 2001, 48, 188).Along with the detection to the expression of the erbB family of receptor tyrosine kinase in more mankind tumor tissues, expection can further strengthen the understanding to their being widely current property and importance in the future.

Regulate the result as one or more the mistake in these acceptors, now be sure of that extensively a lot of tumours aggressiveness that becomes clinically is stronger, and to patient's relatively poor diagnosis relevant (Brabender etc., Clin.Cancer Res., 2001, 7, 1850; Ross etc., Cancer Investigation, 2001, 19, 554; Yu etc., Bioessays, 2000, 22.7, 673).Except that these clinical discoveries, a large amount of clinical preceding information show that the erbB family of receptor tyrosine kinase relates to transformation.This comprises observes one or more erbB acceptor of many tumor cell line overexpressions, and when EGFR or erbB2 transfection were to non-tumor cell, they had the ability that transforms these cells.Since the transgenic mice of overexpression erbB2 can be in the Mammals body of gland spontaneous generation tumour, confirmed the potentiality of this tumorigenesis.In addition, many preclinical studies show, by by micromolecular inhibitor, dominance negating (dominant negatives) or suppress one or more erbB activity of antibody blocking, can bring out antiproliferative effect (see Mendelsohn etc., Oncogene, 2000, 19, 6550 summary).Therefore, the inhibitor that now has recognized that these receptor tyrosine kinases should have as the value of the selective depressant of the proliferation function of mammalian cancer cells (Yaish etc., Science, 1988, 242, 933; Kolibaba etc., Biochimicaet Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi etc., 2000, Oncogene, 19, 5690-5701; Mendelsohn etc., 2000, Oncogene, 19,6550-6565).Before these are clinical data, adopt result to the inhibited antibody (being respectively c-225 and tratsuzumab) of EGFR and/or erbB2 confirmed in clinical treatment to selected solid tumor be useful (see Mendelsohn etc., 2000, Oncogene, 19, summarize among the 6550-6565).

Detected the member's of erbB receptor Tyrosylprotein kinase amplification and/or activity, from the hint they following multiple non-malignant proliferation disease, play a role, as psoriasis (Ben-Bassat, Curt.Pharm Des.2000, 6, 933; Elder etc., Science, 1989, 243, 811), benign prostatauxe (BPH) (Kumar etc., Int.Urol.Nephrol., 2000, 32, 73), atherosclerosis and restenosis (Bokemeyer etc., Kidney Int., 2000, 58, 549).Therefore the inhibitor of expecting erbB receptor Tyrosylprotein kinase can be used for the treatment of these or other non-pernicious excessive cell proliferation disorders.

European patent application EP 566 266 discloses some and is the 4-anilinoquinazoline compounds of receptor tyrosine kinase inhibitors.

International Patent Application WO 96/33977, WO 96/33978, WO 96/33979, WO96/33980, WO 96/33981, WO 97/30034, WO 97/38994 openly have receptor tyrosine kinase and suppress active some quinazoline derivant, described derivative has the anilino substituting group on the 4-position, have substituting group on 6-and/or 7-position.

The 4-amido quinazoline derivatives that European patent application EP 837 063 open aryl replace, it has the part that comprises aryl or heteroaryl on the 6-of described quinazoline ring or 7-position.Described compound is considered to can be used for treating excess proliferative disease.

International Patent Application WO 97/30035 and WO 98/13354 disclose some 4-anilinoquinazoline that replaces on the 7-position be the vascular endothelial growth factor receptor tyrosine kinase inhibitor.

WO 00/55141 discloses 6, and the 4-anilinoquinazoline compound that 7-replaces is characterized in that the substituting group on 6-and/or the 7-position has ester connection portion (RO-CO).

WO 00/56720 openly is used for the treatment of 6 of cancer or anaphylaxis, 7-dialkoxy-4-anilinoquinazoline compound.

WO 02/41882 is disclosed in the 4-anilinoquinazoline compound that substituted pyrrolidyl-alkoxyl group on 6-and/or the 7-position or piperidyl-alkoxyl group replace.

Prior art is not seen open 4-(2,3-phenyl-dihalide amido) quinazoline compound.

Summary of the invention

At present, we are surprised to find, and some tool 4-(2,3-phenyl-dihalide amido) quinazoline derivant has the effective antitumour activity.Only do not play pharmacological action although do not wish to hint compound disclosed by the invention by a kind of single biological procedures, but think that described compound is to provide antitumor action by the erbB family that suppresses one or more receptor tyrosine kinases, described kinases is relevant with the signal conduction step that causes tumor cell proliferation.Particularly, compound of the present invention is considered to provide antitumor action by suppressing EGFR and/or erbB2 receptor tyrosine kinase.

Usually, although compound of the present invention has less inhibition activity to other Tyrosylprotein kinase, they for example have effective inhibition activity by suppressing EGFR and/or erbB2 and/or erbB4 receptor tyrosine kinase to erbB receptor tyrosine kinase family.In addition, render a service with respect to the inhibition to the erbB2 Tyrosylprotein kinase, some compound of the present invention shows EGFR and well suppresses more significantly to render a service.The present invention comprises that also all EGFR, erbB2 and erbB4 receptor tyrosine kinase or its combination are had activity, thereby the compound of effective therapeutic action can be provided the disease of one or more these receptor tyrosine kinases mediations.

Usually, compound of the present invention presents favourable physical properties (as high resolution), has kept high antiproliferative activity simultaneously.In addition, chemical compound lot of the present invention non-activity or only present weak activity in hERG measures.

First aspect of the present invention provides quinazoline derivant or its pharmacy acceptable salt of formula I:

Wherein:

G ¹And G ²Independent separately is halogeno-group;

X ¹Be direct key or O;

R ¹Be selected from hydrogen and (1-6C) alkyl, wherein said (1-6C) alkyl optional by one or more can be identical or different the following substituting group that is selected from replace: hydroxyl and halogeno-group and/or be selected from following substituting group and replace: amino, nitro, carboxyl, cyano group, halogeno-group, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, 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), (1-6C) alkoxy carbonyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino and N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C);

X ²Be direct key or [CR ²R ³] _m, wherein m is the integer of 1-6,

And R ²And R ³Independently be selected from hydrogen, hydroxyl, (1-4C) alkyl and hydroxyl (1-4C) alkyl separately; Q ¹Be (3-7C) cycloalkyl or heterocyclic radical, wherein Q ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; acryl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (2-6C) alkenyl thio; (2-6C) alkynes sulfenyl; (1-6C) alkyl sulphinyl; (2-6C) alkenyl sulfinyl; (2-6C) alkynyl sulfinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (2-6C) alkynyl alkylsulfonyl; (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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino, N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl of alkyl-(2-6C) and (1-6C) group of alkoxy carbonyl (1-6C) alkyl or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be heterocyclic radical,

Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group, hydroxyl, (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl,

Q wherein ¹In any (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl and (2-6C) alkyloyl optional have one or more (for example 1; 2 or 3) can be identical or different be selected from following substituting group: halogeno-group; hydroxyl alkyl and/or optional having is selected from following substituting group with (1-6C): cyano group; nitro; carboxyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; hydroxyl (1-6C) alkoxyl group; (1-4C) alkoxyl group (1-6C) alkoxyl group; (2-6C) alkyloyl; (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more (for example 1,2 or 3) can be identical or different optional having: cyano group, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group and (1-2C) alkoxyl group (1-4C) alkoxyl group

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl (prerequisite be this ring not can so by quaternized)

Wherein be present in by R as substituting group ^aAnd R ^bAny (1-4C) alkyl on the ring that the nitrogen-atoms that links to each other with their forms or (2-4C) alkyloyl is optional has the substituting group that is selected from halogeno-group and hydroxyl that one or more (for example 1,2 or 3) can be identical or different and/or be selected from (1-4C) alkyl and (1-4C) substituting group of alkoxyl group optional having

Q wherein ¹-X ²Any heterocyclic group in the-group is optional have 1 or 2 oxo (=O) or sulfo-(=S) substituting group.

The present invention provides quinazoline derivant or its pharmacy acceptable salt of formula I, wherein each R on the other hand ¹, G ¹, G ², X ¹And X ²Has above qualification in all senses; And Q ¹Be (3-7C) cycloalkyl or heterocyclic radical, wherein Q ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino, N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl of alkyl-(2-6C) and (1-6C) group of alkoxy carbonyl (1-6C) alkyl or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be heterocyclic radical,

Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl,

Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl is optional has a following substituting group that is selected from that one or more (for example 1,2 or 3) can be identical or different: halogeno-group, hydroxyl and (1-6C) alkyl and/or be selected from following substituting group optional having: cyano group, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings, this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from (1-4C) alkyl, and can on any available theheterocyclic nitrogen atom, choose have be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl (prerequisite be this ring not can so by quaternized);

The present invention provides quinazoline derivant or its pharmacy acceptable salt of formula I, wherein each R on the other hand ¹, G ¹, G ², X ¹And X ²Has above qualification in all senses; And

Q ¹Be (3-7C) cycloalkyl or heterocyclic radical, wherein Q ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (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) 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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino, N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl of alkyl-(2-6C) and (1-6C) alkoxy carbonyl (1-6C) alkyl,

Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl is optional has a following substituting group that is selected from that one or more (for example 1,2 or 3) can be identical or different: halogeno-group, hydroxyl and (1-6C) alkyl and/or be selected from following substituting group optional having: cyano group, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings;

The present invention provides quinazoline derivant or its pharmacy acceptable salt of formula I, wherein each R on the other hand ¹, G ¹, G ², X ¹And X ²Has above qualification in all senses; And Q ¹Be to have 3-7 unit (for example 4,5 or 6 a yuan) monocyclic heterocycles ring nitrogen heteroatom and optional 1 or 2 heteroatomic non-aromatics that is selected from nitrogen and sulphur, saturated or fractional saturation, this ring is by carbon atom and radicals X on the ring ²-O-connects, and Q wherein ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; formamyl; acryl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (2-6C) alkenyl thio; (2-6C) alkynes sulfenyl; (1-6C) alkyl sulphinyl; (2-6C) alkenyl sulfinyl; (2-6C) alkynyl sulfinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (2-6C) alkynyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino, N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) group of alkanoylamino (1-6C) alkyl of alkyl-(2-6C) or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be heterocyclic radical, it is selected from morpholino (morpholino) and contains a nitrogen heteroatom and optional 1 or 2 heteroatomic 4,5 or 6 yuan of monocyclic heterocycles base that are selected from sulphur and nitrogen,

Q wherein ¹In any (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl and (2-6C) alkyloyl optional have one or more (for example 1; 2 or 3) can be identical or different be selected from halogeno-group; hydroxyl the substituting group and/or optional the having of alkyl is selected from following substituting group with (1-6C): cyano group; nitro; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; hydroxyl (1-6C) alkoxyl group; (1-4C) alkoxyl group (1-6C) alkoxyl group; (2-6C) alkyloyl; (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more (for example 1,2 or 3) can be identical or different optional having: cyano group, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group and (1-2C) alkoxyl group (1-4C) alkoxyl group

Q wherein ¹-X ²Any heterocyclic group in the-group is optional have 1 or 2 oxo (=O) or sulfo-(=S) substituting group;

Prerequisite is to work as X ²Be [CH ₂] _m, m is the integer of 1-6, Q ¹For on the 1-position by (2-4C) alkyl or (2-5C) when the pyrrolidyl that replaces of alkyloyl or piperidyl, Q then ¹The 1-position on (2-4C) alkyl or (2-5C) alkyloyl do not replaced by 2-oxo morpholino.

In this manual, generic term " alkyl " comprises straight chain and branched-chain alkyl, as propyl group, sec.-propyl and the tertiary butyl, and (3-7C) cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.Yet, when mentioning the independent alkyl such as " propyl group ", only be to refer in particular to the straight chain variant, when mentioning the independent branched-chain alkyl such as " sec.-propyl ", only be to refer in particular to chain variants, and when mentioning independent cycloalkyl such as " cyclopentyl ", only refer in particular to 5 yuan of rings.Similar convention is used for other generic term, for example (1-6C) alkoxyl group comprises methoxyl group, oxyethyl group, ring propoxy-and cyclopentyloxy, (1-6C) alkylamino comprises methylamino-, ethylamino, ring fourth amino and hexamethylene amino, and two-[(1-6C alkyl)] amino comprise dimethylamino, diethylamino, N-cyclobutyl-N-methylamino-and N-cyclohexyl-N-ethylamino.

Should be appreciated that, more than Ding Yi some formula I compound is owing to have the carbon of one or more asymmetric replacement and/or sulphur atom and can existing with optically active or racemic form, therefore can exist or separates with pure enantiomorph, non-enantiomer mixture or racemic modification form.The present invention comprises form or its mixture of racemize, the optically active of any formula I compound, pure enantiomorph, non-enantiomer mixture, steric isomer in its definition, they have above-mentioned activity.By standard technique of organic chemistry well known in the art, for example, can carry out the synthetic of optically active form by fractionation synthetic from the optically active raw material or by racemic form.Similarly, use the standard laboratory technology of indication hereinafter, can estimate above-mentioned activity.

The present invention relates to have all tautomeric forms of the formula I compound of antiproliferative activity.

It should also be clear that some formula I compound can exist solvate and non-solvent compound form, as hydrate forms.Should understand and the present invention includes all these solvate form thereof with antiproliferative activity.

It should also be clear that can there be polymorphic in some formula I compound, polymorphic of the present invention comprises all these forms with antiproliferative activity.

The suitable connotation of general group mentioned above comprises following listed those.

Work as Q ¹When being (3-7C) cycloalkyl, its suitable connotation is for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or dicyclo [2.2.1] heptyl.

Work as Q ¹Or Q ²During for heterocyclic radical, it is the 3-10 unit monocycle of non-aromatics saturated (promptly having maximum saturation) or fractional saturation (be loop systems keep some but be not whole degrees of unsaturation), this ring has at most and can be selected from oxygen, sulphur and the nitrogen heteroatoms of (but not containing any O-O, O-S or S-S key) to 5, and by ring carbon atom or theheterocyclic nitrogen atom link to each other (prerequisite is that this ring is not therefore by quaternized).Q ¹Or Q ²Suitable connotation comprises for example Oxyranyle, oxetanyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, oxepane alkyl (oxepanyl), oxaza heptane base (oxazepanyl), pyrrolinyl, pyrrolidyl, morpholinyl, 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, tetrahydro thiapyran base, thio-morpholinyl, more specifically comprise for example tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-2-base, tetrahydropyran-4-base, tetramethylene sulfide-3-base, tetrahydric thiapyran-4-group, pyrroline-3-base, pyrroline-2-base, 3-pyrroline-3-base, morpholino, 1,1-dioxo tetrahydrochysene-4H-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-oxaza heptane base or 1,2,3,6-tetrahydropyridine-4-base.

Nitrogen in the heterocyclic radical or sulphur atom can oxidizedly obtain corresponding N or S oxide compound, and for example 1,1-dioxo tetrahydro-thienyl, 1-oxo tetrahydro-thienyl, 1,1-dioxo tetrahydro thiapyran base or 1-oxo tetrahydro thiapyran base.The suitable letter justice that has 1 or 2 oxos or substituent this type of group of sulfo-is for as 2-oxo-pyrrolidine base, 2-oxo piperazinyl, 2-sulfo-pyrrolidyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidyl or 2,6-dioxopiperidine base.

Q ¹And Q ²Preferred letter justice comprises the first monocyclic heterocycles base of for example non-aromatics 3-7 saturated or fractional saturation, and it has a theheterocyclic nitrogen atom or sulfur heteroatom and optional 1 or 2 heteroatoms that is selected from nitrogen, oxygen and sulphur.The example of these rings comprises azetidinyl, oxaza heptane base (oxazepanyl), pyrrolinyl, pyrrolidyl, morpholinyl, 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 ¹Further preferred letter justice comprises the first monocyclic heterocycles base of for example non-aromatics 3-7 saturated or fractional saturation, and it has a ring nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from nitrogen and sulphur, and this ring passes through carbon atom and the radicals X on the ring ²-O-connects, for example azetidinyl, pyrrolinyl, pyrrolidyl, tetrahydrochysene-1,4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro thiapyran base or thio-morpholinyl.Q ¹4,5 or 6 yuan of monocyclic heterocycles of the saturated or fractional saturation of more preferably non-aromatics, it has 1 or 2 nitrogen heteroatom, this ring is connected with radicals X 2-O-by the carbon atom on the ring, tetramethyleneimine-3-base, tetramethyleneimine-2-base, 3-pyrroline-3-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, high piperidines-3-base, high piperidin-4-yl, piperazine-2-base, piperazine-3-base or 1 more especially, 2,3,6-tetrahydropyridine-4-base.Nitrogen-atoms in the heterocyclic radical can oxidizedly obtain corresponding N oxide compound.

Q ²Concrete letter justice for example comprise morpholino or contain 1 nitrogen-atoms and optional 1 or 2 heteroatomic 4,5 or 6 yuan of monocyclic heterocycles base that are selected from nitrogen and sulphur, as piperazinyl, pyrrolidyl, piperidyl, especially tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperazine-1-base or piperidino-(1-position only).

Work as R ^aOr R ^bWhen the nitrogen-atoms that connects with their forms 4,5 or 6 yuan of rings, this ring is the non-aromatic heterocycle of saturated or fractional saturation, this ring contains 1 nitrogen-atoms and is selected from oxygen, sulphur and the nitrogen heteroatoms of (but not containing any O-O, O-S or S-S key) with optional 1 or 2, and the ring that wherein so forms links to each other with the group that this ring is connected by theheterocyclic nitrogen atom.This ring is optional on available ring carbon atom to have 1 or 2 substituting group (for example being selected from (1-4C) alkyl) as defined above, and can choose the substituting group (prerequisite is that this ring is not therefore by quaternized) that has as defined above (for example be selected from (1-4C) alkyl, (2-4C) alkyloyl with (1-4C) alkyl sulphonyl) on any available theheterocyclic nitrogen atom.R ^aOr R ^bThe suitable connotation of 4,5 or 6 yuan of rings that the nitrogen-atoms that connects with them forms comprises for example 2-pyrroline-1-base, 3-pyrroline-1-base, tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base and morpholino.

In this specification sheets as above or as any R of giving a definition ¹, R ², R ³, R ⁴, R ⁴, R ^a, R ^b, G ¹, G ²Or Q ¹The suitable connotation of each interior group comprises:

For halo: be fluorine, chlorine, bromine and iodine;

For (1-6C) alkyl: be methyl, ethyl, propyl group, sec.-propyl, uncle

Butyl, amyl group and hexyl;

For (1-4C) alkyl: be methyl, ethyl, propyl group, sec.-propyl and uncle

Butyl;

For (1-6C) alkoxyl group: be methoxyl group, oxyethyl group, propoxy-, different third

Oxygen base and butoxy;

For (2-8C) alkenyl: be vinyl, pseudoallyl, allyl group and fourth

-2-thiazolinyl;

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

For (2-6C) alkenyl oxy: be vinyl oxygen base and allyl group oxygen base;

For (2-6C) alkynyloxy base: be ethynyl oxygen base and 2-propynyl oxygen base;

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

For (2-6C) alkenyl thio: be vinyl sulfenyl and allyl group sulfenyl;

For (2-6C) alkynyl sulfenyl: be ethynyl sulfenyl and 2-propynyl sulfenyl;

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

For (2-6C) alkenyl sulfinyl: be vinyl sulfinyl and allyl group sulfinyl

Base;

For (2-6C) alkynyl sulfinyl: be the inferior sulphur of ethynyl sulfinyl and 2-propynyl

Acyl group;

For (1-6C) alkyl sulphonyl: be methylsulfonyl and ethylsulfonyl;

For (2-6C) alkenyl alkylsulfonyl: be vinylsulfonyl and allyl group alkylsulfonyl;

For (2-6C) alkynyl alkylsulfonyl: be ethynyl alkylsulfonyl and 2-propynyl sulphonyl

Base;

For (1-6C) alkylamino: be methylamino-, ethylamino, third amino, different third

Amino and fourth amino;

For two-[(1-6C) alkyl] amino: for dimethylamino, diethylamino, N-second

Base- N-methylamino and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: be methoxycarbonyl, ethoxy carbonyl, third oxygen

Base carbonyl and tert-butoxycarbonyl;

For N-(1-6C) alkyl-carbamoyl: for N-methylamino formyl radical, N-ethylamino

Formyl radical, N-propyl group formamyl and N-

The sec.-propyl formamyl;

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

Acyl group :- N-methylamino formyl radical and N, N-diethyl

Formamyl;

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

For (2-6C) alkanoyloxy: be acetoxyl group and propionyl oxygen base;

For (2-6C) alkanoylamino: be kharophen and propionamido;

For N-(1-6C) alkyl-(2-6C) alkyloyl is N-methyl kharophen and N-methyl propionyl

Amino: amino;

For N-(1-6C) alkylsulfamoyl group: for N-methyl sulfamyl, N-ethyl sulphonamide

The base and N-sec.-propyl sulfamyl;

For N, N-two-[(1-6C) alkyl] sulphonamide is N, N-dimethylamino alkylsulfonyl and N-methyl-

Base: N-ethyl sulfamyl

For (1-6C) alkane sulfuryl amino: be methylsulfonyl amino and ethylsulfonylamino;

For N-(1-6C) alkyl-(1-6C) the alkane sulphonyl is N-methyl methylsulfonyl amino and N-methyl

Base is amino: ethylsulfonylamino;

For amino-(1-6C) alkyl: be amino methyl, 2-amino-ethyl, the amino second of 1-

Base and 3-aminopropyl;

For (1-6C) alkylamino-(1-6C) alkane is methylamino-methyl, ethylamino methyl, 1-

Base: methylamino-ethyl, 2-methylamino-ethyl, 2-ethyl

Amino-ethyl and 3-methylamino-propyl group;

For two-[(1-6C) alkyl] amino-(1-6C) be dimethylamino methyl, diethylacbamazine

Alkyl: base, 1-dimethylaminoethyl, 2-dimethylamino second

Base and 3-dimethylamino-propyl;

For the alkyl of halo-(1-6C): be chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-

Chloropropyl;

For the alkyl of hydroxyl-(1-6C): be hydroxymethyl, 2-hydroxyethyl, the 1-hydroxyethyl and

The 3-hydroxypropyl;

For the alkoxyl group of hydroxyl-(1-6C): be hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 1-

Hydroxyl-oxethyl and 3-hydroxyl propoxy-;

For the alkyl of (1-6C) alkoxyl group-(1-6C): be methoxymethyl, ethoxyl methyl, 1-first

Oxygen base ethyl, 2-methoxy ethyl, 2-oxyethyl group

Ethyl and 3-methoxy-propyl;

For the alkyl of cyano group-(1-6C): be cyano methyl, 2-cyano ethyl, 1-cyano group second

Base and 3-cyano group propyl group;

For amino (2-6C) alkyloyl: be the amino propionyl of glycyl and 2-;

For (1-6C) alkylamino-(2-6C) the alkane acyl is methylamino-ethanoyl and 3-(methylamino-) propionyl

Base: base;

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

(2-6C) alkyloyl: propionyl;

For the alkane of (2-6C) alkanoylamino-(1-6C) be acetylamino methyl, propionamido methyl and

Base: 2-kharophen ethyl

Alkyl-(2-6C) alkyloyl is for N-(1-6C) N-methyl acetylamino methyl, N-methyl-prop

Amino-(1-6C) alkyl: amido methyl, 2-( N-methyl kharophen)

Ethyl and 2-( N-methyl-prop amido) ethyl;

For (1-6C) alkoxycarbonyl amino-(1-is methoxycarbonyl amino methyl, oxyethyl group carbonyl

6C) alkyl: basic amino methyl, the amino first of tert-butoxycarbonyl

Base and 2-methoxycarbonyl amino-ethyl;

For formamyl (1-6C) alkyl: be carbamyl ylmethyl, 1-formamyl

Ethyl, 2-formamyl ethyl and 3-amino

The formyl radical propyl group;

For N-(1-6C) alkyl-carbamoyl (1-be N-methylamino formyl radical methyl, N-ethyl

6C) alkyl: the carbamyl ylmethyl, N-propyl group carbamyl

Ylmethyl, 1-( N-methylamino formyl radical) second

The base, 2-( N-methylamino formyl radical) ethyl and

3-( N-methylamino formyl radical) propyl group;

For N, N-two (1-6C) alkyl carbamoyl is N, N-formyl-dimethylamino methyl,

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

Base- N-ethylamino formyl radical methyl, 1-( N, N-

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

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

Formyl-dimethylamino) ethyl,

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

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

For sulfamyl (1-6C) alkyl: be sulfamyl methyl, 1-sulfamyl second

Base, 2-sulfamyl ethyl and 3-sulfamyl

Propyl group;

(1-is for N-(1-6C) alkylsulfamoyl group N-methyl sulfamyl methyl, N-ethyl ammonia

6C) alkyl: the alkylsulfonyl methyl, N-propyl group sulfamyl first

The base, 1-( N-methyl sulfamyl) ethyl, 2-( N-

The methyl sulfamyl) ethyl and 3-( N-methyl ammonia

Alkylsulfonyl) propyl group;

For N, N-two (1-6C) alkylsulfamoyl group is N, N-dimethylamino alkylsulfonyl methyl, N, N-

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

Ethyl sulfamyl methyl, 1-( N, N-dimethyl

Sulfamyl) ethyl, 1-( N, N-diethyl amino sulphur

Acyl group) ethyl, 2-( N, N-dimethylamino sulphonyl

Basic) ethyl,

2-( N, N-diethyl amino alkylsulfonyl) ethyl and 3-

( N, N-dimethylamino alkylsulfonyl) propyl group;

For (2-6C) alkyloyl (1-6C) alkyl: be ethanoyl methyl, propionyl methyl, 2-second

Acyl group ethyl and 2-propionyl ethyl;

For (2-6C) alkanoyloxy (1-6C) alkane be acetoxy-methyl, propionyloxy methyl,

Base: 2-acetoxyl group ethyl and 3-acetoxyl group third

Base;

For (1-6C) alkoxyl group (1-6C) alkyl is 2-methoxyl group ethylsulfonyl, 2-methoxyl group second

S (O) _q: sulfinyl and 2-methoxyl group ethylmercapto group;

For amino (1-6C) alkyl S (O) _q: be 2-tauryl base, the inferior sulphur of the amino second of 2-

The amino ethylmercapto group of acyl group and 2-;

For N-(1-6C) alkylamino (1-6C) alkane is 2-(methylamino-) ethylsulfonyl, 2-(ethylamino)

Base S (O) _q: second sulfinyl and 2-(methylamino-) ethylmercapto group;

With

For N, N-two [(1-6C) alkyl] is amino, and (1-is 2-(dimethylamino) ethylsulfonyl, 3-(diformazan

6C) alkyl S (O) _q: amino) third alkylsulfonyl, 2-(diethylamino) second

Sulfinyl and 2-(N-methyl-N-ethylamino) second

Sulfenyl.

(1-3C) alkylenedioxy group can be used as by R ^aAnd R ^bWhen the substituting group on the ring that the nitrogen-atoms that connects with them forms existed, it was suitably for, and as methylene-dioxy, ethyl subunit dioxy base (ethylidenedioxy), isopropylidene dioxy base or ethylenedioxy, and its Sauerstoffatom occupies the ortho position of ring.For example, work as R ^aAnd R ^bWhen the nitrogen-atoms that connects with their formed tetramethyleneimine-1-basic ring, this ring can be replaced by methylene-dioxy, obtains 3,4-methylene-dioxy tetramethyleneimine-1-base.

As previously mentioned, Q ¹In (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl or (2-6C) alkyloyl can be by for example hydroxyl, (2-8C) alkenyl, (2-6C) alkyloyl, (2-6C) alkanoyloxy or NR ^aR ^bReplace, wherein R ^aAnd R ^bAs preceding definition.For example, work as Q ¹When being replaced by ethanoyl, this ethanoyl itself can be by the amino replacement of two [(1-6C) alkyl], at Q ¹On form for example dimethylamino ethanoyl or N-methyl-N-ethylamino-ethanoyl, perhaps ethanoyl can be replaced by (2-8C) alkenyl and obtain alkenoyl, for example, ethanoyl is replaced by allyl group, obtains fourth-3-enoyl-.Similarly, as for example Q ¹When being replaced, should can be replaced by for example dimethylamino by (1-6C) alkyl, obtain the alkyl sulphonyl (as 3-(dimethylamino) third alkylsulfonyl) of dimethylamino-(1-6C) by (1-6C) alkyl sulphonyl (as third alkylsulfonyl).Again for example, work as Q ¹When being replaced by N-methylamino formyl radical, this methyl can be obtained for example N-allyl amino formyl radical or N-(2-propynyl) formamyl by for example (2-6C) alkenyl or (2-6C) alkynyl substituted.

Should know and work as R ¹Replaced (1-6C) alkyl and when for example obtaining the 2-amino-ethyl by for example amino, then should (1-6C) alkyl and X ¹Connect and (perhaps work as X ¹During for direct key is the quinazoline ring).Similarly apply transformations in other group of this paper definition.For example, work as Q ¹Have (1-6C) alkyl that is replaced by (1-6C) alkoxyl group and when obtaining (1-6C) alkoxyl group (1-6C) alkyl substituent, should (1-6C) alkyl and Q ¹Connect.

Should know and work as X ³When being CO, it is a carbonyl.

When this paper points out " Q ¹-X ²Any heterocyclic radical in the-group is optional have 1 or 2 oxo (=O) or sulfo-(=S) during substituting group ", described oxo and/or thio group can be present in and comprise Q ¹In any heterocyclic radical on, comprise by Q ¹Own, Q ²The heterocyclic radical and the R of representative ^aAnd R ^b4,5 or 6 yuan of heterocyclic radicals that the nitrogen-atoms that connects with them forms.

When relating to (1-4C) alkyl in this specification sheets, should know that this type of group is meant that contain at most can be to the alkyl of 4 carbon atoms.The technician understand the representative example of these groups be under above (1-6C) alkyl item listed those contain at most can be to the group of 4 carbon atoms, as methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.Similarly, (1-3C) alkyl is meant that contain at most can be to the alkyl of 3 carbon atoms, as methyl, ethyl, propyl group and sec.-propyl.Similarly regulation is suitable for above listed other group, as (1-4C) alkoxyl group, (2-4C) alkenyl, (2-4C) alkynyl and (2-4C) alkyloyl.

In formula I compound, hydrogen atom is present on 2,5 and 8 of described quinazoline ring.

The pharmacy acceptable salt that is fit to of formula I compound is the acid salt of formula I compound for example, for example they and mineral acid or organic acid acid salt, and described acid has example hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid; Perhaps, for example, the salt of enough tart formula I compounds, as basic metal or alkaline earth salt (as calcium salt or magnesium salts) or ammonium salt, the perhaps salt that forms with organic bases such as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.

Concrete new compound of the present invention comprises for example quinazoline derivant or its pharmacy acceptable salt of formula I, wherein except that specializing, and m, R ¹, R ², R ³, Q ¹, Q ², X ¹, X ², m, G ¹And G ²Have front or following (a) to (qqq) section defined in all senses:

(a) Q ¹Be the first monocyclic heterocycles of non-aromatics 3-7 saturated or fractional saturation, it has 1,2 or 3 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by ring carbon atom or theheterocyclic nitrogen atom and radicals X ²-O-connects (prerequisite is that this ring is not therefore by quaternized), and Q wherein ¹In any available nitrogen-atoms be selected from following substituting group (wherein this replacement does not cause quaternized) optional having: trifluoromethyl, cyano group, formamyl, trifluoromethoxy, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl of alkyl-(2-6C) and (1-6C) alkoxy carbonyl (1-6C) alkyl,

Wherein any (1-6C) alkyl in the optional substituting group on available nitrogen-atoms, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl optional by one or more can be identical or different the following substituting group that is selected from replace: fluoro base, chloro base, hydroxyl and (1-4C) alkyl and/or be selected from following substituting group optional having: cyano group, nitro, carboxyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl,

And Q ¹Optionally on any available carbon atom in ring have 1 or 2 (being suitably for 1) and be selected from following substituting group: halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-4C) alkyl; (2-6C) alkenyl; (2-6C) alkynyl; (1-4C) alkoxyl group; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); hydroxyl (1-6C) alkyl; cyano group (1-6C) alkyl; amino (1-6C) alkyl; (1-6C) alkylamino (1-6C) alkyl; two-[(1-6C) alkyl] amino (1-6C) alkyl and (1-6C) alkoxyl group (1-6C) alkyl

Q wherein ¹Optional 1 or 2 oxo or the sulfo-substituting group of having;

(b) Q ¹Be the first monocyclic heterocycles of non-aromatics 3-7 saturated or fractional saturation, it has 1,2 or 3 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on the ring ²-O-connects, and Q wherein ¹In any available nitrogen-atoms be selected from following substituting group (wherein this replacement does not cause quaternized) optional having: trifluoromethyl, cyano group, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl of alkyl-(2-6C) and (1-6C) alkoxy carbonyl (1-6C) alkyl,

And Q ¹Optionally on any available carbon atom in ring have 1 or 2 (being suitably for 1) and be selected from following substituting group: halogeno-group, trifluoromethyl, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), hydroxyl (1-6C) alkyl, cyano group (1-6C) alkyl, amino (1-6C) alkyl, amino (1-6C) alkyl of (1-6C) alkylamino (1-6C) alkyl, two-[(1-6C) alkyl] and (1-6C) alkoxyl group (1-6C) alkyl

Q wherein ¹Optional 1 or 2 oxo or the sulfo-substituting group of having; (c) Q ¹Be the first monocyclic heterocycles of non-aromatics 3-7 saturated or fractional saturation, it has 1 nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on encircling ²-O-connects,

And Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, formamyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, NThe alkyloyl of amino (1-6C) alkyl of-two-[(1-6C) alkyl] sulfamyl, hydroxyl (1-6C) alkyl, cyano group (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, two-[(1-6C) alkyl], amino (2-6C) alkyloyl, (1-6C) alkylamino-(2-6C), N, N-two-[(1-6C) alkyl] amino-(2-6C) alkyloyl, (1-6C) alkoxyl group (1-6C) alkyl, hydroxyl (1-6C) alkoxyl group (1-6C) alkyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl, (1-6C) alkoxy carbonyl (1-6C) alkyl, (1-6C) alkoxyl group (1-6C) the alkyl S (O) of alkyl-(2-6C) _q(wherein q is 0,1 or 2), amino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2), N-(1-6C) alkylamino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2) and N, N-two-[(1-6C) alkyl] amino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2),

And Q ¹Optionally on any available carbon atom in ring have 1 or 2 and be selected from following substituting group: cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyloxy base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; hydroxyl (1-6C) alkyl; cyano group (1-6C) alkyl; amino (1-6C) alkyl; (1-6C) alkylamino (1-6C) alkyl; two-[(1-6C) alkyl] amino (1-6C) alkyl and (1-6C) alkoxyl group (1-6C) alkyl, wherein Q ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base and chloro base,

Q wherein ¹Choose wantonly and have 1 or 2 oxo substituting group;

(d) Q ¹Be the saturated 3-7 unit monocyclic heterocycles of non-aromatics, it has 1 nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on the ring ²-O-connects,

And Q wherein ¹In the nitrogen-atoms of any NH group on the optional substituting group that has as definition in above (c), and Q ¹In any ring carbon atom optional as above (c) in definition be substituted Q wherein ¹Choose wantonly and have 1 or 2 oxo substituting group;

(e) Q ¹Be the 3-7 unit monocyclic heterocycles of non-aromatics fractional saturation, it has 1 single carbon-to-carbon double bond, 1 nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring has the ring carbon atom and the radicals X of described carbon-to-carbon double bond by one of them ²-O-connects (for example 3-pyrroline-3-base or 1,2,3,6-tetrahydropyridine-4-yl), and Q wherein ¹In the nitrogen-atoms of any NH group on the optional substituting group that has as definition in above (c), and Q ¹In any ring carbon atom optional as above (c) in definition be substituted,

Q wherein ¹Choose wantonly and have 1 or 2 oxo substituting group;

(f) Q ¹Be selected from optional by 1 or 2 cyclobutyl, cyclopentyl and cyclohexyl that is selected from (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) the substituting group replacement of alkoxyl group;

(g) Q ¹Be 5 or 6 yuan of saturated monocyclic heterocycles of non-aromatics, it has 1 nitrogen heteroatom and chooses the heteroatoms that 1 or 2 (being suitably for 1) is selected from oxygen and nitrogen wantonly, and this ring is by carbon atom and radicals X on the ring ²-O-connects,

And Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, formamyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, NThe alkyloyl of-two-[(1-4C) alkyl] sulfamyl, cyano group (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyl of alkyloyl, formamyl-(1-3C), N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (1-4C) alkoxyl group (1-3C) alkyl S (O) _q(wherein q is 0,1 or especially 2), amino (1-3C) alkyl S (O) _q(wherein q is 0,1 or especially 2), N-(1-4C) alkylamino (1-3C) alkyl S (O) _q(wherein q is 0,1 or especially 2) and N, N-two-[(1-4C) alkyl] amino (1-3C) alkyl S (O) _q(wherein q is 0,1 or especially 2),

And Q ¹Optionally on any available carbon atom in ring have 1 or 2 and be selected from following substituting group: cyano group, oxo base, amino, carboxyl, formamyl, (1-4C) alkyl, (2-6C) alkenyl and (2-6C) alkynyl,

Q wherein ¹In any (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl or (2-4C) alkyloyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base and chloro base;

(h) Q ¹Be selected from cyclopropyl, cyclopentyl, cyclohexyl, trimethylene oxide-3-base, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-2-base, 1,3-dioxolane-(2,4 or the 5-yl), 3-or 4-THP trtrahydropyranyl, 3-or 4-oxepane alkyl, 1-, 2-or 3-pyrrolidyl, 2-pyrroline-2-base, 2-pyrroline-3-base, 3-pyrroline-3-base, morpholino, morpholine-2-Ji, morpholine-3-base, thiomorpholine generation, thiomorpholine-2-base, thiomorpholine-3-base, piperidino-(1-position only), piperidines-2-base, piperidines-3-base, piperidin-4-yl, 1-, 2-, 3-or 4-homopiperidinyl, piperazine-1-base, piperazine-2-base, 1,2,3,6-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-5-base, 1,2,3,4-tetrahydropyridine-5-base, 1,2,3,6-tetrahydropyridine-6-base, high piperazinyl, azetidine-3-base, tetramethylene sulfide-3-base, 1,1-dioxo tetramethylene sulfide-3-base, 1-oxo tetramethylene sulfide-3-base, tetrahydric thiapyran-3-group, tetrahydric thiapyran-4-group, 1-oxo tetrahydric thiapyran-3-group, 1,1-dioxo tetrahydric thiapyran-3-group, 1-oxo tetrahydric thiapyran-4-group and 1,1-dioxo tetrahydric thiapyran-4-group

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, (1-4C) alkyl, cyano group (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (1-4C) alkyl sulphonyl, trifluoromethyl, formamyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, NThe alkyloyl of-two-[(1-4C) alkyl] sulfamyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (1-4C) alkoxyl group (1-3C) alkyl sulphonyl, amino (1-3C) alkyl sulphonyl, N-(1-4C) alkylamino (1-3C) alkyl sulphonyl and N, N-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, and Q ¹Choose wantonly and on any available carbon atom of this ring, have 1 or 2 and be selected from the oxo base and (1-4C) substituting group of alkyl,

And Q wherein ¹In any (1-4C) alkyl optional have 1 or 2 fluoric substituting group;

(i) Q ¹Be selected from tetramethyleneimine-2-base, tetramethyleneimine-3-base, 2-pyrroline-2-base, 2-pyrroline-3-base, 3-pyrroline-3-base, morpholine-2-Ji, morpholine-3-base, thiomorpholine-2-base, thiomorpholine-3-base, piperidines-2-base, piperidines-3-base, piperidin-4-yl, 2-, 3-or 4-homopiperidinyl, piperazine-1-base, 2-oxo piperazine-1-base, 3-oxo piperazine-1-base, piperazine-2-base, 1,2,3,6-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-5-base, 1,2,3,4-tetrahydropyridine-5-base, 1,2,3,6-tetrahydropyridine-6-base, 2,3,4,6 or the high piperazinyl of 7-, azetidine-3-base

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, (1-4C) alkyl, cyano group (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, (1-4C) alkyl sulphonyl, trifluoromethyl, formamyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, NThe alkyloyl of-two-[(1-4C) alkyl] sulfamyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (1-4C) alkoxyl group (1-3C) alkyl sulphonyl, amino (1-3C) alkyl sulphonyl, N-(1-4C) alkylamino (1-3C) alkyl sulphonyl and N, N-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, and Q ¹Choose wantonly and on any available carbon atom of this ring, have 1 or 2 substituting group that is selected from (1-4C) alkyl and oxo base,

And Q wherein ¹In any (1-4C) alkyl optional have 1 or 2 fluoro substituting group;

(j) Q ¹Be selected from tetramethyleneimine-2-base, tetramethyleneimine-3-base, piperidines-2-base, piperidines-3-base and piperidin-4-yl,

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, cyano methyl, methyl, ethyl, formamyl, carbamyl ylmethyl, 2-methoxy ethyl, methylsulfonyl and ethylsulfonyl (especially methylsulfonyl and carbamyl ylmethyl)

And Q ¹In ring, choose wantonly on any available carbon atom and have 1 or 2 substituting group that is selected from methyl, ethyl and oxo base;

(k) X ²It is direct key;

(l) X ²Be [CR ²R ³] _m, wherein m is 1 or 2, R ²And R ³Be hydrogen;

(m) X ²Be direct key or CH ₂

(n) Q ¹-X ²Be selected from tetramethyleneimine-2-base, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, tetramethyleneimine-3-base, tetramethyleneimine-3-ylmethyl, 2-tetramethyleneimine-3-base ethyl, 3-tetramethyleneimine-3-base propyl group, 2-pyrroline-2-base, 2-pyrroline-2-ylmethyl, 2-pyrroline-3-base, pyrroline-3-ylmethyl, 3-pyrroline-3-base, 3-pyrroline-3-base, morpholine-2-Ji, morpholine-2-ylmethyl, 2-morpholine-2-Ji ethyl, morpholine-3-base, morpholine-3-ylmethyl, 2-morpholine-3-base ethyl, thiomorpholine is for methyl, thiomorpholine-2-base, thiomorpholine-2-ylmethyl, 2-thiomorpholine-2-base ethyl, thiomorpholine-3-base, thiomorpholine-3-ylmethyl, 2-thiomorpholine-3-base ethyl, the piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, piperidines-2-base, piperidines-2-ylmethyl, 2-piperidines-2-base ethyl, 3-piperidines-2-base propyl group, piperidines-3-base, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, 3-piperidines-3-base propyl group, piperidin-4-yl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, 3-piperidin-4-yl propyl group, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group, 2-oxo piperazine-1-ylmethyl, 2-(2-oxo piperazine-1-yl) ethyl, 3-(2-oxo piperazine-1-yl) propyl group, 3-oxo piperazine-1-ylmethyl, 2-(3-oxo piperazine-1-yl) ethyl, 3-(3-oxo piperazine-1-yl) propyl group, piperazine-2-base, piperazine-2-ylmethyl, 2-piperazine-2-base ethyl and 3-piperazine-2-base propyl group

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, cyano methyl, 2-cyano ethyl, methyl, ethyl, 2-methoxy ethyl, 2-ethoxyethyl group, methylsulfonyl, trifluoromethyl, formamyl, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, ethanoyl, propionyl, sulfamyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, NThe amino propionyl of-diethyl amino alkylsulfonyl, 3-, 3-(methylamino-) propionyl, 3-(dimethylamino) propionyl, carbamyl ylmethyl, 2-formamyl ethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, methoxy methyl alkylsulfonyl, 2-methoxyl group ethylsulfonyl, 2-tauryl base, 2-( N-methylamino-) ethylsulfonyl and 2-( N, N-dimethylamino) ethylsulfonyl;

(o) Q ¹-X ²Be selected from piperidin-4-yl and piperidin-4-yl methyl, wherein the nitrogen-atoms on the piperidines basic ring is selected from following substituting group optional having: cyano group, cyano methyl, methyl, ethyl, formamyl, carbamyl ylmethyl, 2-methoxy ethyl, methylsulfonyl and ethylsulfonyl;

(p) Q ¹-X ²Be selected from 1-formamyl methyl piperidine-4-base and 1-methylsulfonyl piperidin-4-yl; (q) R ¹-X ¹Be selected from hydrogen, (1-4C) alkoxyl group and (1-4C) alkoxyl group (1-4C) alkoxyl group;

(r) R ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy;

(s) R ¹-X ¹Be methoxyl group;

(t) G ¹And G ²Independently be selected from fluoro base and chloro base separately;

(u) G ¹Be fluoro base, G ²Be the chloro base;

(v) Q ¹Be the saturated 5 or 6 yuan of monocyclic heterocycles of non-aromatics, it has 1 nitrogen heteroatom and optional 1 or 2 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on the ring ²-O-connects, wherein Q ¹Have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyloxy base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; 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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) group of alkanoylamino (1-6C) alkyl of alkyl-(2-6C) or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be saturated 5 or 6 yuan of monocyclic heterocycles, it has 1 nitrogen heteroatom and optional 1 or 2 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by nitrogen-atoms and radicals X on the ring ³Connect, wherein Q ²Optional have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl,

Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more (for example 1,2 or 3) can be identical or different optional having: cyano group, nitro, carboxyl, (2-8C) alkenyl, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl,

Perhaps R ^aOr R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings, this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from (1-4C) alkyl, and on any available theheterocyclic nitrogen atom optional having be selected from following substituting group (prerequisite is that this ring is not therefore by quaternized): (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl;

(w) Q ¹Be the saturated 5 or 6 yuan of monocyclic heterocycles of non-aromatics, it has 1 nitrogen heteroatom and optional 1 or 2 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on the ring ²-O-connects, wherein Q ¹Have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyloxy base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; 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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) group of alkanoylamino (1-6C) alkyl of alkyl-(2-6C) or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base and morpholino, wherein Q ²Optional have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl,

(x) Q ¹Be the saturated 5 or 6 yuan of monocyclic heterocycles of non-aromatics, it has 1 nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is connected with radicals X 2-O-by the carbon atom on the ring, wherein Q ¹Have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyloxy base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; 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), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) group of alkanoylamino (1-6C) alkyl of alkyl-(2-6C) or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, morpholino and piperidino-(1-position only),

Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more (for example 1,2 or 3) can be identical or different optional having: cyano group, nitro, carboxyl, (2-8C) alkenyl, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, R ^bBe hydrogen or (1-4C) alkyl,

(y) Q ¹Be complete 5 or 6 yuan of saturated monocyclic heterocycles, it has 1 nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on encircling ²-O-connects, wherein Q ¹Have 1 or 2 can be identical or different be selected from following substituting group: formamyl, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] be amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl and (2-6C) group of alkyloyl (1-6C) alkyl or following formula:

Q ²-X ³-

Q wherein ¹In any (1-6C) alkyl or (2-6C) alkyloyl be selected from hydroxyl, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR optional having ^aR ^bSubstituting group, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe (1-4C) alkyl,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with their forms tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base or morpholino ring, this ring choose wantonly have 1 or 2 can be identical or different the substituting group that is selected from (1-4C) alkyl;

Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have 1 or 2 oxo (=O) substituting group; With

X ²Be direct key or CH ₂

(z) Q ¹Be complete 5 or 6 yuan of saturated monocyclic heterocycles, it has 1 nitrogen heteroatom and optional 1 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on encircling ²-O-connects, wherein Q ¹In the nitrogen-atoms of any NH group have and be selected from following substituting group: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] be amino, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl of alkyloyl of the alkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) and morpholino-(2-4C);

Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have oxo (=O) substituting group; With

X ²Be direct key or CH ₂

(aa) Q ¹Be complete 5 or 6 yuan of saturated monocyclic heterocycles, it has 1 nitrogen heteroatom and optional 1 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this ring is by carbon atom and radicals X on encircling ²-O-connects, wherein Q ¹On ring carbon atom, have 1 and be selected from following substituting group: formamyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl, the perhaps group of following formula of the alkyloyl of the alkyloyl of the alkyloyl of alkyloyl, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) and morpholino-(2-4C):

Q ²-X ³-

Q wherein ¹In the optional substituting group that is selected from (1-4C) alkyl that has of nitrogen-atoms of any NH group; With

X ²Be direct key or CH ₂

(bb) Q ¹Be selected from by ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, wherein said pyrrolidyl or piperidyl are selected from following substituting group by 1 or 2 and replace: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] be amino, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe group of alkyloyl of the alkyloyl of the alkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C), morpholino-(2-4C) and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, morpholino and piperidino-(1-position only);

X ²Be direct key or CH ₂

(cc) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, N, N-two-[(1-4C) alkyl] sulfamyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, N-(1-4C) alkyloyl of alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe group of alkyloyl of the alkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), morpholino-(2-4C) and following formula:

Q ²-X ³-

(dd) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (1-4C) alkyl sulphonyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, N, N-two-[(1-4C) alkyl] sulfamyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, N-(1-4C) alkyloyl of alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), N, NAlkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C) and morpholino-(2-4C) alkyloyl or following formula group:

Q ²-X ³-

X wherein ³Be CO, Q ²It is morpholino;

(ee) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethyl, methylsulfonyl, ethylsulfonyl, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- N-ethylamino formyl radical, ethanoyl, propionyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl- N-ethyl sulfamyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, hydroxyacetyl, 2-hydroxyl propionyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) group of third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, morpholino ethanoyl, 2-morpholino propionyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²It is morpholino;

(ff) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethyl, methylsulfonyl, N, N-formyl-dimethylamino, ethanoyl, hydroxyacetyl, N-methylamino-ethanoyl, N, N-dimethylamino ethanoyl, 3-( N, N-dimethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl and morpholino ethanoyl;

(gg) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein group Q ¹-X ²In pyrrolidyl or piperidyl on the ortho position of the theheterocyclic nitrogen atom of pyrrolidyl or piperidyl, have 1 and be selected from following substituting group: formamyl, N-(1-4C) alkyl-carbamoyl, N, NThe group of-two-[(1-4C) alkyl] formamyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, piperidino-(1-position only) and morpholino;

And Q wherein ¹In pyrrolidyl or the optional substituting group that is selected from (1-4C) alkyl that has of the theheterocyclic nitrogen atom on the piperidyl;

(hh) Q ¹-X ²Be selected from tetramethyleneimine-3-base, tetramethyleneimine-2-ylmethyl and tetramethyleneimine-3-ylmethyl, wherein pyrrolidyl has 1 and is selected from following substituting group on the 5-position: N, NThe group of-two-[(1-4C) alkyl] formamyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²It is morpholino;

And wherein pyrrolidyl is chosen wantonly and is had the substituting group that is selected from (1-4C) alkyl (should understand this embodiment and for example contain wherein Q on the 1-position ¹-X ²Be the group of following formula tetramethyleneimine-3-base:

Wherein X is the substituting group on the 5-position, referring to present embodiment, for example the 2-on the 6-position on the quinazoline ring ( N, N-formyl-dimethylamino) tetramethyleneimine-4-base promptly is such examples of groups);

(ii) Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl on ring carbon atom, have 1 and be selected from following substituting group: N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- NThe group of-ethylamino formyl radical and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be morpholino,

And Q wherein ¹In pyrrolidyl or the optional substituting group that is selected from methyl and ethyl that has of the theheterocyclic nitrogen atom on the piperidyl;

(jj) Q ¹-X ²Be selected from tetramethyleneimine-3-base, tetramethyleneimine-2-ylmethyl and tetramethyleneimine-3-ylmethyl, wherein said pyrrolidyl has on the 5-position N, N-formyl-dimethylamino substituting group;

(kk) X ²Be CH ₂

(ll) Q ¹Be 4, the 5 or 6 yuan of monocyclic heterocycles non-aromatics, saturated or fractional saturation that have 1 or 2 ring nitrogen heteroatom, this encircles by ring carbon atom and radicals X ²-O-connects, and Q wherein ¹Optional have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group, cyano group, nitro, hydroxyl, formamyl, acryl, (1-6C) alkyl, (1-6C) alkylthio, (2-6C) alkenyl thio, (2-6C) alkynes sulfenyl, (1-6C) alkyl sulphinyl, (2-6C) alkenyl sulfinyl, (2-6C) alkynyl sulfinyl, (1-6C) alkyl sulphonyl, (2-6C) alkenyl alkylsulfonyl, (2-6C) alkynyl alkylsulfonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) group of alkanoylamino (1-6C) alkyl of alkyl-(2-6C) or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be heterocyclic radical, it is selected from morpholino, piperidyl, piperazinyl and pyrrolidyl, and (wherein piperidyl, piperazinyl or pyrrolidyl can be by ring carbon or theheterocyclic nitrogen atom and X ³Connect),

Q wherein ¹In any (1-6C) alkyl or (2-6C) alkyloyl optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group: cyano group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from halogeno-group and hydroxyl that one or more (for example 1,2 or 3) can be identical or different and/or optionally have one and be selected from the cyano group and (1-4C) substituting group of alkoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings that do not contain Sauerstoffatom; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl (prerequisite be this ring not can so by quaternized)

(mm) Q ¹Be selected from by ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, wherein said pyrrolidyl or piperidyl be optional to be selected from following group by 1 or 2 and to replace: halogeno-group, cyano group, hydroxyl, formamyl, (1-6C) alkyl, (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) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl and (2-6C) group of alkyloyl (1-6C) alkyl or following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be heterocyclic radical, it is selected from morpholino, piperidino-(1-position only), piperazine-1-base, tetramethyleneimine-1-base and tetramethyleneimine-2-base,

Q wherein ¹In any (1-6C) alkyl or (2-6C) alkyloyl optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group: cyano group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from halogeno-group and hydroxyl that one or more (for example 1,2 or 3) can be identical or different and/or optionally have one and be selected from the cyano group and (1-4C) substituting group of alkoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms the ring that is selected from tetramethyleneimine-1-base, piperidino-(1-position only) and piperazine-1-base; this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from halogeno-group, hydroxyl, (1-4C) alkyl and methylene radical dioxy base; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl (prerequisite be this ring not can so by quaternized)

Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have 1 or 2 oxo (=O) substituting group;

(nn) Q ¹Be selected from by ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, wherein said pyrrolidyl or piperidyl are selected from following group by 1 or 2 and replace: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the group of alkyloyl of the alkyloyl of the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C), morpholino-(2-4C) and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino and piperidino-(1-position only),

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different be selected from hydroxyl, (1-4C) alkyl, (2-4C) alkyloyl and halogeno-group (chloro base especially; more preferably fluoro base) substituting group

Q wherein ¹On substituting group in any (2-4C) alkyloyl optional have 1 or 2 can be identical or different be selected from the hydroxyl and (1-3C) substituting group of alkyl,

Q wherein ¹On substituting group in any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, (1-4C) alkoxyl group and halogeno-group (especially chloro base, more preferably fluoro base),

X ²It is direct key;

(oo) Q ¹Be selected from by ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, wherein said pyrrolidyl or piperidyl by 1 or 2 can be identical or different the following group that is selected from replace: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the group of alkyloyl of the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, tetramethyleneimine-2-base and piperidino-(1-position only),

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different be selected from hydroxyl, (1-4C) alkyl, (2-4C) alkyloyl and halogeno-group (chloro base especially; more preferably fluoro base) substituting group

X ²Be CH ₂

(pp) Q ¹Be selected from by ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, wherein said pyrrolidyl or piperidyl by 1 or 2 can be identical or different the following group that is selected from replace: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, N-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls,

X ²Be direct key or CH ₂

(qq) Q ¹-X ²Be selected from tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidin-4-yl, piperidin-4-yl methyl, piperidines-3-base, (3R)-piperidines-3-base and (3S)-piperidines-3-base, wherein Q ¹By 1 or 2 can be identical or different the following substituting group of being selected from replace: formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, N-two-[(1-4C) alkyl] sulfamyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the group of alkyloyl of the alkyloyl of the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C), morpholino-(2-4C) and following formula:

Q ²-X ³-

Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have oxo (=O) substituting group;

(rr) Q ¹-X ²Be selected from tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidin-4-yl, piperidines-3-base, (3R)-piperidines-3-base and (3S)-piperidines-3-base, wherein Q ¹In pyrrolidyl or piperidyl on the 1-position, be selected from following substituting group and replaced: (1-4C) alkyloyl of alkyl, (1-4C) alkyl sulphonyl, (2-4C) alkyloyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the group of alkyloyl of the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be tetramethyleneimine-2-base,

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different be selected from hydroxyl, oxo base, (1-4C) alkyl, (2-4C) alkyloyl and halogeno-group (chloro base especially; more preferably fluoro base) substituting group

Q wherein ¹On substituting group in any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, (1-4C) alkoxyl group and halogeno-group (especially chloro base, more preferably fluoro base);

(ss) Q ¹-X ²Be selected from tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidin-4-yl, piperidines-3-base, (3R)-piperidines-3-base and (3S)-piperidines-3-base, wherein Q ¹Being selected from following substituting group on the 1-position replaces: (1-4C) alkyloyl of alkyl, (1-4C) alkyl sulphonyl, (2-4C) alkyloyl, (2-4C) alkyloyl (1-3C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), amino (1-3C) alkyl sulphonyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the group of alkyloyl of the alkyloyl of the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C), morpholino-(2-4C) and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be tetramethyleneimine-2-base,

(tt) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, N-methylamino formyl radical, N-ethylamino formyl radical, N-sec.-propyl formamyl, N-cyclopropyl methylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- N-ethylamino formyl radical, ethanoyl, propionyl, isobutyryl, N-methyl sulfamyl, N-ethyl sulfamyl, N-different third sulfamyl, N-cyclopropyl methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl- N-ethyl sulfamyl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, hydroxyacetyl, 2-hydroxyl propionyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from morpholino, tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) and piperazine-1-base,

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo base, methyl, ethyl, ethanoyl and fluoro base,

Q wherein ¹On substituting group in any ethanoyl, propionyl or isobutyryl optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl and methyl,

Q wherein ¹On substituting group in any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, methoxyl group, fluoro base, chloro base;

(uu) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: ethanoyl, propionyl, isobutyryl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3; 4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl and 2-piperazine-1-base propionyl

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo base, methyl, ethyl, ethanoyl and fluoro base,

(vv) Q ¹-X ²Be selected from: tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, wherein Q ¹-X ²In pyrrolidyl on theheterocyclic nitrogen atom, be selected from following substituting group and replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, N-methylamino formyl radical, N-ethylamino formyl radical, N-sec.-propyl formamyl, N-cyclopropyl methylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- N-ethylamino formyl radical, ethanoyl, propionyl, isobutyryl, N-methyl sulfamyl, N-ethyl sulfamyl, N-different third sulfamyl, N-cyclopropyl methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl- N-ethyl sulfamyl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

(ww) Q ¹-X ²Be selected from: tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, wherein Q ¹-X ²In pyrrolidyl on theheterocyclic nitrogen atom, be selected from following substituting group and replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, N-methylamino formyl radical, N-ethylamino formyl radical, N-sec.-propyl formamyl, N-cyclopropyl methylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- N-ethylamino formyl radical, ethanoyl, propionyl, isobutyryl, N-methyl sulfamyl, N-ethyl sulfamyl, N-different third sulfamyl, N-cyclopropyl methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl- N-ethyl sulfamyl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) and piperazine-1-base,

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo base, methyl, ethyl, ethanoyl and fluoro base,

(xx) Q ¹-X ²Be selected from: tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, wherein Q ¹-X ²In the pyrrolidyl substituting group that on theheterocyclic nitrogen atom, is selected from morpholino ethanoyl and 2-morpholino propionyl replace, and described substituting group optional have 1 or 2 can be identical or different be selected from hydroxyl, oxo, methyl, ethyl and fluoric substituting group;

(yy) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base and piperidin-4-yl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, ethanoyl, propionyl, isobutyryl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, morpholino ethanoyl, 2-morpholino propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

(zz) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, wherein Q ¹-X ²In pyrrolidyl on theheterocyclic nitrogen atom, be selected from following substituting group and replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, ethanoyl, propionyl, isobutyryl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, morpholino ethanoyl, 2-morpholino propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

(aaa) Q ¹-X ²Be selected from: piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base and piperidin-4-yl, wherein Q ¹-X ²In piperidyl on theheterocyclic nitrogen atom, be selected from following substituting group and replaced: methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, ethanoyl, propionyl, isobutyryl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, morpholino ethanoyl, 2-morpholino propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, morpholino, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo, methyl, ethyl, ethanoyl, fluoro base and chloro,

(bbb) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl;

(ccc) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base and (3 S)-tetramethyleneimine-3-base; (ddd) Q ¹-X ²Be selected from: piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base and piperidin-4-yl;

(eee) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl

Q wherein ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: N-methylamino formyl radical, N-ethylamino formyl radical, N-sec.-propyl formamyl, N-cyclopropyl methylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- N-ethylamino formyl radical, N-methyl sulfamyl, N-ethyl sulfamyl, N-different third sulfamyl, N-cyclopropyl methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-methyl- N-ethyl sulfamyl, carbamyl ylmethyl, N-methylamino formyl radical methyl, 2-( N-methylamino formyl radical) ethyl, N-ethylamino formyl radical methyl, 2-( N-ethylamino formyl radical) ethyl, N, N-formyl-dimethylamino methyl, 2-( N, N-formyl-dimethylamino) ethyl, N, N-diethylamino formyl radical methyl, 2-( N, N-diethylamino formyl radical) ethyl, N-methylamino-ethanoyl, N-ethylamino ethanoyl, 2-(N-methylamino-) propionyl, 2-(N-ethylamino) propionyl, N, N-dimethylamino ethanoyl, 2-( N, N-dimethylamino) propionyl, N, N-diethylamino ethanoyl, 2-( N, N-diethylamino) propionyl, N-methyl- N-ethylamino ethanoyl, 2-( N-methyl- N-ethylamino) propionyl, acetoxyl group ethanoyl, 2-(acetoxyl group) propionyl, 2-( N-methylamino-) ethylsulfonyl, 2-( N-ethylamino) ethylsulfonyl, 2-( N, N-dimethylamino) ethylsulfonyl, 2-( N, N-diethylamino) ethylsulfonyl, 3-( N-methylamino-) third alkylsulfonyl, 3-( N-ethylamino) third alkylsulfonyl, 3-( N, N-dimethylamino) third alkylsulfonyl, 3-( N, N-diethylamino) third alkylsulfonyl, tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; the group of 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3,4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl, 2-piperazine-1-base propionyl and following formula:

Q ²-X ³-

Q wherein ¹On substituting group in or by Q ²Any tetramethyleneimine-1-base, tetramethyleneimine-2-base, piperidino-(1-position only) or piperazine-1-base of representative is optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo, methyl, ethyl, ethanoyl, fluoro base and chloro,

(fff) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl

Q wherein ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: tetramethyleneimine-1-base ethanoyl, 2-(tetramethyleneimine-1-yl) propionyl, 3; 4-methylene-dioxy tetramethyleneimine-1-base ethanoyl, 2-(3; 4-methylene-dioxy tetramethyleneimine-1-yl) propionyl, piperidino-(1-position only) ethanoyl, 2-piperidino-(1-position only) propionyl, piperazine-1-base ethanoyl and 2-piperazine-1-base propionyl

Q wherein ¹On substituting group in any tetramethyleneimine-1-base, piperidino-(1-position only) or piperazine-1-base optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo base, methyl, ethyl, ethanoyl and fluoro base,

(ggg) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethanoyl, carbamyl ylmethyl, N-methylamino-ethanoyl, N, N-dimethylamino ethanoyl, 3-( N, N-dimethylamino) third alkylsulfonyl and tetramethyleneimine-1-base ethanoyl,

Q wherein ¹On substituting group in any tetramethyleneimine-1-base optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, oxo base, methyl, ethyl, ethanoyl and fluoro base,

Q wherein ¹On substituting group in any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from hydroxyl, methoxyl group, fluoro base, chloro base,

Q wherein ¹On substituting group in the optional hydroxyl substituent that has of any ethanoyl;

(hhh) Q ¹-X ²Be selected from: tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: methyl, ethanoyl, hydroxyacetyl, carbamyl ylmethyl, N-methylamino-ethanoyl, N, N-dimethylamino ethanoyl and tetramethyleneimine-1-base ethanoyl;

(iii) Q ¹-X ²Be selected from: piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl and (2S)-tetramethyleneimine-2-ylmethyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl be selected from theheterocyclic nitrogen atom that following substituting group is optional to be replaced: ethanoyl, hydroxyacetyl, N, N-dimethylamino ethanoyl and tetramethyleneimine-1-base ethanoyl;

(jjj) Q ¹-X ²Be selected from: tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl and (2S)-tetramethyleneimine-2-ylmethyl, wherein Q ¹-X ²In pyrrolidyl on theheterocyclic nitrogen atom, be selected from following substituting group and replaced: N-methylamino-ethanoyl, N, N-dimethylamino ethanoyl and tetramethyleneimine-1-base ethanoyl;

(kkk) Q ¹-X ²Group for following formula A:

Wherein:

R ⁴Be selected from formamyl, N-(1-6C) alkyl-carbamoyl, N, NThe group of-two-[(1-6C) alkyl] formamyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be the heterocyclic group that is selected from 4,5 or 6 yuan of monocyclic heterocycles bases, it contains 1 nitrogen heteroatom and optional contains 1 or 2 heteroatoms that is selected from sulphur, oxygen and nitrogen,

Q wherein ²By theheterocyclic nitrogen atom and X ³Connect,

Q wherein ²Optional have a following substituting group that is selected from that one or more (as 1,2 or 3) can be identical or different: halogeno-group, hydroxyl, (1-4C) alkyl and (2-4C) alkyloyl,

R wherein ⁴In any (1-6C) alkyl or (2-6C) optional have that one or more (as 1,2 or 3) can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group of alkyloyl: cyano group, nitro, (2-8C) alkenyl, (2-8C) alkynyl and (1-6C) alkoxyl group

R ⁵Be selected from hydrogen, (1-6C) alkyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (2-6C) alkyloyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl and (2-6C) alkyloyl (1-6C) alkyl,

R wherein ⁵In any (1-6C) alkyl or (2-6C) optional have that one or more (as 1,2 or 3) can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group of alkyloyl: cyano group, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from halogeno-group and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or be selected from cyano group, nitro and (1-4C) substituting group of alkoxyl group optional having,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl and (2-4C) substituting group of alkyloyl (prerequisite be this ring not can so by quaternized)

Wherein be present in by R as substituting group ^aAnd R ^bAny (1-4C) alkyl on the ring that the nitrogen-atoms that links to each other with their forms or (2-4C) alkyloyl is optional has the substituting group that is selected from halogeno-group and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or be selected from (1-4C) alkyl and (1-4C) substituting group of alkoxyl group optional having

And Q wherein ¹-X ²In any heterocyclic radical optional have 1 or 2 oxo base (=O) or thio group (=S) substituting group;

(lll) Q ¹-X ²Be the formula A group that as above in (kkk), defines, wherein:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, morpholino, piperidino-(1-position only) and piperazine-1-base,

Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group, hydroxyl, (1-4C) alkyl, oxo base and (2-4C) alkyloyl,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with their forms and is selected from following ring: tetramethyleneimine-1-base, piperidino-(1-position only), morpholino and piperazine-1-base; this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from halogeno-group, hydroxyl, (1-4C) alkyl and oxo base; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl and (2-4C) substituting group of alkyloyl (prerequisite be this ring not can so by quaternized)

Wherein be present in by R as substituting group ^aAnd R ^bAny (1-4C) alkyl on the ring that the nitrogen-atoms that links to each other with their forms or (2-4C) alkyloyl is optional has the substituting group that is selected from halogeno-group and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or be selected from (1-4C) alkyl and (1-4C) substituting group of alkoxyl group optional having;

(mmm) Q ¹-X ²Be formula A group of definition in as above (kkk), wherein:

Q ²-X ³-

Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: fluoro base, chloro base, hydroxyl, methyl, oxo base and ethanoyl,

R wherein ⁴In any (1-6C) alkyl optional have the substituting group that is selected from fluoro base, chloro base and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or optionally have one and be selected from following substituting group: cyano group, nitro, vinyl, ethynyl and methoxyl group

R ⁵Be selected from hydrogen, (1-4C) alkyl, (1-4C) alkylthio, (1-4C) alkyl sulphinyl, (1-4C) alkyl sulphonyl, (2-4C) alkyloyl, formamyl (1-4C) alkyl, N-(1-4C) alkyl-carbamoyl (1-4C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-4C) alkyl, sulfamyl (1-4C) alkyl, N-(1-4C) alkylsulfamoyl group (1-4C) alkyl, N, N-two-[(1-4C) alkyl] sulfamyl (1-4C) alkyl and (2-4C) alkyloyl (1-4C) alkyl,

R wherein ⁵In any (1-4C) alkyl or (2-4C) alkyloyl is optional has the substituting group that is selected from fluorine, chlorine, hydroxyl, methyl and ethyl that one or more (as 1,2 or 3) can be identical or different and/or optionally have one and be selected from following substituting group: cyano group, nitro, vinyl, ethynyl, methoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from fluoro base, chloro base and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or optionally have a substituting group that is selected from cyano group, nitro and methoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with their forms and is selected from following ring: tetramethyleneimine-1-base, piperidino-(1-position only), morpholino and piperazine-1-base, this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from halogeno-group, hydroxyl, methyl, ethyl and oxo base, and can on any available theheterocyclic nitrogen atom, choose have the substituting group that is selected from methyl, ethyl and ethanoyl (prerequisite be this ring not can so by quaternized);

(nnn) Q ¹-X ²Be formula A group of definition in as above (kkk), wherein:

R ⁴Be selected from formamyl, N-(1-4C) alkyl-carbamoyl, N, NThe group of-two-[(1-4C) alkyl] formamyl and following formula:

Q ²-X ³-

R wherein ⁴In any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base, chloro base and hydroxyl and/or optionally have one and be selected from following substituting group: cyano group, nitro, vinyl, ethynyl and methoxyl group,

R ⁵Be selected from hydrogen, methyl, ethyl, sec.-propyl, isobutyl-, cyclopropyl methyl, methylsulfonyl, ethylsulfonyl, ethanoyl, propionyl, isobutyryl, carbamyl ylmethyl, N-(1-4C) the alkyl-carbamoyl methyl, N, N-two-[(1-4C) alkyl] carbamyl ylmethyls, sulfamyl methyl, N-(1-4C) the alkylsulfamoyl group methyl and N, N-two-[(1-4C) alkyl] sulfamyl methyl,

R wherein ⁴In any (1-4C) alkyl, ethanoyl, propionyl or isobutyryl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base, chloro base and hydroxyl, methyl and ethyl and/or optionally have one and be selected from following substituting group: cyano group, nitro, vinyl, ethynyl, methoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base, chloro base and hydroxyl and/or optionally have a substituting group that is selected from cyano group, nitro and methoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with their forms and is selected from following ring: tetramethyleneimine-1-base, piperidino-(1-position only), morpholino and piperazine-1-base, this ring on available ring carbon atom optional have 1 or 2 can be identical or different the substituting group that is selected from halogeno-group, hydroxyl, methyl and oxo base, and can on any available theheterocyclic nitrogen atom, choose have the substituting group that is selected from methyl and ethanoyl (prerequisite be this ring not can so by quaternized);

(ooo) Q ¹-X ²Be formula A group of definition in as above (kkk), wherein:

R ⁴Be selected from N, NThe group of-two-[(1-4C) alkyl] formamyl and following formula:

Q ²-X ³-

Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: fluoro base, chloro base, hydroxyl, methyl and oxo base,

R wherein ⁴In any (1-4C) alkyl optional have 1 or 2 can be identical or different substituting group that is selected from fluoro base, chloro base and hydroxyl and/or the optional substituting group that is selected from methoxyl group that has,

R ⁵Be selected from hydrogen, methyl, ethyl, sec.-propyl, isobutyl-and cyclopropyl methyl,

R wherein ⁵In any (1-4C) alkyl optional have 1 or 2 can be identical or different substituting group that is selected from fluoro base, chloro base and hydroxyl and/or the optional substituting group that is selected from methoxyl group that has;

(ppp) Q ¹-X ²Be formula A group of definition in as above (kkk), wherein:

R ⁴Be selected from N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl- NThe group of-ethylamino formyl radical and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be morpholino (preferred R ⁴Be N, the N-formyl-dimethylamino),

R ⁵Be selected from hydrogen, methyl and ethyl (preferred R ⁵Be hydrogen or methyl, more preferably methyl);

(qqq) R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have 1,2 or 3 can be identical or different the substituting group that is selected from hydroxyl, fluoro base and chloro, R for example ¹-X ¹Be selected from methoxyl group, oxyethyl group, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy.

Should understand the group of in above paragraph (kkk)-(ppp), representing and on the tetramethyleneimine basic ring, contain 2 chiral centres by formula A.As above mentioned, the present invention comprises all steric isomers of formula A group, as (2R, 4R), (2S, 4S), (2R, 4S) and (2S, 4R) isomer.

The quinazoline derivant that another embodiment of the present invention is formula I or its pharmacy acceptable salt, wherein:

R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have one or more hydroxyl substituent (being fit to one or more) and/or be selected from following substituting group: amino, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, formamyl, N-(1-4C) alkyl-carbamoyl and N, N-two-[(1-4C) alkyl] formamyls, sulfamyl, N-(1-4C) alkylsulfamoyl group and N, N-two-[(1-4C) alkyl] sulfamyl;

X ²Be direct key or [CR ²R ³] _m, wherein m is 1,2 or 3 (especially 1 or 2, be more preferably 1), R ²And R ³Independently be hydrogen, methyl, ethyl or hydroxyl (preferred hydrogen) separately;

Q ¹Be the first monocyclic heterocycles of non-aromatics 3-7 saturated or fractional saturation, it contains a nitrogen heteroatom and optional 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur, carbon atom and the radicals X on this ring passes through to encircle of containing ²-O-connects,

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, formamyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, NThe alkyloyl of amino (1-6C) alkyl of-two-[(1-6C) alkyl] sulfamyl, hydroxyl (1-6C) alkyl, cyano group (1-6C) alkyl, amino (1-6C) alkyl, (1-6C) alkylamino (1-6C) alkyl, two-[(1-6C) alkyl], amino (2-6C) alkyloyl, (1-6C) alkylamino-(2-6C), N, N-two-[(1-6C) alkyl] amino-(2-6C) alkyloyl, (1-6C) alkoxyl group (1-6C) alkyl, hydroxyl (1-6C) alkoxyl group (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl, N-(1-6C) alkanoylamino (1-6C) alkyl, (1-6C) alkoxy carbonyl (1-6C) alkyl, (1-6C) alkoxyl group (1-6C) the alkyl S (O) of alkyl-(2-6C) _q(wherein q is 0,1 or 2), amino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2), N-(1-6C) alkylamino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2) and N, N-two-[(1-6C) alkyl] amino (1-6C) alkyl S (O) _q(wherein q is 0,1 or 2),

Q ¹Choose wantonly and on any available carbon atom of this ring, have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl and oxo base,

And Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) alkyloyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base and chloro base;

G ¹And G ²Independently be selected from fluoro base, chloro base and bromo base (preferred G separately ¹Be fluoro base and G ²Be the chloro base).

R ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy;

X ²Be direct key or [CH ₂] _m, wherein m is 1 or 2 (be fit to is 1);

Q ¹Be 5 or 6 yuan of saturated monocyclic heterocycles of non-aromatics, it contains a nitrogen heteroatom and the optional heteroatoms that 1 or 2 (be fit to is 1) is selected from oxygen and nitrogen, carbon atom and the radicals X on this ring passes through to encircle of containing ²-O-connects,

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, formamyl, (1-4C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, sulfamyl, N-(1-4C) alkylsulfamoyl group, N, NThe alkyloyl of-two-[(1-4C) alkyl] sulfamyl, cyano group (1-4C) alkyl, (1-4C) alkoxyl group (1-4C) alkyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (1-4C) alkoxyl group (1-3C) alkyl S (O) _q(wherein q is 0,1 or is suitably for 2), amino (1-3C) alkyl S (O) _q(wherein q is 0,1 or is suitably for 2), N-(1-4C) alkylamino (1-3C) alkyl S (O) _q(wherein q is 0,1 or is suitably for 2) and N, N-two-[(1-4C) alkyl] amino (1-3C) alkyl S (O) _q(wherein q is 0,1 or is suitably for 2),

Q ¹Choose wantonly and on any available carbon atom of this ring, have 1 or 2 and be selected from following substituting group: oxo base, (1-4C) alkyl, (2-6C) alkenyl and (2-6C) alkynyl,

And Q wherein ¹In any (1-4C) alkyl, (2-6C) alkenyl or (2-6C) alkynyl optional have 1 or 2 can be identical or different the substituting group that is selected from fluoro base and chloro base; And G ¹And G ²Independently be selected from fluoro base, chloro base and bromo base (preferred G separately ¹Be fluoro base and G ²Be the chloro base).

X ²Be direct key or CH ₂

Q ¹Be selected from tetramethyleneimine-2-base, tetramethyleneimine-3-base, 2-pyrroline-2-base, 2-pyrroline-3-base, 3-pyrroline-3-base, morpholine-2-Ji, morpholine-3-base, thiomorpholine-2-base, thiomorpholine-3-base, piperidines-2-base, piperidines-3-base, piperidin-4-yl, 2-, 3-or 4-homopiperidinyl, piperazine-1-base, 2-oxo piperazine-1-base, 3-oxo piperazine-1-base, piperazine-2-base, 1,2,3,6-tetrahydropyridine-4-base, 1,2,3,6-tetrahydropyridine-5-base, 1,2,3,4-tetrahydropyridine-5-base, 1,2,3,6-tetrahydropyridine-6-base, 2,3,4,6 or the high piperazinyl of 7-and azetidine-3-base

And Q wherein ¹In optional 1 or 2 the fluoro substituting group (providing example such as 2-fluoro ethyl or 2,2-two fluoro ethyls) that has of any (1-4C) alkyl; With

G ¹And G ²Independently be selected from fluoro and chloro (preferred G separately ¹Be fluoro base and G ²Be the chloro base).

Q in this embodiment ¹X ²Suitable connotation comprise for example 1-methylpyrrolidin-3-base; piperidin-4-yl; the piperidin-4-yl methyl; 1-methyl piperidine-4-base; 1-methyl piperidine-4-ylmethyl; 1-(2-methoxy ethyl) piperidin-4-yl; 1-(2-methoxy ethyl) piperidin-4-yl methyl; 1-methylsulfonyl piperidin-4-yl; 1-methylsulfonyl piperidin-4-yl methyl; 1-cyano group piperidin-4-yl; 1-cyano group piperidin-4-yl methyl; 1-cyano methyl piperidin-4-yl; 1-cyano methyl piperidin-4-yl methyl; 1-formamyl methyl piperidine-4-base; 1-formamyl methyl piperidine-4-ylmethyl.

R ¹-X ¹Be selected from hydrogen and methoxyl group;

X ²It is direct key;

Q ¹Be selected from tetramethyleneimine-2-base, tetramethyleneimine-3-base, piperidines-2-base, piperidines-3-base and piperidin-4-yl,

Q wherein ¹In the nitrogen-atoms of any NH group be selected from following substituting group optional having: cyano group, cyano methyl, methyl, ethyl, formamyl, carbamyl ylmethyl, 2-methoxy ethyl, methylsulfonyl and ethylsulfonyl (being suitably for methylsulfonyl and carbamyl ylmethyl)

And Q ¹Choose wantonly and on any available carbon atom of this ring, have 1 or 2 substituting group that is selected from methyl, ethyl and oxo base; And

Q in this embodiment ¹X ²Suitable connotation comprise for example piperidin-4-yl, 1-methyl piperidine-4-base, 1-(2-methoxy ethyl) piperidin-4-yl, 1-methylsulfonyl piperidin-4-yl, 1-cyano group piperidin-4-yl, 1-cyano methyl piperidin-4-yl and 1-formamyl methyl piperidine-4-base.

R ¹-X ¹Be selected from hydrogen, (1-4C) alkoxyl group and (1-4C) alkoxyl group (1-4C) alkoxyl group (especially hydrogen and methoxyl group);

X ²Be direct key or CH ₂

Q ¹Be complete 5 or 6 yuan of saturated monocyclic heterocycles, it contains a nitrogen heteroatom and the optional heteroatoms that another one is selected from oxygen, nitrogen and sulphur, carbon atom and the radicals X on this ring passes through to encircle of containing ²-O-connects,

Q wherein ¹On ring carbon atom, have 1 and be selected from following substituting group: formamyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, (2-4C) alkyloyl, amino (2-4C) alkyloyl, (1-4C) alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl or the following formula group of the alkyloyl of the alkyloyl of the alkyloyl of alkyloyl, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) and morpholino-(2-4C):

Q ²-X ³-

Q wherein ¹In the optional substituting group that is selected from (1-4C) alkyl that has of nitrogen-atoms of any NH group,

And Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have oxo (=O) substituting group; With

G ¹And G ²Independently be selected from fluoro base and chloro base (preferred G separately ¹Be fluoro base and G ²Be the chloro base).

R ¹-X ¹Be selected from hydrogen and (1-4C) alkoxyl group (especially hydrogen and methoxyl group);

Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl have 1 or 2 and be selected from following substituting group: (1-4C) alkyl, (1-4C) alkyl sulphonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, (2-4C) alkyloyl, N, N-two-[(1-4C) alkyl] alkylsulfonyls, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, NThe alkyloyl of-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, (2-4C) alkyloyl oxygen base-(2-4C), N-(1-4C) alkyloyl of alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl, N-(1-4C) alkyl sulphonyl of alkylamino-(1-3C), N, NThe alkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), morpholino-(2-4C) alkyloyl or following formula group:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, morpholino and piperidino-(1-position only); And

R ¹-X ¹Be selected from hydrogen and (1-4C) alkoxyl group (especially methoxyl group);

Q ¹-X ²Be selected from tetramethyleneimine-3-base, tetramethyleneimine-2-ylmethyl and tetramethyleneimine-3-ylmethyl, wherein pyrrolidyl has 1 and is selected from following substituting group on the 5-position: N, NThe group of-two-[(1-4C) alkyl] formamyl and following formula:

Q ²-X ³-

X wherein ³Be CO, Q ²Be morpholino, and

Wherein pyrrolidyl has 1 substituting group that is selected from (1-4C) alkyl on the 1-position;

G ¹Be the fluoro base; With

G ²Be the chloro base.

Q ¹-X ²Be selected from tetramethyleneimine-3-base, piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl on the 1-position, have and be selected from following substituting group: (1-4C) alkyl, (1-4C) alkyl sulphonyl, (2-4C) alkyloyl, hydroxyl (2-4C) alkyloyl, N-(1-4C) alkyloyl of alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), N, NAlkyloyl of the alkyloyl of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C) and morpholino-(2-4C) alkyloyl or following formula group:

Q ²-X ³-

X wherein ³Be CO, Q ²Be morpholino;

G ¹Be the fluoro base; With

G ²Be the chloro base.

R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have 1,2 or 3 can be identical or different the substituting group that is selected from hydroxyl, fluoro base, chloro base (R for example ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy, R ¹-X ¹Concrete implication be hydrogen or (1-4C) alkoxyl group, (1-4C) alkoxyl group more particularly is as methoxyl group); Q ¹-X ²Be selected from tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl on the 1-position, have and be selected from following substituting group: (1-4C) alkyl, (1-4C) alkyl sulphonyl, (2-4C) alkyloyl, formamyl (1-3C) alkyl, N-(1-4C) alkyl-carbamoyl (1-3C) alkyl, N, N-two-[(1-4C) alkyl] formamyl (1-3C) alkyl, hydroxyl (2-4C) alkyloyl, N-(1-4C) alkyloyl of alkylamino-(2-4C), N, N-two-[(1-4C) alkyl] amino-(2-4C) alkyloyl of alkyloyl, (2-4C) alkanoyloxy-(2-4C), N-(1-4C) alkylamino (1-3C) alkyl sulphonyl, N, NThe alkyloyl, 3 of-two-[(1-4C) alkyl] amino (1-3C) alkyl sulphonyls, tetramethyleneimine-1-base-(2-4C), the alkyloyl of the alkyloyl of 4-methylene-dioxy tetramethyleneimine-1-base-(2-4C), piperidino-(1-position only)-(2-4C), piperazine-1-base-(2-4C) alkyloyl or following formula group:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-2-base;

Q wherein ¹On substituting group in any pyrrolidyl, piperidino-(1-position only) or piperazine-1-base optionally have 1 or 2 substituting group that is selected from fluoro base, chloro base, hydroxyl, oxo base, methyl and ethanoyl,

G ¹Be the fluoro base; With

G ²Be the chloro base.

R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have 1,2 or 3 can be identical or different the substituting group that is selected from hydroxyl, fluoro base, chloro base (R for example ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy, R ¹-X ¹Concrete implication be hydrogen or (1-4C) alkoxyl group, (1-4C) alkoxyl group more particularly is as methoxyl group); Q ¹-X ²Be selected from tetramethyleneimine-3-base, (3R)-tetramethyleneimine-3-base, (3S)-tetramethyleneimine-3-base, piperidines-3-base, (3R)-piperidines-3-base, (3S)-piperidines-3-base, piperidin-4-yl, tetramethyleneimine-2-ylmethyl, (2R)-tetramethyleneimine-2-ylmethyl, (2S)-tetramethyleneimine-2-ylmethyl, tetramethyleneimine-3-ylmethyl, (3R)-tetramethyleneimine-3-ylmethyl, (3S)-tetramethyleneimine-3-ylmethyl, piperidines-2-ylmethyl, (2R)-piperidines-2-ylmethyl, (2S)-piperidines-2-ylmethyl, piperidines-3-ylmethyl, (3R)-piperidines-3-ylmethyl, (3S)-piperidines-3-ylmethyl and piperidin-4-yl methyl, wherein Q ¹-X ²In pyrrolidyl or piperidyl on the 1-position, have the substituting group that is selected from morpholino (2-4C) alkyloyl;

G ¹Be the fluoro base; With

G ²Be the chloro base.

R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have 1,2 or 3 can be identical or different the substituting group that is selected from hydroxyl, fluoro base, chloro base (R for example ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy, R ¹-X ¹Concrete implication be hydrogen or (1-4C) alkoxyl group, (1-4C) alkoxyl group more particularly is as methoxyl group);

Q ¹-X ²Group for following formula A:

Wherein:

Q ²-X ³-

Q wherein ²By theheterocyclic nitrogen atom and X ³Connect,

Q wherein ²Optional have a following substituting group that is selected from that one or more (as 1,2 or 3) can be identical or different: halogeno-group, hydroxyl, (1-4C) alkyl, oxo base and (2-4C) alkyloyl,

R wherein ⁵In any (1-6C) alkyl or (2-6C) optional have that one or more (as 1,2 or 3) can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group of alkyloyl: cyano group, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from halogeno-group and hydroxyl that one or more (as 1,2 or 3) can be identical or different and/or be selected from cyano group, nitro and (1-4C) substituting group of alkoxyl group optional having,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group and oxo base; and can on any available theheterocyclic nitrogen atom, choose wantonly have be selected from (1-4C) alkyl and (2-4C) substituting group of alkyloyl (prerequisite be this ring not can so by quaternized)

G ¹Be the fluoro base; With

G ²Be the chloro base.

Q ¹-X ²Group for following formula A:

Wherein:

Q ²-X ³-

X wherein ³Be CO, Q ²Be selected from tetramethyleneimine-1-base, morpholino and piperidino-(1-position only) (R for example ⁴Be N, N-formyl-dimethylamino or morpholino carbonyl, preferred R ⁴Be N, the N-formyl-dimethylamino),

R ⁵Be selected from hydrogen, methyl, ethyl, sec.-propyl, isobutyl-and cyclopropyl methyl, wherein R ⁵In any (1-4C) alkyl optional have 1 or 2 can be identical or different substituting group that is selected from fluoro base, chloro base and hydroxyl and/or the optional substituting group that is selected from methoxyl group, the G of having ¹Be the fluoro base; With

G ²Be the chloro base.

R ¹-X ¹Be selected from hydrogen, (1-6C) alkoxyl group and (1-4C) alkoxyl group (1-6C) alkoxyl group, wherein R ¹X ¹In any (1-6C) alkoxyl group optional have 1,2 or 3 can be identical or different be selected from following substituting group: hydroxyl, fluoro, chloro (R for example ¹-X ¹Be selected from hydrogen, methoxyl group, oxyethyl group, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy, R ¹-X ¹Suitable implication be hydrogen or (1-4C) alkoxyl group, (1-4C) alkoxyl group more particularly is as methoxyl group); Q ¹-X ²Be selected from (2S, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base,

(2R, 4S)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base,

(2R, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base,

(2S, 4S)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base,

(2S, 4R)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base,

(2R, 4S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base,

(2R, 4R)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base and

(2S, 4S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base;

G ¹Be the fluoro base; With

G ²Be the chloro base.

The preferred compound of the present invention is for for example being selected from quinazoline derivant or its pharmaceutically-acceptable acid addition of following formula I:

(1) 4-(3-chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl) piperidin-4-yl] the oxygen base }-7-methoxyl group quinazoline; With

(2) 6-{[1-(carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline.

Another preferred compound of the present invention is for for example being selected from quinazoline derivant or its pharmaceutically-acceptable acid addition of following formula I:

(1) oxygen base 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methylpyrrolidin-3-yl)] quinazoline;

(2) oxygen base 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl)] quinazoline;

(3) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl)] quinazoline;

(4) oxygen base 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methyl piperidine-4-yl)] quinazoline;

(5) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methyl piperidine-4-yl)] quinazoline;

(6) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[2-(1-methyl piperidine-4-yl) oxyethyl group] quinazoline;

(7) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(2-methoxy ethyl) piperidin-4-yl] the oxygen base } quinazoline;

(8) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(2-methoxy ethyl) piperidin-4-yl] methoxyl group } quinazoline;

(9) 4-(3-chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl) piperidin-4-yl] methoxyl group }-7-methoxyl group quinazoline;

(10) 6-{[1-(carbamyl ylmethyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(11) 4-(3-chloro-2-fluoroanilino)-6-{[1-(cyano methyl) piperidin-4-yl] the oxygen base }-7-methoxyl group quinazoline;

(12) 4-(3-chloro-2-fluoroanilino)-6-{[1-(cyano methyl) piperidin-4-yl] methoxyl group }-7-methoxyl group quinazoline; With

(13) methoxyl group 4-(3-chloro-2-fluoroanilino)-6-[(1-cyano group piperidin-4-yl)]-7-methoxyl group quinazoline.

Another preferred compound of the present invention is for for example being selected from quinazoline derivant or its pharmacy acceptable salt of following formula I:

(1) 6-(1-ethanoyl piperidin-4-yl oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(2) 4-(3-chloro-2-fluoroanilino)-6-[1-(N, N-dimethylamino ethanoyl) piperidin-4-yl oxygen base]-7-methoxyl group quinazoline;

(3) 6-[1-(N, N-dimethylamino alkylsulfonyl) piperidin-4-yl oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(4) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(morpholino ethanoyl) piperidin-4-yl oxygen base] quinazoline;

(5) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(tetramethyleneimine-1-base ethanoyl) piperidin-4-yl oxygen base] quinazoline;

(6) 4-(3-chloro-2-fluoroanilino)-6-{1-[3-(dimethylamino) third alkylsulfonyl] piperidin-4-yl oxygen base }-7-methoxyl group quinazoline;

(7) 4-(3-chloro-2-fluoroanilino)-6-[1-(methylsulfonyl) piperidines-3-yl] the oxygen base }-7-methoxyl group quinazoline;

(8) 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(9) 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(10) 6-(1-ethanoyl piperidines-3-base oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(11) 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline;

(12) 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline;

(13) 4-(3-chloro-2-fluoroanilino)-6-[1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(14) 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(15) 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(16) 4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline;

(17) 6-[1-(acetoxyl group ethanoyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(18) 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline;

(19) 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline;

(20) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(21) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(22) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(methylsulfonyl) tetramethyleneimine-3-yl] methoxyl group } quinazoline;

(23) 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-methylpyrrolidin-3-base oxygen base]-7-methoxyl group quinazoline;

(24) 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-methylpyrrolidin-3-base oxygen base]-7-methoxyl group quinazoline;

(25) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline;

(26) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methylpyrrolidin-3-yl)] quinazoline;

(27) 6-[(3R)-1-acetyl-pyrrolidine-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(28) 6-{[(2S)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(29) 6-{[(2R)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(30) methoxyl group 6-[(1-acetyl-pyrrolidine-3-yl)]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(31) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-1-(N, N-dimethylamino alkylsulfonyl) tetramethyleneimine-3-base oxygen base] quinazoline;

(32) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(morpholino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(33) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(hydroxyacetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(34) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline;

(35) 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline;

(36) 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-2-base oxygen base]-7-methoxyl group quinazoline;

(37) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N-methylamino-ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(38) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N, N-dimethylamino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(39) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(40) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2RS, 4R)-1-methyl-2-(morpholino carbonyl) tetramethyleneimine-4-base oxygen base] quinazoline;

(41) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-piperidines-3-base oxygen base] quinazoline;

(42) 6-[(3S)-1-ethanoyl piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(43) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-1-(methylsulfonyl) piperidines-3-base oxygen base] quinazoline;

(44) ethanoyl 4-(3-chloro-2-fluoroanilino)-6-{ (3S)-1-[(dimethylamino)] piperidines-3-base oxygen base }-7-methoxyl group quinazoline;

(45) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(tetramethyleneimine-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline;

(46) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-1-(tetramethyleneimine-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline;

(47) 4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylene radical dioxy base tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group }-7-methoxyl group quinazoline;

(48) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(1-methylpiperazine-4-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(49) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-(1-methylpiperazine-4-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(50) 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(hydroxyacetyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline;

(51) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(2-hydroxyl isobutyryl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(52) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[(2S)-1-methylpyrrolidin-2-base carbonyl] piperidines-3-base oxygen base } quinazoline;

(53) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(N, N-formyl-dimethylamino methyl) piperidines-3-base oxygen base] quinazoline;

(54) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(3,3-two fluoropyrrolidines-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline;

(55) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[[(3R)-3-hydroxyl pyrrolidine-1-yl] ethanoyl] piperidines-3-base oxygen base } quinazoline;

(56) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(4-methyl-3-oxo piperazine-1-yl) ethanoyl] piperidines-3-base oxygen base } quinazoline;

(57) ethanoyl 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[(4-ethanoyl piperazine-1-yl)] piperidines-3-base oxygen base } quinazoline; With

(58) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline.

Synthesizing of the quinazoline derivant of formula I

The present invention provides the method for quinazoline derivant or its pharmacy acceptable salt of a kind of preparation formula I on the other hand.Should know that in some following method some substituting group may need protection to prevent its unwanted reaction.The chemist who is skilled in technique will know when this protection of needs how to introduce these blocking groups in position, and how remove these blocking groups subsequently.

The example of relevant protecting group can be referring to the common teaching materials of many relevant these contents, for example ' Protective Groups in Organic the Synthesis ' (JohnWiley﹠amp that shown of Theodora Green; Sons publishes).Removing of protecting group can be undertaken by the method that being fit to known to any ordinary method described in the document or the chemist that is skilled in technique removed the protecting group of being discussed; selected these class methods should be able to be removed protecting group, and the interference to other group of molecule simultaneously reduces to minimum.

Therefore, if reactant comprises for example groups such as amino, carboxyl or hydroxyl, described group may need protection in some reaction mentioned above.

The blocking group that is fit to amino or alkylamino is for example acyl group, for example alkyloyl (as ethanoyl), alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl or uncle-butoxy carbonyl), aryl methoxy carbonyl (as benzyloxycarbonyl) or aroyl (for example benzyl acyl group).The deprotection condition of above-mentioned protecting group must change with selected protecting group.Therefore, for example can be such as the acyl group of alkyloyl or alkoxy carbonyl or aroyl by removing with suitable alkali such as alkali metal hydroxide (as lithium hydroxide or sodium) hydrolysis.Perhaps; acyl group such as uncle-butoxy carbonyl for example can be removed by handling with suitable acid (example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid), for example can be by removing through catalyzer (as palladium on carbon) hydrogenation or by handling with Lewis acid (as three (trifluoroacetic acid) boron) such as the fragrant methoxycarbonyl of benzyloxycarbonyl.The protecting group that other of primary amino is fit to is for example phthaloyl, and it can be by handling with alkylamine (as dimethylaminopropylamine) or removing with the hydrazine processing.

The appropriate protection group of hydroxyl is for example acyl group, for example alkyloyl (as ethanoyl), aroyl (for example benzyl acyl group) or arylmethyl (as benzyl).The deprotection condition of above-mentioned protecting group must change with selected protecting group.Therefore, for example can remove such as the acyl group of alkyloyl or aroyl by separating with suitable alkali such as alkali metal hydroxide (as lithium hydroxide or sodium) or ammoniacal liquor.Perhaps, for example can be such as the arylmethyl of benzyl by removing through catalyzer (as palladium on carbon) hydrogenation.

The appropriate protection group of carboxyl is for for example becoming the group of ester; for example methyl or ethyl; it can be by removing with alkali such as sodium hydroxide hydrolysis; the perhaps tertiary butyl for example; it can be removed by handling as organic acid (as trifluoroacetic acid) with acid; perhaps benzyl for example, it can be by removing through catalyzer (as palladium on carbon) hydrogenation.

Also usable resins is as protecting group.

The routine techniques that can adopt chemical field to know is removed protecting group in any step easily of described synthetic.

Can be by being applicable to quinazoline derivant or its pharmacy acceptable salt of the known any method preparation formula I for preparing the chemofacies related compounds.Being used for the quinazoline derivant of preparation formula I or these methods of its pharmacy acceptable salt provides another feature of the present invention, and these methods are illustrated by following representative embodiment.Necessary raw material can obtain by the organic chemistry standard method (referring to, Advanced Organic Chemistry (Wiley-Interscience) for example, Jerry March).The preparation of these raw materials is described in subsidiary non-limiting example.In addition, can obtain necessary raw material by the similar approach with those explanations, these methods are within organic chemist's ordinary skill ability.Also can discovery in following patent and application are open about the information of the essential raw material of preparation or related compound (can adopt its form must raw material), its methods involving content partly is attached among the present invention at this by reference: WO 94/27965, WO95/03283, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO 01/66099, US5252586, EP 520722, EP 566266, EP 602851 and EP 635507.

The present invention also provide by the following method (a) but-(h) quinazoline derivant of preparation formula I or the method (wherein unless otherwise indicated, each variable as above defines) of its pharmacy acceptable salt.Method (a) makes the compound of formula II:

R wherein ¹, X ¹, G ¹And G ²Have above definition in all senses, but need where necessary any functional group is protected,

Compound reaction with formula III:

Q ¹-X ²-Lg

Formula III

Q wherein ¹And X ²Have above definition in all senses, but need where necessary any functional group is protected, Lg is replaceable group, and wherein this reaction suits to carry out in the presence of suitable alkali,

After this remove any blocking group of existence by ordinary method.

Conventional replaceable group L g is; as halo, alkylsulfonyloxy or aryl-sulfonyl oxygen, such as chloro base, bromo base, methylsulfonyl oxygen base, 4-oil of mirbane sulfonyloxy or toluene-4-alkylsulfonyl oxygen base (being suitably methylsulfonyl oxygen base, 4-oil of mirbane sulfonyloxy or toluene-4-alkylsulfonyl oxygen base).

This reaction is beneficial in the presence of alkali to be carried out.The alkali that is fit to is as organic amine alkali, such as pyridine, 2, and 6-lutidine, collidine, 4-Dimethylamino pyridine, triethylamine, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene; Perhaps be carbonate or oxyhydroxide, such as yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate, sodium hydroxide or potassium hydroxide as basic metal or alkaline-earth metal.Other this class alkali is as alkalimetal hydride, such as sodium hydride; The amide of basic metal or alkaline-earth metal is as ammonification sodium or two (trimethyl silyl) ammonification sodium; Or enough alkaline alkali metal halide, as cesium fluoride or sodium iodide.This reaction suits to carry out in the presence of inert solvent or thinner, and described solvent or thinner are as alcohol or ester, such as methyl alcohol, ethanol, 2-propyl alcohol or ethyl acetate; Halogenated solvent is as methylene dichloride, chloroform or tetracol phenixin; Ether, as tetrahydrofuran (THF) or 1, the 4-dioxane; Aromatic solvent is as toluene; Or (suiting) dipolar aprotic solvent, as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO).This is reflected at temperature such as 10-150 ℃ (or boiling point of solvent), preferably carries out expediently in 20-90 ℃ of scope.

Work as X ²When being direct key, Shi Yi alkali is cesium fluoride especially.This reaction suits at the inertia dipolar aprotic solvent, as N,N-dimethylacetamide or N, carries out in the dinethylformamide.This reaction is adapted at carrying out under temperature 25-85 ℃.

Method (b) is modified substituting group or is introduced substituting group and makes it to transform into quinazoline derivant or its pharmacy acceptable salt of another kind of formula I as defined above; but need where necessary any functional group is protected, after this remove any blocking group of existence by ordinary method.

It is known in the art that substituting group is converted into other substituent method.For example; alkylthio can be oxidized to alkyl sulphinyl or alkyl sulphonyl; cyano reduction is become amino; nitroreduction is become amino; hydroxyalkyl is turned to methoxyl group; carbonyl is transformed into thiocarbonyl (for example adopting LawssonShi reagent), the bromo base is converted into alkylthio, aminoacylization can be obtained alkanoylamino (for example by with the acyl chlorides and the anhydride reaction that are fit to) or alkanoyloxy is hydrolyzed into hydroxyl (for example the acetoxyl group ethanoyl can be converted into hydroxyacetyl).Therefore, can be in the final step of formula I compound, with a R ¹Groups converted is another R ¹Group.Also can in the final step of formula I compound, substituting group be incorporated into Q ¹On the group.For example, when formula I compound contains uncle's hydrogen base or secondary amino group, for example encircle Q ¹In the NH group time; can be by making formula I compound and the reaction of formula R-Lg compound that contains primary amino or secondary amino group; substituting group is added on the nitrogen-atoms of described primary amino or secondary amino group; wherein Lg is a commutable group (halogeno-group for example; as chloro base or bromo base), R be needed substituting group (for example (1-6C) alkyl, (2-6C) alkyloyl, cyano group, cyano group (1-6C) alkyl, (1-6C) alkyl sulphonyl, formamyl, N-(1-6C) alkyl-carbamoyl, _N, _N-two-[(1-6C) alkyl] formamyls, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl or group Q ²-X ³-, Q wherein ²-X ³-as above definition, its group can be substituted by as above definition is optional).Above-mentioned reaction can be expediently suitable alkali (alkali described in above method (a) is as salt of wormwood, sodium iodide or diisopropylethylamine) exist down and expediently inert solvent or thinner (inert solvent or the thinner described in the method (a) for example, as N, N-N,N-DIMETHYLACETAMIDE, methyl alcohol, ethanol or methylene dichloride) carry out under existing.Work as Q ¹Having can be by group NR as defined above ^aR ^b(2-6C) alkyloyl that replaces or (1-6C) during alkyl sulphonyl, described NR ^aR ^bGroup can be by making wherein Q ¹The formula I compound and the formula NHR that have formula Lg-(2-6C) alkyloyl or Lg-(1-6C) alkyl sulphonyl (wherein Lg is for suitable replaceable group, as the chloro base) ^aR ^bThe compound reaction is introduced expediently; Wherein this reaction is expediently in the presence of suitable alkali and choose wantonly in the presence of suitable inert solvent or thinner and carry out.For example, Q ¹On tetramethyleneimine-1-base ethanoyl can be by making wherein Q ¹By formula I compound and tetramethyleneimine prepared in reaction that chloracetyl replaces, available similar method prepares Q ¹On substituting group, as morpholino ethanoyl, N-methylamino-ethanoyl, N, N-dimethylamino ethanoyl.Similarly, Q ¹On 3-(N, N-dimethylamino) the third alkylsulfonyl substituting group can be by making wherein Q ¹Have substituent formula I compound of 3-chlorine third alkylsulfonyl and dimethylamine prepared in reaction.Modify substituting group or substituting group is converted into other substituent other example and know for those skilled in the art, other method is included in subsequently the limiting examples.

Method (c) is removed protecting group from the quinazoline derivant of formula I or its pharmacy acceptable salt.

The proper method of removing protecting group be know and discuss at this.For example, for preparing wherein Q ¹Or R ¹The compound that contains the formula I of uncle or secondary amino group needs wherein Q of cracking ¹Or R ¹The formula I compound that contains the correspondence of protected uncle or secondary amino group.

The protecting group that is fit to amino is for example in the disclosed any protecting group to amino of preamble.The method that is fit to of these amino protecting groups of cracking is also open in preamble.More particularly, the protecting group that is fit to is an elementary alkoxy carbonyl, and as tert-butoxycarbonyl, it can be under the popular response condition, under at acid-catalyzed hydrolysis, and for example cracking in the presence of trifluoroacetic acid.

Method (d) under the Mitsunobu condition, make as the compound of the formula II of preceding definition with as the compound reaction of the formula III of preceding definition, but Lg is OH, after this removes any blocking group of existence by ordinary method.

The Mitsunobu condition that is fit to comprises, for example in the presence of tertiary phosphine that is fit to and carboxylic azodicarboxy acid dialkyl ester, in organic solvent such as THF or suitable methylene dichloride, in 0 ℃-60 ℃ of temperature ranges, but suitablely at room temperature reacts.The tertiary phosphine that is fit to comprises for example tributylphosphine or suitable triphenyl phosphine.The azodicarboxy acid dialkyl ester that is fit to comprises for example diethyl azodiformate (DEAD) or suitable azoformic acid di-t-butyl ester.The detailed content of Mitsunobu reaction is included in Tet.Letts., and 31,699, (1990); The Mitsunobu Reaction, D.L.Hughes, Organic Reactions, 1992, Vol.42,335-656 and Progress inthe Mitsunobu Reaction, D.L.Hughes, Organic Preparations and ProceduresInternational, 1996, Vol.28,127-164.

Method (e) prepares wherein R ¹-X ¹During for those formulas I compound of hydroxyl, by making wherein R ¹-X ¹Quinazoline derivant cracking preparation for the formula I of (1-6C) alkoxyl group.

This scission reaction can be carried out expediently by any method in the several different methods that becomes known for this kind conversion.R wherein ¹For the scission reaction of the formula I compound of (1-6C) alkoxyl group for example can be by handling this quinazoline derivant or for example by carrying out with basic metal diaryl phosphides (as phenylbenzene phosphatization lithium) processing with basic metal (1-6C) alkyl sulfide alkoxide (as ethanethio sodium).Perhaps, this scission reaction for example can be by handling this quinazoline derivant or carrying out expediently by reacting with organic or inorganic acid (as trifluoroacetic acid) with boron trihalides or aluminium (as boron tribromide).These reactions are adapted at suitable inert solvent or thinner as preceding definition and carry out under existing.Preferred scission reaction is that the quinazoline derivant of formula I is handled with pyridine hydrochloride.Described scission reaction is adapted in the temperature range, as carrying out in 10-150 ℃ (for example 25-80 ℃).

Method (f) prepares wherein X ¹During for those formulas I compound of O, by making formula IV compound (formula I compound, wherein R ¹-X ¹Be OH):

Formula IV

Q wherein ¹, X ², G ¹And G ²Have above definition in all senses, but need where necessary functional group is protected, with formula R ¹The compound reaction of-Lg, wherein R ¹Have above definition in all senses, but need where necessary any functional group is protected, Lg is replaceable group, and wherein this reaction is carried out in the presence of suitable alkali expediently;

After this remove any blocking group of existence by ordinary method.The replaced group L g that is fit in the preceding method (a) definition, as chloro base or bromo base.This reaction is adapted at carrying out under the suitable alkali existence.Appropriate solvent, thinner and alkali for example comprise and those of above method (a) associated description.

Method (g) prepares wherein Q ¹Or R ¹Contain (1-6C) alkoxyl group of (1-6C) alkoxyl group or replacement or (1-6C) during those formulas I compound of (1-6C) alkylamino of alkylamino or replacement, usually as preceding method (a) in the presence of the defined suitable alkali, make wherein Q ¹Or R ¹Contain the quinazoline derivant alkylation preparation of the formula I of suitable hydroxyl or primary amino or secondary amino group.

The alkylating agent that is fit to is for example alkoxyl group that hydroxyalkyl is turned to alkoxyl group or replacement known in the art, or aminoalkyl group turns to any reagent of the alkylamino of alkylamino or replacement, the alkyl halide of alkyl or replacement for example, as (1-6C) alkyl chloride, (1-6C) alkyl chloride of bromide or iodide or replacement, bromide or iodide, expediently in the presence of suitable as defined above alkali, in the inert solvent or thinner that are fit to as defined above, in certain temperature range, carry out as (expediently in room temperature or near under the room temperature) in 10-140 ℃.Available similar method will choose wantonly (2-6C) alkanoyloxy, (2-6C) alkanoylamino of replacement and (1-6C) alkyl sulfonyl-amino be incorporated into Q ¹Or R ¹In.

For preparing wherein Q expediently ¹Or R ¹The formula I compound that contains (1-6C) alkylamino of (1-6C) alkylamino or replacement, can adopt formaldehyde or (2-6C) alkyl aldehydes (alkanolaldehyde) (for example acetaldehyde or propionic aldehyde) use reduction amination and carry out.For example, for preparing wherein Q ¹Or R ¹Contain NThose formulas I compound of-methyl can finish the compound and the formaldehyde reaction that contain the N-H group accordingly in the presence of the reductive agent that is fit to.The reductive agent that is fit to is for example hydride reducer (as formic acid), alkali metal aluminum hydride (as lithium aluminium hydride) or the alkali metal borohydride (as sodium borohydride, sodium cyanoborohydride, triethyl-boron sodium hydride, trimethoxy sodium borohydride and sodium triacetoxy borohydride) that is fit to.This is reflected in suitable inert solvent or the thinner and carries out expediently, for example tetrahydrofuran (THF) and ether are used to act on stronger reductive agent (as lithium aluminium hydride), and methylene dichloride or protonic solvent (as methyl alcohol and ethanol) are used to act on more weak reductive agent (as sodium triacetoxy borohydride and sodium cyanoborohydride).When reductive agent was formic acid, this reaction adopted the aqueous solution of formic acid to carry out expediently.This is reflected in the certain temperature range and carries out, in 10-100 ℃, and for example 70-90 ℃ or expediently in room temperature or near carrying out under the room temperature.When reductive agent is formic acid, can be expediently in reaction process original position remove the protecting group treated on the alkylating NH group (as the protecting group of existence in starting raw material synthetic, as tert-butoxycarbonyl).

Method (h) prepares wherein R ¹During those formulas I compound of being replaced by group T; wherein T is selected from (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, (1-6C) alkylthio, (1-6C) alkyl sulphinyl and (1-6C) alkyl sulphonyl, makes the compound of following formula V:

Formula V

Q wherein ¹, X ¹, X ², R ¹, G ¹And G ²Have above definition in all senses, tackle any functional group when still needing and protect, Lg is replaceable group (for example chloro base or a bromo base), and with the compound reaction of formula TH, wherein the T definition is the same, when still needing functional group is protected.

After this remove any blocking group of existence by ordinary method.This is reflected at suitable alkali existence and carries out expediently down.This reaction can be carried out in inert solvent that is fit to or thinner expediently.Alkali, solvent and the thinner that is fit to has such as middle those that describe of method (a).In for example being adapted at 10-150 ℃, this reaction carries out under the temperature of (for example 30-60 ℃).

Should know some Tong Guo standard aromatics substitution reaction introducing of the various ring substituents in the The compounds of this invention or can pass through conventional modified with functional group and produce, described step or before above each method of carrying or immediately carry out, these contents are included in the method for the present invention aspect.These reactions and modifying method comprise, for example, introduce substituting group by modes such as aromatics substitution reaction, substituting group reduction, substituting group alkylation and substituent oxidations.The reagent and the reaction conditions of these methods are known in chemical field is.The specific examples of aromatics substitution reaction comprises that the employing concentrated nitric acid is introduced nitro, employing is introduced acyl group as carboxylic acid halides and Lewis acid (as aluminum chloride) under Friedel Crafts condition; Under Friedel Crafts condition, adopt as alkylogen and Lewis acid (as aluminum chloride) and introduce alkyl; And introducing halogeno-group.

Method (i) is by making the compound of following formula VI:

Formula VI

R wherein ¹, X ¹, X ², Q ¹Have above definition in all senses, but functional group is protected when needing, Lg is replaceable group as defined above,

Aniline reaction with formula VII:

Formula VII

G wherein ¹And G ²Have above definition in all senses, but functional group is protected when needing, and wherein this is reflected at suitable acid and exists down and carry out expediently,

After this remove any blocking group of existence by ordinary method.

As preceding definition, halogeno-group especially is as the chloro base by suitable the replaced group of Lg representative.

Described being reflected under suitable inert solvent or the thinner existence carried out expediently, described inert solvent or thinner for example have alcohol or ester (as methyl alcohol, ethanol, Virahol or ethyl acetate), halogenated solvent (as methylene dichloride, chloroform or tetracol phenixin), ether (as tetrahydrofuran (THF) or 1, the 4-dioxane), aromatic solvent (as toluene) or dipolar aprotic solvent (as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone, acetonitrile or methyl-sulphoxide).This reaction expediently in scope for for example in 10-250 ℃, preferably in 40-120 ℃, carry out, perhaps wherein use under the reflux temperature of solvent or thinner and carry out.Routinely, can be under these conditions, in the presence of protonic solvent (as Virahol), expediently at acid (hydrogen chloride gas or the hydrochloric acid in ether or the dioxane for example, the dioxane solution of 4M hydrogenchloride for example) exists down, formula VI compound and formula VII compound are reacted.Perhaps, this reaction can aprotic solvent (as dioxane) or dipolar aprotic solvent (as N, N-N,N-DIMETHYLACETAMIDE or acetonitrile) in, in the presence of acid (for example hydrogen chloride gas or the hydrochloric acid in ether or the dioxane), carry out expediently.Can make Lg wherein is that the formula VI compound and the formula VII compound of halogeno-group reacts in the presence of acid not.In this reaction, the displacement of halo leavings group Lg can original position form sour HLg in described reaction, and autocatalytically should reaction.This reaction expediently the inert organic solvents that is fit to (as Virahol, dioxane or N, N-N,N-DIMETHYLACETAMIDE) carries out in.The suitable condition of this reaction as mentioned above.

Perhaps, can in the presence of suitable alkali, make the reaction of formula VI compound and formula VII compound.The suitable alkali of this reaction is the above-mentioned alkali of definition in the method (a).This is reflected at such as carrying out expediently in above-mentioned inert solvent relevant with method (i) or the thinner.

Method (j) prepares wherein Q ¹Have replacement formamyl (as N, N-two [(1-6C) alkyl] formamyl) or group Q ²-X ³-those formulas I compound the time, Q wherein ²Be by theheterocyclic nitrogen atom and X ³The nitrogen heterocycle that connects, X ³Be CO; Make as above definition and wherein Q ¹The formula I compound (when still needing functional group being protected) and primary amine or secondary amine or formula Q that have carboxyl ²The H group carries out coupling, wherein Q ²H is the heterocyclic radical that contains the NH group; After this remove any blocking group of existence by ordinary method.

Described coupled reaction is expediently at suitable coupler such as carbodiimide (for example 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide) or the peptide coupler that is fit to (phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea  (HATU)) carries out under existing.This coupled reaction expediently inert solvent (as halogenated solvent (as methylene dichloride)) or dipolar aprotic solvent (as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone) in carry out.Described coupled reaction is adapted at carrying out under suitable alkali such as organic amine (diisopropylethylamine or the 4-Dimethylamino pyridine) existence.This coupled reaction be suitable for-25 to 150 ℃, at room temperature carry out easily.

It will be appreciated by those skilled in the art that, for obtaining The compounds of this invention in mode more easily in other situation and some occasion, order that can be different carries out above-described each process step, and/or carries out each reaction (promptly adopting the intermediate relevant with being different from above-mentioned concrete reaction to carry out each chemical conversion) with the different stages in whole route.

When the pharmacy acceptable salt (for example acid salt) of the quinazoline derivant that needs formula I, can adopt conventional method, for example by making described quinazoline derivant and suitable acid-respons acquisition.For in preparation process, being easy to separate described compound, can prepare the compound of the form of non-pharmacy acceptable salt.Modify resulting salt by routine techniques then, generate the pharmacy acceptable salt of described compound.These technology comprise ion exchange technique for example or the technology of the described compound of redeposition in the presence of pharmaceutically acceptable counter ion.For example, redeposition in the presence of the acid (as HCl) that is fit to obtains the salt acid salt.

As mentioned above, some compound of the present invention can contain one of a plurality of chiral centres, therefore can exist with stereoisomer form and (for example work as Q ¹When comprising tetramethyleneimine-3-base).Each steric isomer can adopt routine techniques (as chromatography or fractional crystallization) to separate.Enantiomorph can separate (for example by fractional crystallization, fractionation or HPLC) by the separation of separation of racemic body.Diastereomer can separate (for example by fractional crystallization, HPLC or flash chromatography) by the different physical properties of utilizing described diastereomer.Perhaps, each concrete steric isomer can be by carrying out the synthetic preparation of chirality by chiral raw material, perhaps by preparing with the chiral reagent derivatize under the condition that does not cause racemization or epimerization.The chirality that is fit to example synthetic and isomer separation is described in an embodiment.When separating a concrete steric isomer, suitable its separation is reached the steric isomer that does not have other substantially, for example contain less than 20%, especially less than 10%, more particularly less than other steric isomer of 5% weight.

In with top, term " inert solvent " refers to the solvent with the mode of the yield that can influence the product that required and raw material, reagent, intermediate or product reaction sharply.

The preparation of raw material

Formula II compound be commercially available or can adopt routine techniques or with similar method preparation described in the prior.Especially above listed those patents and application are as WO96/15118, WO 01/66099 and EP566226.For example, can be according to reaction process 1 preparation formula II compound.

Reaction process 1

R wherein ¹, X ¹, Lg, G ¹And G ²As above definition, Pg is a hydroxyl protecting group.

(i) reaction be suitable for inertia protonic solvent (as alkanol, for example Virahol), aprotic solvent (as dioxane) or dipolar aprotic solvent (as N, N-N,N-DIMETHYLACETAMIDE) in, in the presence of acid (as hydrogen chloride gas in ether or the dioxane or hydrochloric acid), under the conditions of similarity described in the aforesaid method (i), carries out.

Perhaps, described reaction can be carried out in the presence of alkali (as salt of wormwood) in one of above-mentioned inert solvent expediently.The scope that more than is reflected at is for for example in 0-150 ℃, suit or near the reflux temperature of reaction solvent under carry out expediently.

(ii) can be at the Pg of these reactions of cracking under the standard conditions.For example, when Pg is alkyloyl (as ethanoyl), can be by heating in the presence of methyl alcohol system ammonia solution with its cracking.

Formula VIII compound is known compound or the currently known methods preparation that can adopt the preparation similar compound.If commercially available can not providing, formula VIII compound can the method for described step be prepared by being selected from the standard chemical technology, being similar to the technology of synthetic known structure analogue compounds or being similar in an embodiment.For example, the standard chemical technology of describing among the Houben Weyl.For example, but adopt the method preparation formula VIII compound of explanation in the reaction process 2, wherein R ¹-X ¹-be methoxyl group, Lg is the chloro base, Pg is an ethanoyl.

Reaction process 2

Compound in this specification sheets that the technician can be applied to reaction process 2 not specify (for example on the 7-position of described quinazoline ring, introducing the substituting group of non-methoxyl group).

The formula III compound be commercially available or can adopt standard technique (as among US 5252586 and the WO 94/27965 explanation technology) preparation.

Formula IV compound can adopt above method (e), is feedstock production with for example compound by employing method (a) preparation.

Formula V compound can adopt for example method (a) or method (d) preparation, wherein R ¹The group of representative is fit to functionalized with suitable replaced group L g (as chloro base or bromo base).

Formula VI compound can adopt ordinary method preparation well known in the art.For example, can remove the hydroxyl protecting group Pg in the formula VIII compound described in the above reaction process 1, obtain formula X compound:

Can adopt routine techniques, from formula X compound, remove protecting group Pg.

Adopt then with method (a) or method (d) in the similar condition described, make formula X compound with as the formula III compound coupling of preceding definition.

The new intermediate of some that utilize in aforesaid method has constituted another feature of the present invention with their preparation method.

The present invention's feature again provides formula II and IX compound and salt (comprising its pharmacy acceptable salt) thereof as preceding definition.R wherein particularly ¹-X ¹Be hydrogen or (1-4C) the formula II and the IX compound of alkoxyl group.R wherein more especially ¹-X ¹Be hydrogen or (1-4C) alkoxyl group and G ¹And G ²Be selected from the formula II and the IX compound of fluoro or chloro.

Biological assay

Below measuring method can be used to detect compound of the present invention as the erb-tyrosine kinase inhibitor, as the usefulness of external KB cell (KB cell) inhibition of proliferation agent and as in vivo to the effect of the inhibitor of the growth of the heterograft of the Lo Vo tumour cell (rectum cancer) of nude mice.

A) protein tyrosine kinase phosphorylation assay

This test determination test compound suppresses to contain the ability of phosphorylation of the peptide substrate of tyrosine by the EGFR Tyrosylprotein kinase.

Reconstitution cell internal fragment EGFR, erbB2 and erbB4 (catalog number (Cat.No.) is respectively X00588, X03363 and L07868) are cloned and are expressed in baculovirus/Sf21 system.By with these cells with ice-cooled molten born of the same parents' damping fluid (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH7.5,150mM NaCl, 10% glycerine, 1%Triton X-100,1.5mMMgCl ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA)) add that proteinase inhibitor handles, prepare lysate by centrifugal clarification then.

Make phosphorylation takes place a kind of synthetic peptide (is that the randomcopolymer of 6: 3: 1 L-glutamic acid, L-Ala and tyrosine is formed by ratio) ability measure the formation kinase activity of described recombinant protein by it.Specifically, with Maxisorb ^TM96 hole immunization test boards are with synthetic peptide (solution of 0.2 μ g peptide in 100 μ l phosphate-buffered saline (PBS)) bag quilt, then 4 ℃ of overnight incubation.Under the room temperature, each plate is washed to remove any excessive unconjugated synthetic peptide in turn with PBS-T (phosphate-buffered saline that has 0.5% polysorbas20) and 50mMHEPES (pH7.4).By under 22 ℃, at 100mM HEPES pH7.4, be used for adenosine triphosphate (ATP), 10mM MnCl under the Km concentration of each enzyme ₂, 0.1mM Na ₃VO ₄, in the 0.2mM DL-dithiothreitol (DTT) (DTT), 0.1%Triton X-100, the assay plate of peptide bag quilt was hatched 20 minutes with the DMSO solution (final concentration 2.5%) of test compound, measure the tyrosine kinase activity of EGFR, ErbB2 or ErbB4.By removing the liquid ingredient of measuring in the liquid, wash each plate termination reaction with PBS-T then.

Immobilized phosphoric acid-peptide (phospho-peptide) product by the described reaction of determination of immunological methods.At first, at room temperature, each plate was hatched 90 minutes with the anti-Tyrosine O-phosphate primary antibody of cultivating in mouse (deriving from the 4G 10 of Upstate Biotechnology).Behind the thorough washing, under the room temperature, each plate used in conjunction with the horseradish peroxidase (HRP) of sheep anti mouse secondary antibodies (deriving from the NXA931 of Amersham) handled 60 minutes.Further after the washing, adopt as 2 of substrate 2 '-azino-two-[3-ethyl benzo thiazole phenanthroline sulfonic acid (6)] di-ammonium salts crystal (ABTS ^TM, available from Roche) and the HRP activity in every hole in the colorimetric estimation plate.

By under 405nm, measuring absorbancy,, measure enzymic activity thus to developing the color quantitatively with Molecular Devices ThermoMax microplate.The kinase inhibitory activity of given compound is with IC ₅₀Value representation.Measure IC by calculating the required compound concentration of 50% restraining effect that in this mensuration, provides phosphorylated ₅₀Value.From positive (medium adds ATP) and negative (medium subtracts ATP) control value, calculate the phosphorylated scope.

B) the KB cell proliferation test of EGFR driving

This test determination test compound suppresses the ability of KB cell (KB cell is obtained by AmeriCanType Culture Collection (ATCC)) propagation.

At 7.5%CO ₂In the air incubator, under 37 ℃, in containing the DulbeccoShi improvement EagleShi substratum (DMEM) of 10% foetal calf serum, 2mM glutamine and non-essential amino acid, cultivate KB cell (KB cell is provided by ATCC).Adopt trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA), harvested cell from the deposit bottle.Adopt hematimeter to measure cell density, then with every hole 1.25 * 10 ³The density of individual cell is inoculated in 7.5%CO ₂, among the DMEM that contains 2.5% activated carbon decolorizing blood plasma (stripped serum), 1mM glutamine and non-essential amino acid in 96 orifice plates under 37 ℃, fix 4 hours, adopt trypan blue solution to calculate vigor then.

Cell adhesion with (or need not) EGF (final concentration 1ng/ml) with methyl-sulphoxide (DMSO) (final concentration 0.1%) processing of the compound in (or need not) finite concentration scope, was hatched cell 4 after on the plate then.After hatching end, by the bromination 3-(4,5-dimethylthiazole-2-yl)-2 that adds 50 μ l, 5-phenylbenzene tetrazolium  (MTT) (storing solution 5mg/ml) measures cell count 2 hours.Then MTT solution is inclined to, culture plate is rapped drying, add 100 μ lDMSO then and dissolve described cell.

By adopting Molecular Devices ThermoMax microplate, the absorbancy of under 540nm, reading the dissolved cell.With inhibition of proliferation effect IC ₅₀Value representation.By calculating the required compound concentration of 50% restraining effect that produces propagation is measured IC ₅₀Value.From positive (medium adds EGF) and negative (medium subtracts EGF) control value, calculate multiplication nursery.

C) H16N-2 cell proliferation test

This test determination test compound suppresses the ability of the H16N-2 cell proliferation of heregulin β or EGF driving.These non-knurl epithelial cells respond EGF or heregulin β (Ram in the propagation mode, G.R. and Ethier, S.P. (1996) Cell Growth and Differentiation, 7, stimulation 551-561), they separate (Band from the human breast tissue, V and Sager, R.Tumour progression in breast cancer.In:J.S.Rhim and A.Dritschilo (eds.), Neoplastic Transformation in human Cell Culture, pp 169-178.Clifton, NJ:Humana Press, 1991), by Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 obtains.

At 7.5%CO ₂In the air incubator, under 37 ℃, at substratum medium (1: 1 GibcoF12 and HamShi α MEM substratum mixture, it contains 1% foetal calf serum, 10mMHEPES, 1 μ g/ml Regular Insulin, 12.5ng/ml EGF, 2.8 μ M hydrocortisones, 2nM estradiol, 5 μ M xitix, 10 μ g/ml transferrins, 0.1mM phosphatidyl ethanolamine, 15nM Sodium Selenite, 2mM glutamine, 10nM triiodothyronine (tri-iodo-thrynoine), 35 μ g/ml Niu Chuiti extract and 0.1mM thanomins), cultivate the H16N-2 cell routinely.Adopt trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA), harvested cell from the deposit bottle.Adopt hematimeter to measure cell density, then with every hole 1.0 * 10 ³The density of individual cell is inoculated in 7.5%CO ₂, in the above-mentioned substratum in 96 orifice plates under 37 ℃, fix 72 hours, adopt trypan blue solution to calculate vigor then.

Then, at 7.5%CO ₂, under 37 ℃, add hungry substratum (starvation medium) (1: 1 Gibco F12 and HamShi α MEM substratum mixture, it contains 10mM HEPES, 2nM estradiol, 5 μ M xitix, 10 μ g/ml transferrins, 0.1mM phosphorylethanolamine, 15nM Sodium Selenite, 2mM glutamine and 0.1mM thanomin), make described cell lack serum and cultivated 24 hours.Subsequently cell was handled 2 hours with the methyl-sulphoxide (DMSO) (final concentration 0.1%) of the compound in (or need not) finite concentration scope, added exogenous part (the heregulin β of final concentration 100ng/ml or the EGF of 5ng/ml) afterwards, at 7.5%CO ₂, under 37 ℃, hatched 4 with part and compound.After incubation period, finish, by suction remove substratum and with the bromination 3-(4,5-dimethylthiazole-2-yl)-2 of 50 μ l, 5-phenylbenzene tetrazolium  (MTT) (storing solution 5mg/ml) incubation 2 hours is measured cell count.Then the suction of MTT solution is removed, dry air adds 100 μ lDMSO then and dissolves described cell.

By under 540nm, reading the absorbancy of dissolved cell, that cellular biomass is quantitative.With inhibition of proliferation effect IC ₅₀Value representation.Measure IC by calculating the required compound concentration of 50% restraining effect that produces propagation ₅₀Value.From positive (medium adds part) and negative (medium subtracts part) control value, calculate multiplication nursery.

D) xenotransplantation is measured in the body

This test detects test compound suppresses LoVo tumour (rectum cancer is derived from ATCC) growth in female Swiss athymic mouse (Alderley Park, nu/nu strain) ability.

Raise female Swiss nude mouse (nu/nu strain), remain on then among the AlderleyPark (PFI Systems Ltd.) among the negative pressure Isolate (shield retaining).Mouse closed support in having 12 little time/dark round-robin barrier apparatus, aseptic food and water freely are provided.all adopt the mouse at least 8 ages in week to carry out in steps.By giving 1 * 10 of the fresh culture of every mouse subcutaneous injection in 100 μ l serum free mediums ⁷Individual cell is set up the xenotransplantation of LoVo tumour cell (the rectum adenocarcinoma of colon is derived from ATCC) at the rear side belly of donor mice.After transplanting the 5th day, mouse is divided into 7 groups at random, then amount every day of 0.1ml/10g body weight to give compound 1 time or control media is handled.Pass through two-sided vernier caliper measurement gross tumor volume 2 times weekly, adopt following formula to calculate: (length x width) * (length x width) * (π/6), wherein length is the longest diameter by this tumour, width is corresponding vertical line.The mean change of the gross tumor volume by compare group and treatment group is calculated from studying initial growth-inhibiting, adopts the statistical significance between two groups of the Students t check assessments.

E) the potassium channel inhibition test of hERG-coding

This test determination test compound suppresses tail current mobile ability by the potassium channel of people's ether-a-go-go-genes involved (hERG)-coding.

Human embryo kidney (HEK) (HEK) cell of expressing the hERG-coding pass is grown in add 10% foetal calf serum (Labtech Intemational; Production number 4-101-500), the 10%M1 serum-free replenishes liquid (Egg Technologies; Production number 70916) and 0.4mg/ml Geneticin G418 (Sigma-Aldrich; Catalog number (Cat.No.) G7034) Eagle minimum essential medium (EMEM; Sigma-Aldrich; Catalog number (Cat.No.) M2279) in.Before each on-test 1 or 2 day, adopt the normal structure cultural method, with Accutase (TCS Biologicals) isolated cell from tissue culture flasks.Then they are placed on the glass cover slide in each hole of 12 well culture plates, cover with the 2ml growth medium.

For writing down every porocyte, the glass cover slide that cell is housed is placed the bottom, Perspex chamber of containing body lotion (seeing below) under the room temperature (～20 ℃).This chamber is fixed on the platform of an inverted phase contrast microscope.Cover glass is placed this chamber, supply with the storehouse (gravity-fed reservoir) from a gravity with the speed of about 2ml/min immediately and in described chamber, poured into body lotion 2 minutes.Stop perfusion then.

To pull out device (Sutter Instrument Co.) with P-97 trace pipette is full of with pipette solution (seeing below) from the membranaceous pipette that borosilicate glass tube (GC120F, Harvard Apparatus) makes.By silver/silver chloride line, described pipette is connected in the top of patch clamp augmentor (Axopatch200B, Axon Instruments).This bottom, top is connected the earth polar.It is made up of the silver/silver chloride line that is inserted in 3% agar of being made up of 0.85% sodium-chlor.

Whole-cell configuration record cell with patch clamp technique.Keep current potential-80mV (by the augmentor setting) carry out " swarming into (break in) " and carry out series resistance and the suitable debugging of electric capacity control after, adopt electric physiology software (Clampex, Axon Instruments) setting is kept current potential and (80mV), is transmitted an agreement voltage (voltage protocol) then.Per 15 seconds of this agreement is used once, by 1 second to+40mV step and subsequently 1s extremely-the 50mV step forms.Under 1kHz, by the low electric current of augmentor by each application protocol voltage of filtering response.Then by with similar quanxtizer with similarly signal digitalized in the augmentor, the filtering signal of online acquisition.On the computer of operation Clampex software (Axon Instruments), catch digitized signal afterwards.Keep voltage and to+40mV step process, under 1kHz, surveying sample electric current.Sample rate with remaining voltage protocol is made as 5kHz then.

List the penetration degree of described composition, pH and described body lotion and pipette solution in the following table.

Salt	Suction pipe (mM)	Body lotion (mM)
Salt	Suction pipe (mM)	Body lotion (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	Suction pipe	Body lotion
Parameter	Suction pipe	Body lotion	PH	7.18-7.22	7.40
The PH conditioning agent	1M KOH	1M NaOH	PH	7.18-7.22	7.40
The PH conditioning agent	1M KOH	1M NaOH	Penetration degree (mOsm)	275-285	285-295

By Clampex software (Axon Instruments) online record voltage from+40mV to-50mV step after the amplitude of potassium channel tail current of hERG-coding.Behind the amplitude stability of this tail current, in cell, add the body lotion that contains the medium that is tried material.The adding medium does not have obvious influence to the amplitude of tail current, sets up the accumulative total mass action curve to compound then.

By expressing the amplitude of tail current down in the given concentration (percentage concentration that in medium, exists) of test compound, quantitative to the effect of each concentration of test compound.

By adopting normal data match software package, the Hill equation that will be fitted to the quaternary parameter by the percentage restraining effect value that concentration-effect constitutes comes the usefulness (IC of determination test compound ₅₀).If being seen inhibition level is no more than 50% under the highest experimental concentration, does not promptly produce efficiency value and quote percent inhibition under this concentration.

Although the pharmacological properties of formula I compound is as changing with structural changes of estimating, usually, one or more plant above test (a) and (b) with (c) in, under following concentration or dosage, susceptible of proof formula I compound has activity:

Test (a) :-IC ₅₀In 0.001-10 μ M scope for example

Test (b) :-IC ₅₀In 0.001-10 μ M scope for example

Test (c) :-IC ₅₀In 0.001-10 μ M scope for example

Test (d) :-for example have activity in 1-200mg/kg/ days the dosage range

Under the effective dose of test compound of the present invention, in test (c), do not observe unacceptable toxicity on the physiology.Therefore, when formula I compound that gives aforementioned definitions with the dosage range that after this limits or pharmacy acceptable salt, the toxicology effect that expection can not produce trouble.

Another aspect of the present invention provides a kind of medicinal compositions, and this medicinal compositions comprises quinazoline derivant or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of the formula I of definition as mentioned.

Composition of the present invention can be for being applicable to the form that orally uses (tablet for example, lozenge, hard or soft capsule, water-based or oily suspensions, emulsion, but dispersion powder or granule, syrup or elixir), be applicable to that the local form of using is (as creme, paste, jelling agent, water-based or oily solution or suspension), be applicable to the form (as finely divided powder or liquid aerosol) of inhalation, be applicable to the form (as finely divided powder agent) that is blown into administration or be the form that is applicable to parenterai administration (for example sterile aqueous or oily solution, can be used for vein, subcutaneous, intramuscular administration is perhaps for being used for the suppository of rectal administration).

Can adopt various conventional pharmaceutical excipient well known in the art, prepare composition of the present invention by ordinary method.Therefore, being intended for use liquid preparations for oral administration can contain just like one or more tinting materials, sweeting agent, correctives and/or sanitas.

The amount that combines with one or more vehicle with the active ingredient that obtains single formulation must change according to host who is treated and concrete route of administration.For example, the preparation that is intended for use the human oral administration is fit to usually contain just like the 0.5mg-0.5g active medicine and (is more suitable for being 0.5-100mg, as be 1-30mg), and also contain an amount of vehicle in the said preparation, the amount of vehicle can be about 5%-98% of composition total weight.

Certainly, according to the known principle of medical field, when formula I compound was used for the treatment of or prevents purpose, its dosage size should change according to the character of the disease of animal (being the patient) and severity, age and sex and route of administration.

When formula I compound being used for the treatment of or preventing purpose, generally be to be the scope administration of 0.1mg/kg-75mg/kg body weight with for example per daily dose, in case of necessity can be with several divided dose administrations.Usually, when adopting the parenteral administration, should give lower dosage.Therefore, for example when intravenously administrable, the dosage range that adopts is as the 0.1mg/kg-30mg/kg body weight usually.Similarly, when inhalation, the dosage range that adopts is for example 0.05mg/kg-25mg/kg body weight usually.But the preferred oral administration is particularly with the form oral administration of tablet.Generally speaking, contain the 0.5mg-0.5g that has an appointment compound of the present invention in the unit dosage.

We find that The compounds of this invention has anti proliferative properties (as anticancer character), and this character is considered to by its erbB family receptors tyrosine-kinase enzyme inhibition activity, and especially the restraining effect of EGF acceptor (erbB1) Tyrosylprotein kinase causes.In addition, some compound of the present invention is compared other Tyrosylprotein kinase (as erbB2) to the EGF receptor tyrosine kinase and is had stronger effect substantially.These compounds have enough strong effect to the EGF receptor tyrosine kinase, therefore can be used to suppress the EGF receptor tyrosine kinase with enough amounts, present very little to other Tyrosylprotein kinase (as erbB2) simultaneously or obvious low activity.These compounds may be used for selectivity and suppress the EGF receptor tyrosine kinase, and may be used for treating effectively the tumour that causes as EGF.

Therefore, the expectation The compounds of this invention can be used for disease or the illness that treatment is independent by erbB receptor tyrosine kinase (especially EGF receptor tyrosine kinase) or part mediates, and promptly described compound is used in and produces erbB receptor tyrosine kinase restraining effect in the warm-blooded animal that needs this kind treatment.Therefore, The compounds of this invention provides a kind of method for the treatment of malignant cell, and this method feature is to suppress one or more erbB family of receptor tyrosine kinase.Specifically, The compounds of this invention can be used for producing by suppressing antiproliferative and/or proapoptosis and/or the anti-erosion effect that the erbB receptor tyrosine kinase is independent or part mediates.Especially expect The compounds of this invention can be used for the prevention or the treatment to suppressing one or more erbB receptor tyrosine kinase, as EGF and/or erbB2 and/or those responsive tumours of erbB4 receptor tyrosine kinase (especially EGF receptor tyrosine kinase), these receptor tyrosine kinases are relevant with the signal conduction step that drives these tumor cell proliferations and existence.Therefore, the expectation The compounds of this invention can be used for treating psoriasis, benign prostatauxe (BPH), atherosclerosis and restenosis and/or cancer by antiproliferative effect is provided, in particular for the cancer of treatment erbB receptor tyrosine kinase sensitivity.These optimum or malignant tumours can influence any tissue, comprise non-solid tumour, as leukemia, multiple myeloma or lymphatic cancer, and solid tumor, as bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva.

One aspect of the present invention provides as the formula I compound of medicine or its pharmacy acceptable salt.

Another aspect of the present invention provides formula I compound or its pharmacy acceptable salt to produce the purposes of antiproliferative effect in warm-blooded animal (as the people).

Therefore, one aspect of the present invention provides as the formula I quinazoline derivant of preceding definition or its pharmacy acceptable salt and is used for producing purposes in the medicine of antiproliferative effect warm-blooded animal (as the people) in preparation.

Another feature according to this aspect of the present invention, produce the method for antiproliferative effect in the warm-blooded animal (as the people) that the invention provides in this type of treatment of needs, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

Another aspect of the present invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt to be used for prevention or the treatment purposes to the medicine that suppresses those responsive tumours of erbB receptor tyrosine kinase (as EGFR and/or erbB2 and/or erbB4 (especially EGFR)) in preparation, and it is relevant that described receptor tyrosine kinase and the signal that causes tumor cell proliferation conduct step.

This another feature on the one hand of the present invention provides a kind of prevention or the methods of treatment to those responsive tumours of the erbB family (as EGFR and/or erbB2 and/or erbB4 (especially EGFR)) that suppresses one or more receptor tyrosine kinase, described receptor tyrosine kinase is relevant with the signal conduction step that causes tumor cell proliferation and/or existence, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

Another feature according to this aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt and preventing or treating suppressing the purposes in those responsive tumours of erbB receptor tyrosine kinase (as EGFR and/or erbB2 and/or erbB4 (especially EGFR)), described receptor tyrosine kinase is relevant with the signal conduction step that causes tumor cell proliferation.

According to another aspect of the present invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt are used for providing the medicine of EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity in preparation purposes.

Another feature according to this aspect of the present invention, the method of a kind of EGFR of providing and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity is provided, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

According to another feature of this aspect of the present invention, the invention provides the formula I compound or its pharmacy acceptable salt that are used to provide EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity.

According to another feature of the present invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt are used for providing the medicine of selectivity EGFR tyrosine kinase inhibitory activity in preparation purposes.

Another feature according to this aspect of the present invention, the invention provides a kind ofly provides selectivity EGFR the method for tyrosine kinase inhibitory activity, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

According to another feature of this aspect of the present invention, the invention provides the formula I compound or its pharmacy acceptable salt that are used to provide selectivity EGFR tyrosine kinase inhibitory activity.

" selectivity EGFR kinase inhibitory activity " refers to that the quinazoline derivant of formula I compares other kinases to the EGF receptor tyrosine kinase and have stronger effect.Particularly some The compounds of this invention is compared other Tyrosylprotein kinase (as other erbB receptor tyrosine kinase (as erbB2)) to the EGF receptor kinase and is had stronger effect.For example, according to the relative IC that in being fit to test (for example foregoing H116N-2 test), measures ₅₀Be worth as seen, the proliferation function that the proliferation function comparison EGFR Tyrosylprotein kinase that selectivity EGFR kinase inhibitor of the present invention drives the erbB2 receptor tyrosine kinase drives is high at least 5 times, preferably high at least 10 times.

According to another feature of this aspect of the present invention, the invention provides the quinazoline derivant of formula I of aforementioned definitions or its pharmacy acceptable salt and be used for the treatment of purposes in the medicine of cancer (for example be selected from following cancer: leukemia, multiple myeloma, lymphatic cancer, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva) in preparation.

Another feature according to this aspect of the present invention, the invention provides in a kind of warm-blooded animal (as the people) the treatment cancer and (for example be selected from following cancer: leukemia in the treatment of this kind of needs, multiple myeloma, lymphatic cancer, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the uterus and the carcinoma of vulva) method, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

According to another feature of this aspect of the present invention, the invention provides a kind of formula I compound or its pharmacy acceptable salt that is used for the treatment of cancer (for example be selected from following cancer: leukemia, multiple myeloma, lymphatic cancer, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva).

As mentioned above, treatment or the big young pathbreaker of the needed dosage of a kind of disease specific of prophylactic treatment must change according to the severity of other factors, the host who is treated, route of administration and the disease for the treatment of.

The antiproliferative treatment of aforementioned definitions can be used as the single therapy method and uses separately, and perhaps except that quinazoline derivant of the present invention, use can also combine with therapeutic method of surgery, radiotherapy or the chemical therapeutic method of routine.This type of chemical therapeutic method can comprise one or more following all kinds of antitumour drugs:

(i) antiproliferative/antitumour drug that adopts in medical oncology is as alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and Nitrosourea); Antimetabolite (as anti-folic acid class (antifolates), for example fluoropyrimidines (as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, methotrexate, cytarabin and hydroxyurea; Antitumor antibiotics (as anthracyclines, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, darubicin, Mitomycin-C, actinomycin and duomycin); Antimitotic agent (as vinca alkaloids, as vincristin, vinealeucoblastine(VLB), vindesine and vinorelbine, and taxanes (taxoids), as taxol and taxotere); And topoisomerase enzyme inhibitor (as the Etoposide class, as Etoposide and teniposide, amsacrine, the special willing and camptothecine of topology);

(ii) cytostatics, as anti-estrogens (as tamoxifen, Toremitene, raloxifene, droloxifene and iodoxyfene), estrogen receptor reduces conditioning agent (as fulvestrant), anti-androgens is (as bicalutamide, flutamide, Nilutamide and acetate cyproterone), lhrh antagonist or LHRH agonist are (as goserelin, Leuprolide and buserelin), progestogens (as the acetate megestrol), arimedex is (as Anastrozole, letrozole, fluorine chlorazol (vorazole) and Exemestane) and the 5 inhibitor, as finasteride;

(iii) anticancer is invaded agent (as inhibitors of metalloproteinase (as Marimastat) and bird kinases Profibrinolysin activator function of receptors inhibitor);

(iv) the somatomedin depressant of functions is drawn together growth factor antibodies, growth factor receptor antibody (as anti-erbb2 antibody trastuzumab[Herceptin as this type of inhibitor packages ^TM] and anti-erbbl antibody cetuximab[C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, for example the inhibitor of epidermal growth factor family is (as EGFR family tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gefitinib, AZD 1839), N-(3-ethynyl phenyl)-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib, OSI-774) and the 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), the inhibitor of the inhibitor of thrombocyte class growth factor family and pHGF family for example;

(v) anti-angiogenic agent suppresses the compound of vascular endothelial growth factor as those, (anti-vascular endothelial cell growth factor antibody bevacizumab[Avastin for example ^TM], disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and those compounds that work by other mechanism (as linomide, beta 2 integrin alpha v β 3 depressant of functions and angiostatin);

(vi) vascular damaging agents is as disclosed compound among Combretastatin A4 and International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the WO 02/08213;

(vii) antisense therapy agent, for example relate to above listed target medicine (as ISIS 2503, a kind of anti--the ras antisense drug);

(viii) gene therapy approach, comprise as replacing the aberrant gene approach, as unusual p53 or unusual BRCA1 or BRCA2, GDEPT (therapy that relates to the enzyme precursor medicine of gene) approach, as adopt those approach of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and strengthen the approach of patient to chemotherapy or radiotherapeutic tolerance, as multiple drug resistance gene therapy; With

(ix) immunotherapy approach, comprise as approach in the immunogenic external and body that strengthens the patient tumors cell, as using cytokine (as interleukin II, interleukin-4 or rHuGM-CSF) transfection, reduce T-cell anergia approach, adopt transfection immunocyte (as the dendritic cell of cytokine transfection) approach, adopt the approach of the tumor cell line of cytokine transfection, and the approach that adopts anti-atopic antibody.

By simultaneously, order or each component of separately treating, can carry out this type of combination therapy.This type of joint product can use compound of the present invention in aforesaid dosage range, other medical active agent is also used in the amount ranges of its approval.

A kind of medicinal product is provided according to an aspect of the present invention, and this product comprises the quinazoline derivant of formula I of aforementioned definitions and other antitumour drug that is used for the aforementioned definitions of cancer combination therapy.

Although formula I compound mainly is the medicine as warm-blooded animal (comprising the people), when needing, they also can be used to suppress the effect of erbB receptor tyrosine protein kinase.Therefore, these compounds can also be as new biological test exploitation and the medicinal standard product in the new pharmacology drug research.

Now the present invention is further specified by following non-limiting example, wherein, unless otherwise indicated, otherwise:

(i) temperature be degree centigrade (℃); All operations promptly carries out in 18-25 ℃ temperature range all in room temperature or envrionment temperature;

(ii) organic solvent is through anhydrous magnesium sulfate drying; Adopt rotatory evaporator, at decompression (600-4000 handkerchief; 4.5-30mmHg) under, be not higher than the evaporation of carrying out solvent under 60 ℃ the bath temperature;

(iii) chromatography refers to flash chromatography on silica gel; Thin-layer chromatography (TLC) carries out on silica-gel plate;

(iv) carry out TLC and/or analytical LCMS after the reaction process usually, the reaction times that provides only supplies the usefulness of explanation;

(v) end product all has gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;

(vi) the productive rate of being given for the usefulness of explanation, might not be by conscientiously studying the yield that flow process obtains only; More if desired product can repeat preparation;

(vii) when providing the NMR data, unless otherwise indicated, the NMR data provide with the δ value form of main diagnosis proton, with respect to ppm (ppm) expression as the tetramethylsilane (TMS) of internal standard substance, adopt full deuterated dimethyl sulfoxide (DMSO-d ₆) be solvent, under 300MHz, measure; Adopt following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multimodal; B, broad peak;

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

(ix) the solvent ratio that provides is a volume: volume (v/v); With

(x) mass spectrum (MS) adopts 70 electron-volts of electron energies under chemi-ionization (CI) mode, uses the direct probe that exposes and detects, and ionization is undertaken by electron spray(ES); Provide the m/z value; The proton of report expression parent quality only; Unless otherwise indicated, mass ion is expressed as (MH) ⁺

(xi) unless otherwise indicated, contain the compound of the carbon of asymmetric replacement and/or sulphur atom without fractionation;

(vii) when describing described in a certain synthetic and previous embodiment when similar, the mmole ratio of institute's usage quantity is equal to the ratio that uses among the described previous embodiment;

(xvi) adopt following abbreviation:

The DCM methylene dichloride;

DMF N, dinethylformamide;

The DMA N,N-dimethylacetamide;

The THF tetrahydrofuran (THF);

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



(xvii) one synthetic when obtaining acid salt (as HCl salt) when describing, do not confirm the concrete stoichiometry of this salt;

(xviii) unless otherwise indicated, in embodiment 1-15 and reference example, all NMR data of report are free base material, and it is converted into the form of free alkali by isolating salt before evaluation.

Embodiment 1

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methylpyrrolidin-3-yl) oxygen base] quinazoline

To 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (reference example 2; 639mg, add in DCM 2.0mmol) (30ml) suspension 1-methyl-3-pyrrolidinol (658 μ l, 6.0mmol) and triphenyl phosphine (1572mg, 6.0mmol).Under nitrogen atmosphere, this suspension is cooled under 0 ℃.With 15 minutes, drip tert-butyl azodicarboxylate (1380mg, 6mmol) solution in DCM (20ml).The light brown solution that obtains is warming up to room temperature, and stirring is spent the night.Evaporate this solution, residue is through chromatography purification, with the DCM eluant solution of 0-5% methyl alcohol.The each several part that merge to be fit to, evaporation is dissolved in crude product (230mg) in 1: 1 methyl alcohol/DCM (5ml) again.(1M 1.14ml), evaporates this mixture to add etherificate HCl.Crystallization from methanol obtains the title product into hydrochloride, is white crystalline solid form (154mg, 16%);

¹H NMR (hydrochloride):

2.30(m，1H)，2.65-2.75(m，1H)，2.88(s，3H)，3.30-3.80(m，3H)，3.85-4.05(m，1H)，4.00(s，3H)，5.46(m，1H)，7.35(dd，1H)，7.45(s，1H)，7.51(dd，1H)，7.62(dd，1H)，8.53(s，1H)，8.72(s，1H)，8.81(s，1H)；

Mass spectrum: 403.3,405.3.

Embodiment 2

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) oxygen base] quinazoline

With the 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 3; 350mg 0.70mmol) is dissolved in the trifluoroacetic acid (5ml), and this solution was placed 2 hours.Evaporate excessive trifluoroacetic acid, with residue and DCM azeotropic 2 times.Residue is through chromatography purification, with 0-4% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Evaporate the each several part that is fit to, obtain the product (270mg, 96%) of pale solid;

¹H NMR：1.53-1.64(m，2H)，2.00-2.05(m，2H)，2.64-2.72(m，2H)，3.00-3.07(m，2H)，3.92(s，3H)，4.60(m，1H)，7.20(s，1H)，7.26(ddd，1H)，7.47(dd，1H)，7.50(dd，1H)，7.82(s，1H)，8.34(s，1H)，9.56(s，1H)；

Mass spectrum: 403.2,405.2.

Embodiment 3

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] quinazoline

Adopt the 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 4) repeats the step described in the embodiment 2.Obtain yield and be 91% title compound;

¹H NMR：1.45-1.61(m，2H)，1.95-2.00(m，2H)，2.18(m，1H)，2.92(m，2H).3.25-3.35(m，2H)，3.93(s，3H)，4.03(d，2H)，7.20(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.89(s，1H)，8.36(s，1H)，8.72(br.s，1H)，9.74(s，1H)；

Mass spectrum: 417.4,419.

Embodiment 4

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methyl piperidine-4-yl) oxygen base] quinazoline

With the 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 3; 300mg 0.66mmol) is dissolved in the formic acid (10ml).Add formalin (40%, 1ml), with mixture heating up to 90 ℃ 3 hours.Evaporate this mixture, in residue water-soluble (30ml).By adding sodium hydroxide solution (1M) this solution is adjusted to pH 8-9, produces white precipitate; Filter and collect, water (20ml) washing.Crude product is through chromatography purification, with 0-2.5% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.The each several part that evaporation is fit to is used residue the acetonitrile crystallization then, obtains the title product (55mg, 20%) of white crystalline solid;

¹H NMR：1.66-1.76(m，2H)，1.95-2.05(m，2H)，2.14-2.22(m，2H)，2.18(s，3H)，2.65-2.70(m，2H)，3.92(s，3H)，4.51(m，1H)，7.19(s，1H)，7.26(dd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.78(s，1H)，8.34(s，1H)，9.53(s，1H)；

Mass spectrum: 417.2,419.3.

Embodiment 5

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methyl piperidine-4-yl) methoxyl group] quinazoline

Adopt the 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 4) repeats the step described in the embodiment 4.After the methyl tertiary butyl ether crystallization, obtain yield and be 42% title compound;

¹H NMR：1.28-1.42(m，2H)，1.79-1.95(m，5H)，2.17(s，3H)，2.80(m，2H)，3.95(s.3H)，3.98(d，2H)，7.20(s，1H)，7.28(dd，1H)，7.48(dd，1H)，7.52(dd，1H)，7.77(s，1H)，8.37(s，1H)，9.59(s，1H)；

Mass spectrum: 431.1,430.0.

Embodiment 6

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[2-(1-methyl piperidine-4-yl) oxyethyl group] quinazoline

Adopt 6-{[2-(1-tert-butoxycarbonyl) piperidin-4-yl] oxyethyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 5) repeats the step described in the embodiment 4.After the methyl tertiary butyl ether crystallization, obtain yield and be 60% title compound;

¹H NMR：1.17-1.30(m，2H)，1.43(m，1H)，1.65-1.85(m，6H)，2.11(s，3H)，2.73(m，2H)，3.92(s，3H)，4.14(t，2H)，7.18(s，1H)，7.26(ddd，1H)，7.46(dd，1H)，7.51(dd，1H)，7.76(s，1H)，8.35(s，1H)，9.53(s，1H)；

Mass spectrum: 445.5,447.

Embodiment 7

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(2-methoxy ethyl) piperidin-4-yl] the oxygen base } quinazoline

With the 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (reference example 3; 485mg 1.07mmol) is dissolved in the trifluoroacetic acid (10ml), under the room temperature with this solution stirring 2 hours.Evaporate excessive trifluoroacetic acid, with residue and DCM azeotropic 2 times.Residue is dissolved among the DMA (25ml); Add salt of wormwood (887mg, 6.42mmol) and 1-bromo-2-methyl ethyl ether (100 μ l, 1.07mmol).Under the room temperature, mixture was stirred 16 hours.(444mg, 3.21mmol) (100 μ l 1.07mmol), heat mixture 4 hours in 60 ℃ with 1-bromo-2-methyl ethyl ether to add salt of wormwood again.Evaporating solvent distributes residue between DCM (50ml) and water (50ml).(2 * 30ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the filter paper filtering that the DCM part that merges is crossed by silicone-treated, evaporation.Residue is through chromatography purification, with 0-2% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.The each several part that evaporation is fit to is used residue the acetonitrile crystallization then, obtains the title product (153mg, 38%) of white crystalline solid;

¹H NMR：1.60-1.75(m，2H)，1.95-2.05(m，2H)，2.30(m，2H)，2.49(t，2H)，2.75-2.82(m，2H)，3.22(s，3H)，3.43(t，2H)，3.92(s，3H)，4.51(m，1H)，7.19(s，1H)，7.26(ddd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.78(s，1H)，834(s，1H)，9.53(s，1H)；

Mass spectrum: 461.2,463.2.

Embodiment 8

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(2-methoxy ethyl) piperidin-4-yl] methoxyl group } quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] (embodiment 3, and 104mg 0.25mmol) is dissolved among the DMA (5ml) for quinazoline.Add salt of wormwood (138mg, 1.00mmol) and 1-bromo-2-methyl ethyl ether (24 μ l, 0.25mmol).Under 60 ℃, mixture was stirred 4 hours.(138mg, 1.00mmol) (24 μ l 0.25mmol), continue to heat 4 hours down at 60 ℃ again with 1-bromo-2-methyl ethyl ether to add salt of wormwood again.Evaporating solvent distributes residue between DCM (20ml) and water (20ml).(2 * 10ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the filter paper filtering that the DCM part that merges is crossed by silicone-treated, evaporation.Residue is through chromatography purification, with 0-2.5% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.The each several part that merge to be fit to, evaporation is dissolved in crude product (40mg) in 1: 1 methyl alcohol/DCM (5ml) again.(1M 0.5ml), evaporates mixture to add ether system HCl.Crystallization from Virahol/ether obtains the title product into hydrochloride, is yellow solid (28mg, 20%); ¹H NMR (hydrochloride):

1.60-1.75(m，2H)，2.00-2.05(m，2H)，2.16(m，1H)，2.95-3.10(m，2H)，3.22(t，2H)，3.29(s，3H)，3.50-3.57(m，2H)，3.70(t，2H)，3.99(s，3H)，4.12(d，2H)，7.34(dd，1H)，7.39(s，1H)，7.51(dd，1H)，7.61(dd，1H)，8.46(s，1H)，8.78(s，1H)，10.08(br.s，1H)；

Mass spectrum: 475.5,477.

Embodiment 9

4-(3-chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl) piperidin-4-yl] the oxygen base }-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base] quinazoline (embodiment 2, and 1360mg 3.38mmol) is dissolved among the DMA (40ml), and the adding diisopropylethylamine (882 μ l, 5.07mmol).Add methylsulfonyl chloride (392 μ l, 5.07mmol), at room temperature, with this solution stirring 16 hours.Evaporating solvent, residue are through chromatography purification, with 0-2% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge the each several part that is fit to, evaporation with residue ethyl acetate/hexane crystallization, obtains the product (650mg, 40%) into white crystalline solid;

¹H NMR：1.80-1.90(m，2H)，2.04-2.13(m，2H)，2.91(s，3H)，3.10-3.20(m，2H)，3.34-3.44(m，2H)，3.93(s，3H)，4.67(m，1H)，7.22(s，1H)，7.27(dd，1H)，7.47(dd，1H)，7.51(dd，1H)，7.86(s，1H)，8.37(s，1H)，9.55(s，1H)；

Mass spectrum: 481.2,483.1.

Embodiment 10

4-(3-chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl) piperidin-4-yl] methoxyl group }-7-methoxyl group quinazoline

Adopt 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] quinazoline (embodiment 3) repeats the step described in the embodiment 9.After grinding with ether, obtain yield and be 71% following compound;

¹H NMR：1.31-1.47(m，2H)，1.90-2.07(m，3H)，2.76(m，2H)，2.85(s，3H)，3.56-3.67(m，2H)，3.93(s，3H)，4.01(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.78(s，1H)，8.36(s，1H)，9.61，(s，1H)；

Mass spectrum: 495.4,497.4.

Embodiment 11

6-{[1-(carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base] quinazoline (embodiment 2, and 70mg 0.17mmol) is dissolved among the DMA (10ml), and the adding diisopropylethylamine (45 μ l, 0.26mmol).Add the 2-bromoacetamide (36mg, 0.26mmo1), at room temperature, with this solution stirring 16 hours.Evaporating solvent, residue are through chromatography purification, with 0-3% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge the each several part that is fit to, evaporation with residue acetonitrile crystallization, obtains the product (48mg, 60%) into white crystalline solid;

¹HNMR：1.70-1.84(m，2H)，1.98-2.09(m，2H)，2.38(m，2H)，2.70-2.80(m，2H)，2.89(s，2H)，3.92(s，3H)，4.54(m，1H)，7.08(br.s，2H)，7.20(s，1H)，7.26(ddd，1H)，7.47(ddd，1H)，7.51(ddd，1H)，7.80(s，1H)，8.35(s，1H)，9.53(s，1H)；

Mass spectrum: 460.5,462.4.

Embodiment 12

6-{[1-(carbamyl ylmethyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Adopt 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] quinazoline (embodiment 3) repeats the step described in the embodiment 11.After the acetonitrile crystallization, obtain yield and be 44% title compound;

¹H NMR：1.34-1.50(m，2H)，1.37-1.90(m，3H)，2.05-2.20(m，2H)，2.80-2.95(m，2H)，3.93(s，3H)，3.97(d，2H)，7.04-7.16(m，2H)，7.19(s，1H)，7.26(ddd，1H)，7.46(ddd，1H)，7.50(ddd，1H)，7.76(s，1H)，8.35(s，1H)，9.58(s，1H)；

Mass spectrum: 474.4,476.4.

Embodiment 13

4-(3-chloro-2-fluoroanilino)-6-{[1-(cyano methyl) piperidin-4-yl] the oxygen base }-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base] (embodiment 2, and 70mg 0.17mmol) is dissolved among the DMA (5ml) for quinazoline.Add salt of wormwood (96mg, 0.70mmol) and chloromethyl cyanide (17 μ l, 0.25mmol).Under 60 ℃, mixture was stirred 4 hours.Evaporating solvent distributes residue between DCM (20ml) and water (20ml).(2 * 10ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the filter paper filtering that the DCM part that merges is crossed by silicone-treated, evaporation.Residue is through chromatography purification, with 0-2% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge the each several part that is fit to, evaporation is ground residue with ether, obtain the product (28mg, 36%) into white solid;

¹H NMR：1.67-1.80(m，2H)，2.03-2.13(m，2H)，2.46(m，2H)，2.77-2.85(m，2H)，3.76(s，2H)，3.92(s，3H)，4.55(m，1H)，7.20(s，1H)，7.27(dd，1H)，7.47(dd，1H)，7.52(dd，1H)，7.80(s，1H)，8.35(s，1H)，9.54(s，1H)；

Mass spectrum: 442.4,444.4.

Embodiment 14

4-(3-chloro-2-fluoroanilino)-6-{[1-(cyano methyl) piperidin-4-yl] methoxyl group }-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] (embodiment 3, and 104mg 0.25mmol) is dissolved among the DMA (5ml) for quinazoline.Add salt of wormwood (138mg, 1.00mmol) and chloromethyl cyanide (17 μ l, 0.25mmol).Under 60 ℃, mixture was stirred 4 hours.Add again salt of wormwood (138mg, 1.00mmol) and chloromethyl cyanide (17 μ l 0.25mmol), continue 60 ℃ of down heating 4 hours again.Evaporating solvent distributes residue between DCM (20ml) and water (20ml).(2 * 10ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the filter paper filtering that the DCM part that merges is crossed by silicone-treated, evaporation.Residue is through chromatography purification, with 0-2% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge the each several part that is fit to, evaporation is used the reversed-phase HPLC purifying with residue, again with the aqueous solution wash-out that contains 0.2% trifluoroacetic acid of 5-95% acetonitrile.Merge the each several part that is fit to; From this solution, evaporate acetonitrile, the aqueous solution that obtains is adjusted to pH8 with strong aqua.The suspension that obtains is extracted 2 times with DCM, and united extraction liquid is by the filter paper filtering that silicone-treated is crossed, evaporation.Residue is ground with ether, obtain product (10mg, 9%) into white solid;

¹HNMR：1.32-1.46(m，2H)，1.75-1.92(m，3H)，2.20(m，2H)，2.84(m，2H)，3.72(s，2H)，3.93(s，3H)，3.98(d，2H)，7.20(s，1H)，7.26(dd，1H)，7.47(dd，1H)，7.50(dd，1H)，7.76(s，1H)，8.36(s，1H)，9.59(s，1H)；

Mass spectrum: 456.4,458.4.

Embodiment 15

4-(3-chloro-2-fluoroanilino)-6-[(1-cyano group piperidin-4-yl) methoxyl group]-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) methoxyl group] quinazoline (embodiment 3, and 104mg 0.25mmol) is dissolved among the DCM (10ml), and the adding diisopropylethylamine (48 μ l, 0.28mmol).Add cyanogen bromide solution (the DCM solution of 3M, 92 μ l, 0.28mmol), at room temperature, with this solution stirring 16 hours.Evaporating solvent, residue are through chromatography purification, with 0-2% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge the each several part that is fit to, evaporation is ground residue with ether, obtain the product (75mg, 68%) into white solid;

¹H NMR：1.34-1.50(m，2H)，1.80-1.90(m，2H)，2.02(m，1H)，3.10(m，2H)，3.37-3.46(m，2H)，3.93(s，3H)，3.99(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.77(s，1H)，8.36(s，1H)，9.57(s，1H)；

Mass spectrum: 442.4,444.4.

Embodiment 16

6-(1-ethanoyl piperidin-4-yl oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Acetyl Chloride 98Min. (179mg) is joined in the dichloromethane solution of 6-(piperidin-4-yl oxygen base)-4-(3-chloro-2-the fluoroanilino)-7-methoxyl group quinazoline dihydrochloride (1g) that is cooled to 0 ℃ and diisopropylethylamine (735mg), mixture was stirred 2 hours, be warmed to room temperature then.This reaction mixture is absorbed to silica gel, and residue is through column chromatography purification, methylene chloride mixed solution (100/0-90/10) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is colourless foam shape thing (0.655g). ¹H NMR spectrum:

(DMSO d ₆)1.54-1.78(m，2H)，1.91-2.10(m，5H)，3.29-3.41(m，2H)，3.66-3.76(m，1H)，3.78-3.88(m，1H)，3.93(s，3H)，4.74(m，1H)，7.20(s，1H)，7.27(t，1H)，7.44-7.55(m，2H)，7.87(s，1H)， 8.36(s，1H)，9.54(s，1H)；

Mass spectrum: (M+H) ⁺445.

Raw material 6-(piperidin-4-yl oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline dihydrochloride is prepared as follows:

With 6-acetoxyl group-4-chloro-7-methoxyl group quinazoline (embodiment 25-5 among the WO 01/66099; 10.0g 39.6mmol) gradation is added in the 7N methyl alcohol system ammonia solution (220ml) that has been cooled to 10 ℃ in ice/water-bath.Stir after 1 hour, filtering-depositing, with the ether washing, finish-drying under the high vacuum obtains 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (5.65g, 67.8%); ¹H NMR spectrum:

(DMSO d ₆)3.96(s，3H)；7.25(s，1H)；7.31(s，1H)；8.68(s，1H)；

Mass spectrum: (M+H) ⁺211.

Under nitrogen atmosphere, 5 ℃, the dichloromethane solution (20ml) of tert-butyl azodicarboxylate (9.22g) is slowly joined in methylene dichloride (100ml) solution of 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (5.63g), 4-hydroxyl-1-tert-butoxycarbonyl piperidines (8.06g) and triphenyl phosphine (10.5g) of stirring.Reaction mixture was warmed to room temperature 16 hours.With reaction mixture vacuum-evaporation, absorb to silica gel then, with product with isohexane/ethyl acetate/triethylamine (75/24/1, subsequently 70/29/1) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains 4-[(4-chloro-7-methoxyl group quinazoline-6-yl) the oxygen base] piperidines-1-formic acid tertiary butyl ester, be white solid (10.3g); ¹HNMR spectrum:

(DMSO d ₆)1.40(s，9H)，1.56-1.69(m，2H)，1.93-2.04(m，2H)，3.20-3.31(m，2H)，3.60-3.70(m，2H)，4.00(s，3H)，4.89(m，1H)，7.45(s，1H)，7.50(s，1H)，8.86(s，1H)；

Mass spectrum: (M+H) ⁺394.

The dioxane solution (4.0ml) of 4.0M HCl is joined 4-[(4-chloro-7-methoxyl group quinazoline-6-yl) the oxygen base] in Virahol (50ml) solution of piperidines-1-formic acid tertiary butyl ester (2.62g) and 3-chloro-2-fluoroaniline (1.08g).Reaction mixture stirred and is heated to 100 ℃ 2 hours.With the yellow mercury oxide heat filtering, to wash in turn with Virahol and ether, vacuum-drying obtains 6-(piperidin-4-yl oxygen base)-4-(3-chloro-2-the fluoroanilino)-7-methoxyl group quinazoline (2.38g) into dihydrochloride; ¹HNMR spectrum:

(DMSO d ₆)1.84-1.999m，2H)，2.22-2.33(m，2H)，3.12-3.33(m，4H)，4.00(s，3H)，5.08(m，1H)，7.34(t，1H)，7.40(s，1H)，7.50(t，1H)，7.62(t，1H)，8.80(s，1H)，8.84-8.94(m，2H)，8.99-9.11（m，1H)；

Mass spectrum: (M+H) ⁺403.

Embodiment 17

4-(3-chloro-2-fluoroanilino)-6-[1-(N, N-dimethylamino ethanoyl) piperidin-4-yl oxygen base]-7-methoxyl group quinazoline

Under the room temperature, with 4-(3-chloro-2-fluoroanilino)-6-[1-(chloracetyl) piperidin-4-yl oxygen base]-7-methoxyl group quinazoline (0.14g) and sodium iodide (0.1g) stirred 2 hours at the ethanolic soln (33%) of the dimethylamine suspension in (10ml).With this mixed solution vacuum-evaporation, residue is dissolved in the methylene dichloride, through purification by silica gel column chromatography, the methylene chloride mixed solution that increases gradually with polarity (saturated with ammonia) is wash-out (100/0-85/15).Merge the each several part that contains title product, vacuum-evaporation is ground residue with ether, filters and obtains title product, is crystalline solid (0.085g); ¹HNMR spectrum:

(DMSO d ₆)1.56-1.78(m，2H)，1.92-2.08(m，2H0，2.20(s，6H)，3.05-3.18(m，2H)，3.30-3.48(m，2H)，3.79-3.90(m，2H)，3.94(s，3H)，4.75(m，1H)，7.21(s，1H)，7.28(t，1H)，7.44 7.56(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

Mass spectrum: (M+H) ⁺488.

Raw material 4-(3-chloro-2-fluoroanilino)-6-[1-(chloracetyl) piperidin-4-yl oxygen base]-7-methoxyl group quinazoline is prepared as follows:

Chloro-acetyl chloride (135mg) is joined in methylene dichloride (15ml) solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-4-yl oxygen the base)-7-methoxyl group quinazoline dihydrochloride (500mg) (raw material of embodiment 16) that is cooled to 0 ℃ and diisopropylethylamine (368mg), mixture was stirred 2 hours, be warmed to room temperature then.Reaction mixture is absorbed to silica gel, through the purification by silica gel column chromatography resistates, methylene chloride mixed solution (100/0-94/6) wash-out that increases gradually with polarity.Merge the each several part contain required product, again through the purification by silica gel column chromatography residue, methylene chloride mixed solution (100/0-96/4) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-[1-(chloracetyl) piperidin-4-yl oxygen base]-7-methoxyl group quinazoline, be crystalline solid (0.33g). ¹H NMR spectrum:

(DMSO d ₆)1.60-1.83(m，2H)，1.94-2.10(m，2H)，3.36-3.46(m，2H)，3.67-3.86(m，2H)，3.94(s，3H)，4.40(s，2H)，4.77(m，1H)，7.22(s，1H)，7.27(t，1H)，7.46-7.55(m，2H)，7.89(s，1H)，8.38(s，1H)，9.60(s，1H)；

Mass spectrum: (M+H) ⁺479.

Embodiment 18

6-[1-(N, N-dimethylamino alkylsulfonyl) piperidin-4-yl oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Dimethyl methyl acyl chlorides (90mg) is joined in methylene dichloride (10ml) solution of 6-(piperidin-4-yl oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline dihydrochloride (250mg) (embodiment 16 raw materials) and diisopropylethylamine (184mg).Under the room temperature, reaction mixture was stirred 16 hours.Reaction mixture is absorbed in the silica gel, and this residue is through purification by silica gel column chromatography, methylene chloride (100/0-95/5) the mixture wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation is ground residue with ether, obtain title product, is white solid (0.23g); ¹H NMR spectrum:

(DMSO d ₆)1.72-1.86(m，2H)，2.00-2.12(m，2H)，2.76(s，6H)；3.12-3.23(m，2H)，3.40-3.51(m，2H)，3.94(s，3H)，4.68(m，1H)，7.19-7.30(m，2H)，7.43-7.54(m，2H)，7.85(s，1H)，8.37(s，1H)，9.52(s，1H)；

Mass spectrum. (M+H) ⁺510.

Embodiment 19

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(morpholino ethanoyl) piperidin-4-yl oxygen base] quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[1-(chloracetyl) piperidin-4-yl oxygen base]-morpholine (5ml) the suspension room temperature of 7-methoxyl group quinazoline (0.15g) (among the embodiment 17 use raw material) and sodium iodide (0.02g) under stirring 16 hours.With this mixed solution vacuum-evaporation, residue is dissolved in the methylene chloride.Then it is absorbed to silica gel, through purification by silica gel column chromatography, methylene chloride mixed solution (100/0-90/10) wash-out that increases gradually with polarity.Merge the each several part that contains title product, vacuum-evaporation.Residue is ground with ether, filter, vacuum-drying obtains title product, is beige crystals solid (0.105g); ¹H NMR spectrum: (DMSO-d6 and

CD ₃COOD)1.57-1.80(m，2H)，1.91-2.12(m，2H)，2.40-2.51(m，4H)，3.14-3.48(m，4H)，3.52-3.61(m，4H)，3.81-3.90(m，2H)，3.94(s，3H)，4.76(m，1H)，7.20-7.30(m， 2H)，7.42-7.54(m，2H)，7.85(s，1H)，8.36(s，1H)；

Mass spectrum: (M+H) ⁺530.

Embodiment 20

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(tetramethyleneimine-1-base ethanoyl) piperidin-4-yl oxygen base] quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[1-(chloracetyl) piperidin-4-yl oxygen base]-tetramethyleneimine (5ml) the suspension room temperature of 7-methoxyl group quinazoline (0.15g) (among the embodiment 17 use raw material) and sodium iodide (0.02g) under stirring 16 hours.With this mixed solution vacuum-evaporation, residue is dissolved in the methylene chloride.Then it is absorbed to silica gel, through column chromatography purification, methylene chloride mixed solution (100/0-92/8) wash-out that increases gradually with polarity.Merge the each several part that contains title product, vacuum-evaporation is ground residue with ether, filters, and vacuum-evaporation obtains title product, is white crystal solid (0.085g); ¹H NMR spectrum:

(DMSO d ₆)1.57-1.77(m，6H)，1.92-2.09(m，2H)，3.20-3.48(m，8H)，3.80-3.90(m，2H)，3.94(s，3H)，4.75(m，1H)，7.2-7.31(m，2H)，7.45-7.55(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

Mass spectrum: (M+H) ⁺514.

Embodiment 21

4-(3-chloro-2-fluoroanilino)-6-{1-[3-(dimethylamino) sulfonyl propyl base] piperidin-4-yl oxygen base }-7-methoxyl group quinazoline

Under the room temperature, with 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropyl alkylsulfonyl] piperidin-4-yl oxygen base }-7-methoxyl group quinazoline (0.15g) and sodium iodide (0.03g) stirred 16 hours at the ethanolic soln (33%) of the dimethylamine suspension in (15ml).This reaction mixture is absorbed to silica gel, and through purification by silica gel column chromatography, the methylene chloride mixed solution that increases gradually with polarity (saturated with ammonia) is wash-out (100/0-88/12).Merge the each several part that contains title product, vacuum-evaporation obtains title product (0.105g); ¹H NMR spectrum:

(DMSO d ₆)1.75-1.87(m，4H)，2.0-2.11(m，2H)，2.12(s，6H)，2.30(t，2H)，3.05-3.14(m，2H)，3.17-3.29(m，2H)，3.40-3.50(m，2H)，3.93(s，3H)，4.69(m，1H)，7.22(s，1H)，7.28(t，1H)，7.44-7.55(m，2H)，7.86(s，1H)，8.37(s，1H)，9.53(s，1H)；

Mass spectrum: (M+H) ⁺552.

Raw material 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropyl alkylsulfonyl] piperidin-4-yl oxygen base }-7-methoxyl group quinazoline is prepared as follows:

Under the room temperature, 3-chloropropyl SULPHURYL CHLORIDE (174mg) is joined 6-(piperidin-4-yl oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline dihydrochloride (190mg; The raw material of embodiment 16) and in methylene dichloride (5ml) solution of diisopropylethylamine (140mg), reaction mixture was stirred 16 hours.This reaction mixture is absorbed to silica gel, through the purification by silica gel column chromatography resistates, methylene chloride mixed solution (100/0-94/6) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropyl alkylsulfonyl] piperidin-4-yl oxygen base }-7-methoxyl group quinazoline, be brown jelly (0.15g). Matter Spectrum: (M+H) ⁺543.

Embodiment 22

4-(3-chloro-2-fluoroanilino)-6-[1-(methylsulfonyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline

Methylsulfonyl chloride (42mg) is joined in methylene dichloride (5ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline (134mg) and diisopropylethylamine (65mg).Under the room temperature, reaction mixture was stirred 16 hours.Reaction mixture is absorbed in the silica gel, and this residue is through column chromatography purification, methylene chloride (100/0-95/5) the mixture wash-out that increases gradually with polarity.Merge the each several part that contains title product, vacuum-evaporation is ground residue with ether, filters, and vacuum-drying obtains title product, is 3R and 3S mixture of isomers (0.10g); ¹H NMR spectrum: (DMSO d ₆And CD ₃COOD)

1.54-2.07(m，4H)，2.95(s，3H)，3.10-3.20(m，1H)，3.21-3.37(m，2H)，3.50-3.59(m，1H)，3.93(s，3H)，4.70(m，1H)，7.20-7.29(m，2H)，7.40-7.55(m，2H)，7.89(s，1H)，8.37(s，1H)；

Mass spectrum: (M+H) ⁺481.

Raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline is prepared as follows:

4-nitrobenzene sulfonyl chloride (4.4g) is joined in methylene dichloride (80ml) solution of the 3-hydroxy piperidine-1-formic acid tertiary butyl ester (4.0g) of stirring and pyridine (2.25ml), at room temperature, stirred 16 hours.Reaction mixture is poured in the saturated sodium bicarbonate solution.Separate organic layer, use the salt water washing, through dried over sodium sulfate.With this solution for vacuum evaporation, grind with ether, remove by filter unwanted solid.With this diethyl ether solution vacuum-evaporation, be dissolved in then in the methylene dichloride, through purification by silica gel column chromatography, with ethyl acetate/isohexane (20/80) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains the 3-[(4-nitrophenyl) alkylsulfonyl oxygen base] piperidines-1-formic acid tertiary butyl ester, be yellow crystal solid (6.77g); ¹H NMR spectrum:

(CDCl ₃)1.43(s，9H)，1.40-1.54(m，1H)，1.70-1.94(m，3H)，3.22-3.60(m，4H)，4.67(m，1H)，8.11(s，2H)，8.40(s，2H).

Dimethyl formamide (23ml) is joined 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline, 3-[(4-nitrophenyl) alkylsulfonyl oxygen base] in piperidines-1-formic acid tertiary butyl ester (1.93g) and the cesium fluoride (2.28g).Under room temperature, reaction mixture was stirred 4 then.With reaction mixture vacuum-evaporation, between methylene dichloride and water, distribute then.This solution is filtered to remove insoluble solid, with this dichloromethane solution water and saturated brine washing, with post-absorption to silica gel.Then through the purification by silica gel column chromatography product, methylene chloride mixed solution (100/0-94/6) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonyl piperidines-3-base oxygen base)-7-methoxyl group quinazoline, is yellow jelly (0.67g); Mass spectrum: (M+H) ⁺503.

Trifluoroacetic acid (5ml) is joined in methylene dichloride (15ml) solution of 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonyl piperidines-3-base oxygen base)-7-methoxyl group quinazoline (0.67g), under the room temperature, reaction mixture was stirred 1 hour.This reaction mixture of vacuum-evaporation is dissolved in residue in the methylene dichloride.With saturated sodium bicarbonate solution, water and salt water washing, through dried over mgso, evaporation obtains 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline (0.28g) with this dichloromethane solution; Mass spectrum: (M+H) ⁺403.

More than raw materials used 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline be prepared as follows:

With 6-acetoxyl group-4-chloro-7-methoxyl group quinazoline (embodiment 25-5 among the WO 01/66099; 10.0g, 39.6mmol) be suspended in the acetonitrile (400ml), add 3-chloro-2-fluoroaniline (6.05g, 41.6mmol) and hydrogenchloride (1 of 4.0M, 4-dioxane solution) (10.4ml, 41.6mmol).Reaction mixture was refluxed 1 hour, be cooled to room temperature then.With the sedimentation and filtration that obtains,, obtain white solid with acetonitrile and ether washing.This solid gradation is joined in the methanol solution (400ml) of 7N ammonia of stirring.This mixture was stirred 2 hours, and filtering-depositing washs in turn with acetonitrile and ether, and vacuum-drying obtains 4-(3-chloro-2-the fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (12.1g, 95%) of white solid; ¹H NMR spectrum:

(DMSOd ₆)3.95(s，3H)；7.18(s，1H)；7.20-7.25(m，1H)；7.39-7.44(m，1H)；7.47-7.52(m，1H)；7.65(s，1H)；8.31(s，1H)；9.45(br.s，1H)；

Mass spectrum: (M+H) ⁺320.

Embodiment 22.1

Split 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline and

4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline

Adopt following condition, by chirality HPLC, the racemic mixture (36mg) that embodiment 22 is obtained splits into 3R and 3S enantiomorph:

The chromatographic column 10 μ m Chiralpak AS (No.AS00CJ-of 20mm * 250mm)

IB004

Eluent isohexane/EtOH (80/20)

Post oven temperature, degree room temperature

Flow velocity 10ml/min

Detect wavelength 254nm

The ethanolic soln of sample concentration 0.9mg/ml

Elution time 110 minutes

The enantiomorph (10.1mg) of elder generation's wash-out; ¹H NMR spectrum:

(DMSO d ₆)1.60-1.80(m，1H)，1.80-1.95(m，1H)，1.95-2.08(m，1H)，2.08-2.22(m，1H)，3.08(s，3H)，3.20-3.45(m，1H)，3.45-3.50(m，2H)，3.70(dd，1H)，4.05(s，3H)，4.70-4.90(m，1H)，7.30-7.50(m，2H)，7.50-7.70(m，2H)，8.02(s，1H)，8.50 (s，1H)，9.50(s，1H)；

Mass spectrum: (M+H) ⁺481.

The enantiomorph of back wash-out (18.7mg); ¹H NMR spectrum:

(DMSO d ₆)1.60-1.80(m，1H)，1.80-1.95(m，1H)，1.95-2.08(m，1H)，2.08-2.22(m，1H)，3.08(s，3H)，3.20-3.45(m，1H)，3.45-3.50(m，2H)，3.70(dd，1H)，4.05(s，3H)，4.70-4.90(m，1H)，7.30-7.50(m，2H)，7.50-7.70(m，2H)，8.02(s，1H)，8.50(s，1H)，9.50(s，1H)；

Mass spectrum: (M+H) ⁺481.

Embodiment 23

6-(1-ethanoyl piperidines-3-base oxygen base)-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Acetyl Chloride 98Min. (27mg) is joined 4-(3-chloro-2-fluoroanilino)-6-(piperidines-3-base oxygen base)-7-methoxyl group quinazoline (raw material described in the embodiment 22; 134mg) and in methylene dichloride (5ml) solution of diisopropylethylamine (65mg), under the room temperature, reaction mixture was stirred 16 hours.Reaction mixture is absorbed to silica gel, through column chromatography purification, the mixed solution wash-out of the methylene chloride (100/0-95/5) that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, evaporation obtains title product (0.07g); ¹H NMR spectrum: (DMSO-d ₆， @373K)

(DMSO

1.52-1.62(m，1H)，1.80-1.94(m，2H)，2.00(s，3H)，2.06-2.15(m，1H)，3.43-3.64(m，3H)，3.82-4.04(m，4H)，4.58(m，1H)，7.20-7.29(m，2H)，7.42(t，1H)，7.59(t，1H)，7.93(s，1H)，8.40(s，1H)，9.30(s，1H)；

Mass spectrum: (M+H) ⁺445.

Embodiment 24

4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline

Trifluoroacetic acid (5ml) is joined 4-(3-chloro-2-fluoroanilino)-6-[(2S; 4S)-1-(tert-butoxycarbonyl)-2-(N; the N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-methylene dichloride (10ml) solution of 7-methoxyl group quinazoline (0.17g) in; under the room temperature, reaction mixture was stirred 2 hours.This reaction mixture of vacuum-evaporation is dissolved in residue in methyl alcohol (saturated with ammonia)/methylene dichloride, absorbs then in the silica gel, and through column chromatography purification, the methylene chloride that increases gradually with polarity (saturated with ammonia) is the mixture wash-out (100/0-85/15).Merge and to contain the each several part that requires product to some extent, vacuum-evaporation obtains the title product of colourless jelly, places crystallization (0.13g); ¹H NMR spectrum: (DMSO d ₆And CD ₃COOD)

1.85-1.96(m，1H)，2.84-2.95(m，4H)，3.00(s，3H)，3.24-3.32(m，1H)，3.40-3.48(m，1H)，3.95(s，3H)，4.31(m，1H)，5.21(m，1H)，7.20-7.30(m，2H)，7.47-7.55(m，2H)，7.76(s，1H)，8.37(s，1H)；

Mass spectrum: (M+H) ⁺460.

Raw material 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-1-(tert-butoxycarbonyl)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline is prepared as follows:

With 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (2.48g) joins in methylene dichloride (100ml) suspension of N-tert-butoxycarbonyl-L-oxyproline (2.0g), 4-(dimethylamino) pyridine (5.28g) and dimethylamine hydrochloride (1.4g) of stirring, under the room temperature, reaction mixture was stirred 16 hours.Reaction mixture is washed with citric acid (1.0M), saturated sodium bicarbonate and saturated brine, then through dried over mgso.With after product through purification by silica gel column chromatography, methylene chloride mixed solution (100/0-90/10) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation, obtain (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxyl-2-(N, N-formyl-dimethylamino) tetramethyleneimine, be colourless jelly (1.01g); ¹H NMR spectrum:

(DMSO d ₆)1.29-1.40(m，9H)，1.74-1.83(m，1H)，2.04-2.15(m，1H)，2.80-2.87(m，3H)，3.03(s，3H)，3.26(m，1H)，3.40(m，1H)，4.28(m，1H)，4.64(m，1H)，4.95(d，1H).

4-nitrobenzene sulfonyl chloride (0.895g) is joined (2S of stirring; 4R)-1-(tert-butoxycarbonyl)-4-hydroxyl-2-(N; the N-formyl-dimethylamino) in methylene dichloride (10ml) solution of tetramethyleneimine (0.993g) and pyridine (0.6g), under nitrogen atmosphere, 4 ℃, stirred 16 hours.Reaction mixture is washed with citric acid (1.0M), saturated sodium bicarbonate, through dried over mgso.Product is through purification by silica gel column chromatography then, methylene chloride mixed solution (100/0-95/5) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation, obtain (2S, 4R)-1-(tert-butoxycarbonyl)-2-(N, N-formyl-dimethylamino)-4-[(4-nitrophenyl) alkylsulfonyl oxygen base] tetramethyleneimine, be yellow jelly (0.685g); ¹H NMR spectrum:

(DMSO d ₆)1.30-1.36(s，9H)，1.98-2.07(m，1H)；2.37-2.48(m，1H)；2.83(s，3H)，3.00(s，3H)，3.45-3.55(m，2H)，4.70(m，1H)，5.23(m，1H)，8.21(d，2H)，8.47(d，2H).

Dimethyl formamide (8ml) is joined 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (0.489g; Described in the preparation of raw material among the embodiment 22, prepare), (2S, 4R)-1-(tert-butoxycarbonyl)-2-(N, N-formyl-dimethylamino)-4-[(4-nitrophenyl) alkylsulfonyl oxygen base] in tetramethyleneimine (0.678g) and the cesium fluoride (0.697g).Under room temperature, reaction mixture was stirred 16 hours then.With reaction mixture vacuum-evaporation, residue is dissolved in the methylene chloride, with post-absorption to silica gel.Then through the column chromatography purification product, methylene chloride mixed solution (100/0-90/10) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, evaporation.Residue is again through column chromatography purification, ethyl acetate/methanol (100/0-92/8) the mixed solution wash-out that increases gradually with polarity.Merge the each several part that contains required product, vacuum-evaporation.Obtain 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-1-(tert-butoxycarbonyl)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline, be colourless jelly, place crystallization (0.36g); ¹H NMR spectrum:

(DMSO d ₆@373K)1.41(s，9H)，1.99(m，1H)，2.92-3.03(m，7H)；3.44(m，1H)，3.96(s 3H)，4.14(m，1H)，4.70(t，1H)，5.10(m，1H)，7.22-7.30(m，2H)，7.44(t，1H)，7.62(t，1H)，7.84 (s，1H)，8.40(s，1H)，9.30(s，1H)；

Mass spectrum: (M+H) ⁺560.

Embodiment 25

4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4S)-1-(tert-butoxycarbonyl)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline (press described in the embodiment 24 and prepares; 0.18g), formic acid (0.31ml) and formaldehyde (0.51ml) is in 85 ℃ of heating 6 hours.With reactant cooling, vacuum-evaporation.The residue that obtains is distributed between methylene dichloride/n-propyl alcohol and saturated sodium bicarbonate.Organic layer through dried over mgso, is absorbed in the silica gel then, through column chromatography purification, methylene chloride (100/0-90/10) the mixture wash-out that increases gradually with polarity.Merge the each several part that contains required product, vacuum-evaporation obtains white crystalline solid.This solid is washed with water, be dissolved in the methylene dichloride, through dried over mgso.Solvent removed in vacuo obtains title product (0.11g); ¹H NMR spectrum:

(DMSO d ₆)1.87(t，1H)，2.24(s，3H)，2.61-2.68(m，1H)，2.83(s，3H)，2.85-2.94(m，1H)，3.10(s，3H)，3.22-3.31(m，2H)，3.92(s，3H)，5.04(m，1H)，7.22(s，1H)，7.29(t，1H)，7.45-7.56(m，2H)，7.64(s，1H)，8.35(s，1H)，9.56(s，1H)；

Mass spectrum: (M+H) ⁺474.

Embodiment 26

4-(3-chloro-2-fluoroanilino)-6-[1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline

With 6-[1-(chloracetyl) piperidines-3-base oxygen base]-(470mg 0.98mmol) with ethanol (20ml) solution-treated of 33% dimethylamine, stirred 3 hours under the room temperature 4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline.Vacuum evaporating solvent, residue are through column chromatography purification, with methylene chloride (9/1) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation.Residue is again through column chromatography purification, with methylene chloride (saturated with ammonia) (92/8) wash-out.Merge and contain the each several part that requires product to some extent, evaporation obtains title product (185mg, 39%); ¹H NMR spectrum:

(DMSO-d ₆，100℃)

1.40-1.65(m，1H)；1.75-1.95(m，2H)；2.00-2.30(m，7H)；3.05(dd，2H)；3.40-3.62(m，2H)；3.62-3.75(m，1H)；3.88(dd，1H)；3.95(s，3H)；4.45-4.65(m，1H)；7.15-7.30(m，2H)；7.30-7.47(m，1H)；7.50 7.7(m，1H)；7.88(s，1H)；8.40(s，1H)；9.25(s，1H)；

Mass spectrum: (M+H) ⁺488.

Raw material 6-[1-(chloracetyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline is prepared as follows:

Under the room temperature, with 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline (430mg, 1.07mmol) (described in the preparation of raw material among the embodiment 22, preparing), chloro-acetyl chloride (126mg, 1.12mmol) and N, (519mg 4.02mmol) stirred 2 hours in methylene dichloride (15ml) the N-diisopropylethylamine.Vacuum evaporating solvent, residue are through column chromatography purification, with methylene chloride (saturated with ammonia) (92/8) solvent elution.Solvent removed in vacuo obtains 6-[1-(chloracetyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline, be yellow jelly (470mg).This material does not need any being further purified and uses. Mass spectrum: (M+H) ⁺479.

Embodiment 26.1

Split 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline and

4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(N, N-dimethylamino ethanoyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline

Adopt following condition, by chirality HPLC, the racemic mixture (320mg) that embodiment 26 is obtained splits into 3R and 3S enantiomorph:

Chromatographic column Merck 50mm 20 μ m Chiralpak AS VCSP No.AS00SC-

JG001

Eluent isohexane/EtOH 80/20

Post oven temperature, degree room temperature

Flow velocity 40ml/min

Detect wavelength 254nm

EtOH/ acetonitrile (80/20) solution of sample concentration 10mg/ml

Elution time 110 minutes

The enantiomorph (103mg) of elder generation's wash-out; Mass spectrum: (M+H) ⁺488.

The enantiomorph of back wash-out (97mg); Mass spectrum: (M+H) ⁺488.

Embodiment 27

6-[1-(acetoxyl group ethanoyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (1.0g, 2.28mmol; According to described in the embodiment 45 preparation) methylene dichloride (30ml) suspension N, the N-diisopropylethylamine (1.21g, 9.33mmol) processing, at room temperature stirred 30 minutes.Under nitrogen atmosphere, the solution that obtains is cooled to 0 ℃, (354mg 2.60mmol), stirs down, and this mixture slowly is warmed to room temperature to add alpha-Acetoxyacetyl chloride.Vacuum evaporating solvent, residue are through column chromatography purification, with methylene chloride (saturated with ammonia) (98/2) solvent elution.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product (1.0g, 87%); ¹H NMR spectrum: (DMSO-d ₆, 100 ℃)

1.50-1.60(m，1H)，1.80-1.93(m，2H)，2.03(s，3H)；2.04-2.10(m，1H)；3.40-3.60(m，3H)；3.78-3.86(m，1H)；3.97(s，3H)；4.52-4.60(m，1H)；4.75(d，2H)；7.20-7.28(m，2H)；7.38-7.44(m，1H)；7.54-7.64(m，1H)；7.88(s，1H)；8.40(s，1H)；9.22(bs，1H)；

Mass spectrum: (M+H) ⁺503.

Embodiment 28

4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl) piperidines-3-base oxygen base]-7-methoxyl group quinazoline

With 6-[1-(acetoxyl group ethanoyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline (930mg; 1.85mmol) (according to described in the embodiment 27 preparation) and salt of wormwood (385mg, methyl alcohol 2.79mmol) (50ml) solution stirred under room temperature 3 hours.Vacuum evaporating solvent, residue are through column chromatography purification, with methylene chloride (saturated with ammonia) (92/8) wash-out.Merge and contain the each several part that requires product to some extent, evaporation.Residue is ground with acetone, filter, drying obtains title product (574mg, 67%); ¹H NMR spectrum: (DMSO-d ₆, 100 ℃)

1.50-1.60(m，1H)；1.80-1.92(m，2H)；2.04-2.13(m，1H)；3.44-3.56(m，3H)；3.77-3.88(m，1H)；3.97(s，3H)；4.10(d，2H)；4.50-4.60(m，1H)；7.20-7.27(m，2H)；7.38-7.42(m，1H)；7.55-7.60(m，1H)；7.88(s，1H)；8.38(s，1H)9.25(bs，1H)；

Mass spectrum: (M+H) ⁺461.

Embodiment 29

4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline

Under nitrogen atmosphere, with 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base]-(0.21g 0.49mmol) is dissolved in the mixed solution of methylene dichloride (4ml), pyridine (1ml) and diisopropylethylamine (0.17ml) 7-methoxyl group quinazoline hydrochloride.In the solution of this stirring, add methylsulfonyl chloride (0.06ml, 0.07mmol).Stir after 2 hours under the room temperature, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With organic layer salt water washing, through anhydrous Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, with methylene chloride (saturated with ammonia) (94/6) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation is ground residual jelly with ether, filters, and vacuum-drying obtains title product, is white solid (0.17g, 74%). ¹H NMR spectrum:

(DMSO d ₆)2.18-2.37(m，2H)；2.93(s，3H)；3.33-3.45(m，2H)；3.5(d，1H)；3.69(dd，1H)；3.92(s，3H)；5.17(m，1H)；7.15-7.35(m，2H)；7.40-7.60(m，2H)；7.5(m，2H)；7.80(s，1H)；8.37(s，1H)；9.6(s，1H)；

Mass spectrum: (M+H) ⁺467.

Raw material 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline hydrochloride is prepared as follows:

Adopt among the embodiment 22 and prepare the 3-[(4-nitrophenyl) sulfonyloxy] identical method described in piperidines-1-formic acid tertiary butyl ester, make (3S)-1-tert-butoxycarbonyl-3-hydroxyl pyrrolidine (3.75g, 20mmol) with the reaction of 4-nitrobenzene sulfonyl chloride, obtain (3S)-3-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1-formic acid tertiary butyl ester, be light brown crystalline solid (5.0g, 67%). ¹H NMR spectrum:

(CDCl ₃)1.44(s，9H)；2.05-2.2(m，2H)；3.37-3.59(m，4H)；5.16-5.23(m，1H)；8.12(d，2H)；8.41(d，2H).

4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (is prepared described in preparation raw materials used among the embodiment 22; 4.0g, 12.5mmol) with (3S)-the 3-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1-formic acid tertiary butyl ester (4.7g, 12.6mmol) and cesium fluoride (5.7g, 7.5mmol) mixing.Add anhydrous N then, dinethylformamide (60ml) under the room temperature, spends the night the mixture stirring.Mixture is diluted with ethyl acetate, filter.With filtrate water, 50% salt solution, wash in turn with salt solution then, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, with methylene chloride (saturated with ammonia) (98/2) wash-out.Merge and contain the each several part that requires product to some extent, evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-[(3R)-(1-tert-butoxycarbonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline, be dried foam shape thing (2.35g, 38%); ¹H NMR spectrum:

(DMSO d ₆)1.39(s，9H)；2.10-2.30(m，2H)；3.35-3.50(m，3H)；3.64-3.71(m，1H)；3.92(s，3H)；5.12(m，1H)；7.21(s，1H)；7.23-7.27(m，1H)；7.44-7.55(m，2H)；7.80(s，1H)；8.37(s，1H)；9.61(s，1H)；

Mass spectrum: (M+H) ⁺489.

Make 4-(3-chloro-2-fluoroanilino)-6-[(3R)-(1-tert-butoxycarbonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline (2.3g, 4.7mmol) be dissolved in the acetonitrile (35ml), adding hydrogenchloride (1 of 4.0M, 4-dioxane solution) (4.7ml, 18.8mmol).Mixture heating up was refluxed 1 hour.After being cooled to room temperature, cross filter solid, with acetonitrile and ether washing, vacuum-drying obtains 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base of white solid]-7-methoxyl group quinazoline hydrochloride (1.9g, 95%); ¹H NMR spectrum:

(DMSO d ₆)2.17-2.29(m，1H)；2.34-2.44(m，1H)；3.1-3.3(m，3H)；3.72-3.84(m，1H)；4.00(s，3H)；5.44(m，1H)；7.31-7.38(m，1H)；7.45(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.67(s，1H)；8.80(s，1H)；9.43(br.s 1H)；9.62(br.s，1H)；12.25(br.s，1H)；

Mass spectrum: (M-H) ^-387.

Embodiment 30

4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline

Adopt similar method described in the embodiment 29, make 4-(3-chloro-2-fluoroanilino)-6-[(3S)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline hydrochloride (210mg) and methylsulfonyl chloride reaction, obtain title product (100mg, 43%). ¹H NMR spectrum:

(DMSO d ₆)2.18-2.37(m，2H)；2.93(s，3H)；3.38-3.52(m，3H)；3.69(dd，1H)；3.92(s，3H)；5.17(m，1H)；7.15-7.35(m，2H)；7.40-7.60(m，2H)；7.80(s，1H)；8.38(s，1H)；9.58(s，1H)；

Mass spectrum: (M+H) ⁺467.

By the following stated, the described similar method of feedstock production prepares raw material 4-(3-chloro-2-fluoroanilino)-6-[(3S)-tetramethyleneimine-3-base oxygen base among the employing embodiment 29]-7-methoxyl group quinazoline hydrochloride:

With (R)-1-tert-butoxycarbonyl-3-hydroxyl pyrrolidine (3.75g 20mmol) is converted into (3R)-3-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1-formic acid tertiary butyl ester (2.21g, 59%). ¹HNMR spectrum:

(DMSO d ₆)1.44(s，9H)；2.05-2.25(m，2H)；3.37-3.59(m，4H)；5.20(s，1H)；8.11(d，2H)；8.41(d，2H).

Make 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline with (3R)-the 3-[(4-nitrophenyl) sulfonyloxy] reaction of tetramethyleneimine-1-formic acid tertiary butyl ester, obtain 4-(3-chloro-2-fluoroanilino)-6-[(3S)-(1-tert-butoxycarbonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline, be dried foam shape thing (2.9g, 95%); ¹H NMR spectrum:

(DMSO d ₆)1.40(s，9H)；2.07-2.29(m，2H)；3.32-3.50(m，3H)；3.64-3.70(dd，1H)；3.92(s，3H)；5.08-5.18(m，1H)；7.21(s，1H)；7.23-7.30(m，1H)；7.43-7.55(m，2H)；7.79(s，1H)；8.36(s，1H)；9.6(s，1H)；

Mass spectrum: (M+H) ⁺489.

Make 4-(3-chloro-2-fluoroanilino)-6-[(3S)-(1-tert-butoxycarbonyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline and hydrogenchloride (1 of 4.0M, the 4-dioxane solution) reaction, obtain 4-(3-chloro-2-fluoroanilino)-6-[(3S)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline hydrochloride (1.94g, 93%); ¹H NMR spectrum:

(DMSO d ₆)2.18-2.28(m，1H)；2.35-2.45(m，1H)；3.27-3.46(m，3H)；3.73-3.82(m，1H)；3.99(s，3H)；5.41-5.47(m，1H)；7.31-7.37(m，1H)；7.44(s，1H)；7.47-7.54(m，1H)；7.58-7.64(m，1H)；8.66(s，1H)；8.80(s，1H)；9.42(br，1H)；9.61(bs，1H)；12.24(br，1H)；

Mass spectrum: (M+H) ⁺389.

Embodiment 31

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt described in the embodiment 29 similarly method, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-tetramethyleneimine-2-yl] methoxyl group } quinazoline hydrochloride (300mg) and methylsulfonyl chloride reaction, obtain title product (200mg, 61%). ¹H NMR spectrum:

(DMSO d ₆)1.88-2.17(m，4H)；2.98(s，3H)；3.38(m，2H)；3.93(s，3H)；4.02(m，1H)；4.15(m，2H)；7.20(s，1H)；7.20-7.30(m，1H)；7.42-7.53(m，2H)；7.81(s，1H)；8.37(s.1H)；9.62(s，1H)；

Mass spectrum: (M+H) ⁺481.

Raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-tetramethyleneimine-2-yl] methoxyl group } the quinazoline hydrochloride is prepared as follows:

4-chloro-6-hydroxyl-7-methoxyl group quinazoline (is prepared described in the preparation of raw material among the embodiment 16; 2.75g, 13mmol) with triphenyl phosphine (5.13g, 19.6mmol) and (2S)-(3.94g 19.6mmol) mixes 1-(tert-butoxycarbonyl)-2-(hydroxymethyl) tetramethyleneimine.Add methylene dichloride (85ml), with mixture ice/water-bath cooling under nitrogen.(4.51g 19.6mmol) is dissolved in the methylene dichloride (35ml), keeps the speed less than 10 ℃ to drip with interior temperature then with azoformic acid di-t-butyl ester.After adding finishes, remove cryostat immediately, reaction mixture was stirred 3 hours.Solvent removed in vacuo, residue is through column chromatography purification, with dichloromethane/ethyl acetate (saturated) (70/30) wash-out, obtain 4-chloro-7-methoxyl group-6-{[(2S)-1-tert-butoxycarbonyl tetramethyleneimine-2-yl with ammonia] methoxyl group } quinazoline, be jelly (6.15g). Mass spectrum: (M+H) ⁺394.

To 4-chloro-7-methoxyl group-6-{[(2S)-1-tert-butoxycarbonyl tetramethyleneimine-2-yl] methoxyl group } in acetonitrile (120ml) solution of quinazoline, add 3-chloro-2-fluoroaniline (1.4ml, 12.7mmol) and hydrogenchloride (1 of 4.0M, 4-dioxane solution) (13ml, 52mmol).Mixture heating up was refluxed 1 hour.After being cooled to room temperature, leach precipitation, wash in turn with acetonitrile and ether, vacuum-drying obtains 4-(3-chloro-2-the fluoroanilino)-7-methoxyl group of yellow solid-6-{[(2S)-tetramethyleneimine-2-yl] methoxyl group } quinazoline hydrochloride (5.73g, 100%); ¹H NMR spectrum:

(DMSO d ₆)1.70-2.10(m，3H)；2.10-2.30(m，1H)；3.00-3.80(m，2H)；3.97-4.10(m，4H)；4.45-4.57(m，2H)；7.32-7.38(m，1H)；7.46(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.65(s，1H)；8.81(s，1H)；9.31(br，1H)；9.67(bs，1H)；12.09(bs，1H)；

Mass spectrum: (M+H) ⁺403.

Embodiment 32

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt described in the embodiment 29 similarly method, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2R)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (300mg) and methylsulfonyl chloride reaction, obtain title product (250mg, 76%). ¹H NMR spectrum:

(DMSO d ₆)1.88-2.12(m，4H)；2.99(s，3H)；3.30-3.34(m，2H)；3.94(s，3H)；4.02(m，1H)；4.15(m，2H)；7.15-7.30(m，2H)；7.40-7.55(m，2H)；7.81(s，1H)；8.36(s，1H)；9.62(s，1H)；

Mass spectrum: (M+H) ⁺481.

Adopt similar method described in the feedstock production among the embodiment 31, preparation raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2R)-and tetramethyleneimine-2-ylmethoxy] the quinazoline hydrochloride:

Make 4-chloro-7-methoxyl group-6-hydroxyl quinazoline (2.78g) with (2R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl) tetramethyleneimine (3.98g) reaction, obtain 4-chloro-7-methoxyl group-6-{[(2R)-1-(tert-butoxycarbonyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (5.0g, 100%). ¹H NMR spectrum:

(DMSO d ₆)1.37(s，9H)；1.66-1.88(m，2H)；1.90-2.07(m，2H)；3.15-3.24(m，1H)；3.41-3.49(m，1H)；4.00(s，3H)；4.10-4.25(m，3H)；7.44(d，2H)；8.85(s，1H)；

Mass spectrum: (M+H) ⁺394.

Make 4-chloro-7-methoxyl group-6-{[(2R)-1-(tert-butoxycarbonyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline and the reaction of 3-chloro-2-fluoroaniline, obtain 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-tetramethyleneimine-2-yl] methoxyl group } quinazoline hydrochloride (5.3g, 100%); ¹H NMR spectrum:

(DMSO d ₆)1.70-1.84(m，1H)；1.87-1.97(m，1H)；1.99-2.08(m，1H)；2.17-2.28(m，1H)；3.18-3.27(m，2H)；3.98-4.10(m，4H)；4.45-4.57(m，2H)；7.32-7.38(m，1H)；7.47(s，1H)；7.49-7.55(m，1H)；7.59-7.65(m，1H)；8.66(s，1H)；8.81(s，1H)；9.30(bs，1H)；9.67 (bs，1H)；12.09(bs，1H)；

Mass spectrum: (M-H) ^-401.

Embodiment 33

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(methylsulfonyl) tetramethyleneimine-3-yl] methoxyl group } quinazoline

Adopt similar method described in the embodiment 29, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(tetramethyleneimine-3-ylmethoxy) quinazoline hydrochloride (300mg) and methylsulfonyl chloride reaction, obtain title product (200mg, 67%). ¹H NMR spectrum:

(DMSO d ₆+CD3COOD)1.75-1.89(m，1H)；2.08-2.18(m，1H)；2.77-2.86(m，1H)；2.91(s，3H)；3.12-3.18(m，1H)；3.25-3.43(m，2H)；3.47-3.52(m，1H)；3.94(s，3H)；4.06-4.09(m，2H)；7.15-7.30(m，2H)；7.43-7.53(m，2H)：7.81(s，1H)；8.38(s，1H)；

Mass spectrum: (M+H) ⁺481.

Adopt the described similar method of feedstock production among the following embodiment 31, preparation raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(tetramethyleneimine-3-ylmethoxy) quinazoline hydrochloride:

Make 4-chloro-7-methoxyl group-6-hydroxyl quinazoline (2.5g) and 1-(tert-butoxycarbonyl)-3-(hydroxymethyl) tetramethyleneimine (3.58g) reaction, obtain 4-chloro-7-methoxyl group-6-{[1-(tert-butoxycarbonyl) tetramethyleneimine-3-yl] methoxyl group } quinazoline (5.36g, 100%). ¹H NMR spectrum:

(DMSO d ₆)1.39(s，9H)；1.45-1.79(m，2H)；1.97-2.08(m，1H)；2.65-2.74(m，1H)；2.91-3.17(m，2H)；3.40-3.52(m，1H)；4.01(s，3H)；4.15-4.22(m，2H)；7.42(s，1H)；7.45(s，1H)；8.86(s，1H)；

Mass spectrum: (M+H) ⁺394.

Make 4-chloro-7-methoxyl group-6-{[1-(tert-butoxycarbonyl) tetramethyleneimine-3-yl] methoxyl group } quinazoline (4.5g) and the reaction of 3-chloro-2-fluoroaniline, obtain 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(tetramethyleneimine-3-ylmethoxy) quinazoline hydrochloride (5.45g, 100%); ¹H NMR spectrum:

(DMSO d ₆)1.71-1.85(m，1H)；2.10-2.22(m，1H)；2.81-2.91(m，1H)；2.97-3.07(m，1H)；3.11-3.22(m，1H)；3.24-3.33(m，1H)；3.35-3.46(m，1H)；4.00(s，3H)；4.28-434(m，2H)；7.31-7.37(m，1H)；7.43(s，1H)；7.49-7.54(m，1H)；7.59-7.64(m，1H)；8.60(s，1H)；8.80(s，1H)；932(bs，2H)；12.05(bs，1H)；

Mass spectrum: (M-H) ^-401.

Embodiment 34

4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-methylpyrrolidin-3-base oxygen base]-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline hydrochloride (0.24g, 0.56mmol, described in embodiment 29-feedstock production, prepare) be dissolved in the formic acid (4ml), add formaldehyde (the 37%w/v aqueous solution) (2ml).With mixed solution be heated to 85 ℃ 1 hour, evaporate under the vacuum then, with methylbenzene azeotropic.Residue is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, with methylene chloride (saturated with ammonia) (94/6) wash-out.Merge and contain the each several part that requires product to some extent, evaporation is ground residue with dissident's alkane/ether, filter, and vacuum-drying obtains title product, is white solid (0.13g; 59%). ¹HNMR spectrum:

(DMSO d ₆)1.70-1.9(m，1H)；2.27(s，3H)；2.30-2.50(m，2H)；2.55-2.75(m，2H)；2.91-3.00(m，1H)；3.91(s，3H)；4.90-5.10(m，1H)；7.18(s，1H)；7.20-7.35(m，1H)；7.40-7.58(m，2H)；7.64(s，1H)；8.35(s，1H)；9.57(s，1H)；

Mass spectrum: (M-H) ^-401.

Embodiment 35

4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-methylpyrrolidin-3-base oxygen base]-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonyl tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline (0.30g) is dissolved in the formic acid (5ml), adds formaldehyde (the 37%w/v aqueous solution) (2.5ml).With mixed solution be heated to 85 ℃ 1 hour, evaporate under the vacuum then, with methanol azeotropic.Residue is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, and the methylene chloride (saturated with ammonia) that increases gradually with polarity is wash-out (100/0-94/6).Merge and contain the each several part that requires product to some extent, evaporation is ground residue with ether, filters, and vacuum-drying obtains title product, is white solid (0.133g; 35%). ¹H NMR spectrum:

(DMSO-d ₆)1.70-1.90(m，1H)，2.28(s，3H)，2.32-2.50(m，2H)，2.55-2.75(m，2H)，2.80-3.00(m，1H)，3.91(s，3H)，4.93-5.10(m，1H)，7.18(s，1H)，7.20-7.35(m，1H)，7.40-7.55(m，2H)，7.65(s，1H)，8.35(s，1H)，9.55(s，1H)；

Mass spectrum: (M+H) ⁺403.

Raw material 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonyl tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline is prepared as follows:

Methylene dichloride (50ml) solution of 4-nitrobenzene sulfonyl chloride (4.44g) is joined in methylene dichloride (30ml) solution of 10 ℃ of 3-(R)-hydroxyl-tetramethyleneimine-1-formic acid tertiary butyl ester (3.75g) that stir down and pyridine (2.5ml), stir down mixture is warmed to room temperature.Reaction mixture is poured in the saturated sodium bicarbonate solution.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Dry.Vacuum evaporated solution obtains 3-(R)-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1-formic acid tertiary butyl ester, is yellow crystal solid (4.37g; 59%). ¹H NMR spectrum:

(CDCl ₃)1.43(s，9H)，1.80-2.40(m，2H)，3.30-3.65(m，4H)，5.20(bs，1H)，8.10(d，2H)，8.42(d，2H).

Under the room temperature, with 4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline (2.0g; Described in the preparation of raw material among the embodiment 22, prepare), 3-(R)-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1-formic acid tertiary butyl ester (2.4g) and cesium fluoride (2.9g) mixture in dimethyl formamide (30ml) stirred 18 hours.With reaction mixture vacuum-evaporation, between methylene dichloride and water, distribute then.Filter this solution to remove insoluble solid,, absorb to silica gel then dichloromethane layer water and saturated brine washing.With after the purification by silica gel column chromatography product, the methylene chloride mixed solution (saturated with ammonia) that increases gradually with polarity is wash-out (100/0-96/4).Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonyl tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline, be yellow foam (2.9g, 95%); ¹H NMR spectrum:

(DMSO-d ₆)1.40(s，9H)，2.00-2.32(m，2H)，3.20-3.55(m，3H)，3.69(dd，1H)，3.92(s，3H)，5.00.5.20(m，1H)，7.20(s，1H)，7.20-7.32(m，1H)，7.40-7.57(m，2H)，7.80(s，1H)，8.37(s，1H)，9.60(s，1H)；

Mass spectrum: (M+H) ⁺489.

Embodiment 36

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline

Adopt and embodiment 34 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-tetramethyleneimine-2-yl] methoxyl group } quinazoline hydrochloride (300mg; Described in embodiment 31-feedstock production, prepare) react with formaldehyde (2.5ml), obtain title product (220mg, 77%); ¹H NMR spectrum:

(DMSOd ₆)1.57-1.76(m，3H)；1.96-2.08(m，1H)；2.24(q，1H)；2.42(s，3H)；2.71(m，1H)；2.97(m，1H)；3.92(s，3H)；3.95-4.09(m，2H)；7.19(s，1H)；7.20-7.30(m，1H)；7.42-7.54(m，2H)；7.81(s，1H)；8.36(s，1H)；9.56(s，1H)；

Mass spectrum: (M+H) ⁺417

Embodiment 37

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(crassitude)-3-yl] methoxyl group } quinazoline

Adopt and synthetic embodiment 34 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(tetramethyleneimine-3-ylmethoxy) quinazoline hydrochloride (250mg; Described in embodiment 33-feedstock production, prepare) react with formaldehyde (2.5ml), obtain title product (125mg, 52%); ¹HNMR spectrum:

(CDCl ₃)1.61-1.72(m，1H)；2.08-2.20(m，1H)；2.38(s，3H)；2.47(q，1H)；2.65(m，2H)；2.69-2.77(m，1H)；2.81-2.88(m，1H)；4.01(s，3H)；4.06-4.13(m，2H)；7.05-7.23(m，3H)；7.26(s，1H)；7.45(s，1H)；8.41-8.47(m，1H)；8.68(s，1H)；

Mass spectrum: (M+H) ⁺415.

Embodiment 38

4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-acetyl-pyrrolidine-3-base oxygen base]-7-methoxyl group quinazoline

Under nitrogen atmosphere, with 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline (0.22g, 0.51mmol; Described in embodiment 29-feedstock production, prepare) be dissolved in the mixed solution of methylene dichloride (4ml), pyridine (1ml) and diisopropylethylamine (0.17ml).(0.1ml 1.0mmol), stirs mixed solution 3 hours under the room temperature to add diacetyl oxide.Then mixed solution is distributed between saturated sodium bicarbonate aqueous solution and ethyl acetate.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, with methylene chloride (saturated with ammonia) (96/4) wash-out.Evaporation contains the each several part that requires product to some extent, grinds with ether.Cross filter solid, vacuum-drying obtains title product, is white solid (0.12g; 55%). ¹H NMR spectrum:

(DMSO d ₆)1.95-1.98(m，3H)；2.14-2.40(m，2H)；3.53-3.708(m，3H)；3.91(m，4H)；5.12-5.21(m，1H)；7.15-7.30(m，2H)；7.4-7.60(m，2H)；7.70-7.90(m，1H)；8.36-8.37(d，1H)；9.60-9.62(m，1H)；

Mass spectrum: (M+H) ⁺431.

Embodiment 39

6-{[(2S)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Adopt and embodiment 38 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (300mg; Press preparation described in the embodiment 31) and acetic anhydride, title product (280mg, 92%) obtained; ¹H NMR spectrum:

(DMSO d ₆)1.89-2.05(m，6H)；2.15(m，1H)；3.43-3.56(m,2H)；3.93(s，3H)；4.00-4.11(m，1H)；4.17-4.21(m，1H)；4.32-4.42(m，1H)；7.19-7.29(m，2H)；7.41-7.54(m，2H)；7.79-7.82(m，1H)；8.36-8.37(m，1H)；9.52-9.55(m，1H)；

Mass spectrum: (M+H) ⁺445.

Embodiment 40

6-{[(2R)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Adopt and embodiment 38 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2R)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (300mg; Described in embodiment 32-feedstock production, prepare) and acetic anhydride, title product (203mg, 66%) obtained; ¹HNMR spectrum:

(DMSO d ₆)1.89-2.05(m，6H)；2.11-2.21(m，1H)；3.43-3.56(m，2H)；3.94(s，3H)；4.00-4.11(m，1H)；4.17-4.21(m，1H)；4.30-4.37(m，1H)；7.19-7.29(m，2H)；7.42-7.53(m，2H)；7.79-7.82(m，1H)；8.37(s，1H)；9.54-9.57(m，1H)；

Mass spectrum: (M+H) ⁺445.

Embodiment 41

6-[(1-acetyl-pyrrolidine-3-yl) methoxyl group]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Adopt and embodiment 38 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(tetramethyleneimine-3-ylmethoxy) quinazoline hydrochloride (300mg; Described in embodiment 33-feedstock production, prepare) and acetic anhydride, title product (194mg, 63%) obtained; ¹H NMR spectrum:

(DMSO d ₆+CD3COOD)1.71-1.90(m，1H)；1.93-1.94(m，3H)；2.00-2.20(m，1H)；2.66-2.86(m，1H)；3.18-3.31(m，1H)；3.43-3.72(m，3H)；3.93(m，3H)；4.04-4.18(m，2H)；7.15-732(m，2H)；7.42-7.53(m，2H)；7.78-7.80(m，1H)；8.35-8.37(m，1H)；

Mass spectrum: (M+H) ⁺445.

Embodiment 42

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-1-(N, N-dimethylamino alkylsulfonyl) tetramethyleneimine-3-base oxygen base] quinazoline

Under nitrogen atmosphere, with 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-tetramethyleneimine-3-base oxygen base] quinazoline hydrochloride (0.21g, 0.49mmol; Described in embodiment 30-feedstock production, prepare) be dissolved in the mixed solution of methylene dichloride (4ml), pyridine (1ml) and diisopropylethylamine (0.17ml).Adding dimethyl methyl acyl chlorides in the solution of this stirring (0.08ml, 0.75mmol).After stirring is spent the night under the room temperature, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With organic layer salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, with methylene chloride (saturated with ammonia) (98/2) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation is ground residual jelly with ether, and evaporation obtains title product, is dried foam shape thing (0.13g; 53%). ¹HNMR spectrum:

(DMSO d ₆)2.16-2.21(m，1H)；2.25-2.38(m，1H)；2.76(s，6H)；3.41-3.50(m，3H)；3.71(dd，1H)；3.93(m，3H)；5.18(m，1H)；7.15-7.35(m，2H)；7.44-7.55(m，2H)；7.78(s，1H)；8.37(s，1H)；9.59(s，1H)；

Mass spectrum: (M+H) ⁺496.

Embodiment 43

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(morpholino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (0.45g; 0.94mmol) be dissolved in the morpholine (7.5ml); in the presence of potassiumiodide (10mg), at room temperature stir and spend the night then.Evaporating solvent, residue are through column chromatography purification, with methylene chloride (saturated with ammonia) (98/2) wash-out.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is foam (0.22g; 44%). ¹H NMR spectrum:

(CDCl3)1.91-2.01(m，1H)；2.06-2.14(m，2H)；2.19-2.27(m，1H)；2.48-2.53(m，2H)；2.62-2.68(m，2H)；3.18(q，2H)；3.41-3.52(m，1H)；3.56-3.72(m，5H)；4.01-4.08(m，4H)；4.53(d，1H)；4.72(t，1H)；7.11-7.28(m，3H)；7.96(m，1H)；8.36(s，1H)；8.60(s，1H)；8.63(s，1H)；

Mass spectrum: (M-H) ^-528.

Raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline is prepared as follows:

Under nitrogen atmosphere, with 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (1.1g, 2.5mmol; Described in embodiment 31-feedstock production, prepare) be dissolved in the mixed solution of methylene dichloride (20ml) and diisopropylethylamine (1.0ml).This solution is cooled to 4 ℃ in ice/water-bath, and the adding chloro-acetyl chloride (0.21ml, 2.63mmol).Reaction mixture was stirred 2 hours under cooling, between methylene dichloride and saturated sodium bicarbonate aqueous solution, distribute then.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Drying is filtered, and evaporation obtains 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (1.14g; 94.9%). Mass spectrum: (M+H) ⁺479.

Embodiment 44

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (0.25g, 0.57mmol; Described in embodiment 31-feedstock production, prepare) be dissolved in the mixed solution of methylene dichloride (5ml) and diisopropylethylamine (0.3ml).This solution is cooled to 4 ℃ in ice/water-bath, and the adding alpha-Acetoxyacetyl chloride (0.064ml, 0.6mmol).Reaction mixture was stirred 2 hours under cooling, between methylene dichloride and saturated sodium bicarbonate aqueous solution, distribute then.Organic layer is separated, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is dissolved in the methyl alcohol (5ml) that contains anhydrous powder salt of wormwood (0.2g).After stirring was spent the night, evaporating solvent, residue were through column chromatography purification, with methylene dichloride/Virahol (96/4) (containing 0.5% triethylamine) wash-out.To contain the each several part evaporation that requires product to some extent, residue will be ground with ether, obtain title product, be white solid (0.1g; 38%). ¹H NMR spectrum:

(CDCl ₃)1.95-2.29(m，4H)；3.29(m，1H)；3.46(m，2H)；4.03(s，3H)；4.07-4.18(m，3H)；4.55(d，1H)；4.69(t，1H)；7.13-7.16(m，2H)；7.26(s，1H)；8.26(m，1H)；8.35(s，1H)；8.48(s，1H)；8.66(s，1H)；

Mass spectrum: (M+H) ⁺461.

Embodiment 45

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline

HCl (4.63ml, 4M dichloromethane solution) is joined 4-chloro-7-methoxyl group-6-[1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] in acetonitrile (40ml) mixed solution of quinazoline (2.47g) and 3-chloro-2-fluoroaniline (1.01g).With mixed solution reflux 1 hour, cooling, collecting precipitation obtains the title product into dihydrochloride, is white solid (2.51g; 91%). ¹H NMR spectrum:

(DMSOd ₆)1.9(m，2H)；2.0(m，1H)；2.2(m，1H)；3.0(m，1H)；3.2(m，2H)；3.5(m，1H)；4.0(s，3H)；5.0(m，1H)；7.4(m，1H)；7.5(m，1H)；7.6(s，1H)；7.6(m，1H)；8.8(s，1H)；8.9(s，1H)；9.2(brs，2H)；12.3(brs，1H)；

Mass spectrum: (M+H) 403.

Raw material 4-chloro-7-methoxyl group-6-[1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] quinazoline is prepared as follows:

Diethyl azodiformate (9.41ml, 40% toluene solution) is joined 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (2.90g; Described in embodiment 16-feedstock production, prepare), in methylene dichloride (75ml) mixed solution of triethylamine (5.43g) and tert-butoxycarbonyl-3-hydroxy piperidine (4.15g).With the solution that obtains be heated to 40 ℃ 6 hours, at room temperature place then and spend the night.Through the rapid column chromatography purifying, adopt isohexane (79%), acetone (20%) and triethylamine (1%) wash-out, obtain 4-chloro-7-methoxyl group-6-[1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] quinazoline, be white solid (2.47g, 53%); ¹H NMR spectrum:

(CDCl ₃)1.5(m，9H)；1.6(m，1H)；1.9(m，2H)；2.1(m，1H)；3.5(m，1H)；3.6(m，1H)；4.0(s，3H)；4.2-3.9(m，2H)；4.5(m，1H)；7.3(s，1H)；7.4(s，1H)；8.9(s，1H)；

Mass spectrum: (M+H) 394.

Embodiment 46

4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline and

4-(3-chloro-2-fluoroanilino)-6-[(2R, 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline

With phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea  (HATU) (192mg, 0.5mmol) join 4-(3-chloro-2-the fluoroanilino)-6-[(2RS of stirring, 4R)-1-methyl-2-carboxy pyrrole alkane-4-base oxygen base]-7-methoxyl group quinazoline (150mg, 0.336mmol), dimethylamine hydrochloride (41mg, 0.5mmol) and diisopropylethylamine (175 μ l are in DMF 1.0mmol) (5ml) solution.After 18 hours, reaction mixture is evaporated to dried.Residue is dissolved in the methylene dichloride (50ml) water (50ml) washing, dry (MgSO ₄), filter, be concentrated into orange jelly.Through the flash chromatography on silica gel purifying, methylene chloride (100/0-90/10) the mixed solution wash-out with polarity increases gradually obtains following diastereomer then.

The product of first wash-out is partly merged, and evaporation obtains colourless jelly, grinds with ether; obtain 4-(3-chloro-2-fluoroanilino)-6-[(2S; 4R)-2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline, be white powder (56.1mg). ¹H NMR spectrum: (benzene-d6)

2.10(s，3H)，2.1-2.28(m，1H)，2.28-2.45(m，6H)，2.65-2.80(m，1H)，2.80-2.90(m，1H)，3.20(t，1H)，3.45(s，3H)，3.60-3.75(m，1H)，5.70-5.80(m，1H)，6.65-6,75(m，1H)，6.85-7.00(m，1H)，7.55(s，1H)，7.93(t，1H)，8.05(s，1H)，8.93(s，1H)，9.08(s，1H)；

Mass spectrum: (M+H) ⁺474.

The product of wash-out partly merges with the second time, and evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-[(2R, 4R)-and 2-(N, N-formyl-dimethylamino)-1-methylpyrrolidin-4-base oxygen base]-7-methoxyl group quinazoline, be white foam shape thing (37.8mg). ¹H NMR spectrum: (benzene-d ₆+ DMSO-d ₆+ acetate-d ₄)

2.10-2.25(m，1H)，2.60(s，36H)，2.68(s，3H)，2.83(s，3H)，3.40-3.60(m，1H)，3.83(s，3R)，3.90 (dd，1H)，4.03(d，1H)，4.90-5.05(m，1H)，5.40-5.55(m，1H)，6.89(t，1H)，7.10(t，1H)，7.65(t，1H)，7.92(s，1H)，7.95(s，1H)，8.80(s，1H)；

Mass spectrum: (M+H) ⁺474.

Raw material 4-(3-chloro-2-fluoroanilino)-6-[(2RS, 4R)-1-methyl-2-carboxy pyrrole alkane-4-base oxygen base]-7-methoxyl group quinazoline is prepared as follows:

With 4-nitrobenzene sulfonyl chloride (1.89g) join stirring (2S 4S)-4-hydroxyl pyrrolidine-1, in methylene dichloride (30ml) solution of 2-dioctyl phthalate 1-tertiary butyl ester 2-methyl esters (2.0g) and pyridine (1.29g), under nitrogen atmosphere, 4 ℃, stirred 16 hours.Reaction mixture is washed with citric acid (1.0M), saturated sodium bicarbonate, through dried over mgso.Product is through purification by silica gel column chromatography then, methylene chloride (100/0-92/8) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation, obtain (2S, 4S)-the 4-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1,2-dioctyl phthalate 1-tertiary butyl ester 2-methyl esters is yellow jelly (0.89g); ¹H NMR spectrum:

(DMSO d ⁶)1.31-1.42(m，9H)，2.12-2.21(m，1H)，2.53-2.67(m，1H)，3.40-3.50(m，1H)，3.58-3.69(m，4H)，4.36(m，1H)，5.25(m，1H)，8.14(d，2H)，8.46(d，2H).

Dimethyl formamide (15ml) is joined 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-hydroxyl quinazoline (0.66g; Described in the preparation of raw material among the embodiment 22, prepare), (2S, 4S)-the 4-[(4-nitrophenyl) sulfonyloxy] tetramethyleneimine-1, in 2-dioctyl phthalate 1-tertiary butyl ester 2-methyl esters (0.889g) and the cesium fluoride (0.941g).Under room temperature, reaction mixture was stirred 16 hours then.With reaction mixture vacuum-evaporation, residue is distributed between ethyl acetate and water.With organism water and saturated brine washing, through MgSO ₄Dry.Then through the column chromatography purification product, methylene chloride (100/0-95/5) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation, obtain 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline, be colourless jelly (0.36g); Mass spectrum: (M+H) ⁺547.

Make 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline (480mg, 0.88mmol) formic acid (50ml) solution and Paraformaldehyde 96 (29mg, 0.97mmol) reaction, the mixture that obtains was heated 6 hours down at 85 ℃.With the reaction mixture evaporation, residue is distributed between saturated sodium bicarbonate aqueous solution (50ml) and ethyl acetate (100ml).Organic layer is through MgSO ₄Drying is filtered, evaporation.Residue is through the flash chromatography on silica gel purifying, methylene chloride (100/0-90/10) the mixture wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, evaporation obtains 4-(3-chloro-2-fluoroanilino)-6-[(2RS, 4R)-and 1-methyl-2-(methoxycarbonyl) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline, be white foam shape thing (265mg); Mass spectrum: (M+H) ⁺461.

With 2M sodium hydroxide (1ml, 2mmol) join 4-(3-chloro-2-the fluoroanilino)-6-[(2RS of stirring, 4R)-1-methyl-2-(methoxycarbonyl) tetramethyleneimine-4-base oxygen base]-7-methoxyl group quinazoline (250mg, 0.54mmol) methyl alcohol (5ml) solution in, under room temperature, mixture was stirred 18 hours.With the reaction mixture evaporation, in residue water-soluble again (50ml).Use ethyl acetate (25ml) washing then, water layer is evaporated to dried, with methylbenzene azeotropic.Residue and methylene chloride (9/1) (25ml) are ground, filter, vaporised liquid obtains 4-(3-chloro-2-fluoroanilino)-6-[(2RS, 4R)-and 1-methyl-2-carboxy pyrrole alkane-4-base oxygen base]-7-methoxyl group quinazoline, be white foam shape thing (155mg); Mass spectrum: (M+H) ⁺447.

Embodiment 47

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2RS, 4R)-1-methyl-2-(morpholino carbonyl) tetramethyleneimine-4-base oxygen base] quinazoline

Under 80 ℃, with 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S, 4R)-1-(tert-butoxycarbonyl)-2-(morpholino carbonyl) tetramethyleneimine-4-base oxygen base] solution stirring 8 hours of quinazoline (0.3g), formic acid (3.0ml) and Paraformaldehyde 96 (0.047mg).With the reactant cooling, vacuum concentration absorbs in the silica gel then.Methylene chloride (100/0-90/10) wash-out that product is increased gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation.Then with product on anti-phase Hi-Chrom HIRPB post through preparation HPLC repurity.Acetonitrile/water (0.1% trifluoroacetic acid) the mixed solution wash-out (20/80-50/50) that product is reduced gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation is dissolved in residue in the methylene chloride (saturated with ammonia), absorbs in the silica gel then.Mixed solution (100/0-90/10) wash-out of the methylene chloride that product is increased gradually with polarity (saturated) with ammonia.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is colourless foam shape thing (0.058g); ¹H NMR spectrum:

(DMSO d ₆)2.10-2.18(m，1H)，2.31(s，3H)，2.53-2.60(m，1H)，3.44-3.67(m，10H)，3.72(t，1H)，3.92(s，3H)，5.10(m，1H)，7.21(s，1H)，7.28(t，1H)，7.467.56(m，2H)，7.71(s，1H)，8.36(s，1H)，9.64(s，1H)；

Mass spectrum: (M+H) ⁺516.

Raw material 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S, 4R)-1-(tert-butoxycarbonyl)-2-(morpholino carbonyl) tetramethyleneimine-4-base oxygen base] quinazoline is prepared as follows:

With aqueous sodium hydroxide solution (2M, 1.0ml) join 4-(3-chloro-2-the fluoroanilino)-6-[(2S of stirring, 4R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl) tetramethyleneimine-4-base oxygen base]-methyl alcohol (8ml) and THF (3ml) solution of 7-methoxyl group quinazoline (described in the preparation of raw material among the embodiment 46, preparing) in, under room temperature, reaction mixture was stirred 16 hours.With the reaction mixture vacuum concentration, that residue is soluble in water then, be adjusted to pH6 by adding hydrochloric acid (2N).Product is extracted with ethyl acetate/n-propyl alcohol, with organic layer salt water washing, through MgSO ₄Drying, solvent removed in vacuo obtains white powder solid 4-(3-chloro-2-fluoroanilino)-6-[(2S, 4R)-1-(tert-butoxycarbonyl)-2-carboxy pyrrole alkane-4-base oxygen base]-7-methoxyl group quinazoline (0.42g); Mass spectrum: (M+H) ⁺532.98

HATU (214mg) is joined 4-(3-chloro-2-the fluoroanilino)-6-[(2S of stirring, 4R)-1-(tert-butoxycarbonyl)-2-carboxy pyrrole alkane-4-base oxygen base]-DMA (5ml) solution of 7-methoxyl group quinazoline (215mg), morpholine (50mg) and diisopropylethylamine (200 μ l) in.Stir after 18 hours under the room temperature, reaction mixture is evaporated to dried.Residue is dissolved in the methylene dichloride (50ml) water (50ml), salt solution (50ml) washing, dry (MgSO ₄), filtering, vacuum evaporating solvent obtains 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S, 4R)-and 1-(tert-butoxycarbonyl)-2-(morpholino carbonyl) tetramethyleneimine-4-base oxygen base] quinazoline, be light yellow gluey thing (300mg).Residue is without being further purified use; Mass spectrum: (M+H) ⁺602.08.

Embodiment 48

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(tetramethyleneimine-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline

Chloro-acetyl chloride (89 μ l) is joined 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (469mg that is cooled to 0 ℃; Press described in the embodiment 45 preparation) and methylene dichloride (15ml) solution of diisopropylethylamine (700 μ l) in.Under room temperature, mixture was stirred 2 hours, obtain 6-[1-(chloracetyl) piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline; Mass spectrum: (M+H) ⁺479.

Add tetramethyleneimine (0.5ml) then,,, adopt methylene chloride (containing ammonia 7N) (97/3) wash-out through the flash chromatography purifying with this solution restir 1 hour.Merge and contain the part that requires product to some extent, vacuum-evaporation obtains title compound, is colourless foam shape thing (0.327g); ¹H NMR spectrum: (DMSO d ₆, 100 ℃)

1.50-1.72(m，5H)，1.83-1.95(m，2H)，2.08-2.18(m，1H)，2.40-2.58(m，4H)，3.18(d，1H)，3.37(d，1H)，3.48-3.56(m，1H)，3.58-3.64(m，1H)，3.68-3.77(m，1H)，3.89-3.93(m，1H)，3.95(s，3H)，4.51-4.59(m，1H)，7.23-7.31(m，2H)，7.40-7.48(m，1H)，7.57-7.64(m，1H)，7.90(s，1H)，8.41(s，1H)，9.25(br s，1H)；

Mass spectrum: (M+H) ⁺514.

Embodiment 49

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-piperidines-3-base oxygen base] quinazoline

HCl (1.0ml, 4M dioxane solution) is joined the 4-chloro-7-methoxyl group that is dissolved in the acetonitrile (25ml)-6-[(3S)-1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] in quinazoline (0.786g) and the 3-chloro-2-fluoroaniline (0.304g).With mixed solution be heated to 60 ℃ 2 hours, cooling, collecting precipitation obtains 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-piperidines-3-base oxygen base] the quinazoline hydrochloride, be white solid (0.577g, 66%); ¹H NMR spectrum:

(DMSOd ₆)1.70-1.95(m，2H)，1.95-2.10(m，1H)；2.10-2.25(m，1H)，2.95-3.10(m，1H)，3.10-3.30(m，2H)，3.45-3.65(m，1H)；4.03(s，3H)；4.95-5.10(m，1H)；7.30-7.45(m，1H)；7.45-7.60(m，2H)；7.60-7.73(m，1H)，8.85(s，1H)；8.90(s，1H)；9.15(bs，2H)；12.3(bs，1H)；

Mass spectrum: (M+H) 403.

Raw material 4-chloro-7-methoxyl group-6-[(3S)-1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] quinazoline is prepared as follows:

Diethyl azodiformate (2.76ml, 40% toluene solution) is joined 4-chloro-6-hydroxyl-7-methoxyl group quinazoline (0.89g; Press described in the embodiment 16 preparation), in triphenyl phosphine (1.66g) and (3R)-1-(tert-butoxycarbonyl)-3-hydroxy piperidine (CAS registration number 143900-43-0) methylene dichloride (25ml) solution (1.28g).Under room temperature, the solution stirring that obtains is spent the night.Through the rapid column chromatography purifying, the mixed solution wash-out of acetonitrile/isohexane/triethylamine (79/20/1 to 64/35/1) that employing polarity increases gradually, obtain 4-chloro-7-methoxyl group-6-[(3S)-1-(tert-butoxycarbonyl) piperidines-3-base oxygen base] quinazoline, be white solid (0.794g, 48%); Mass spectrum: (M+H) ⁺394.

Embodiment 50

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(3S)-1-(tetramethyleneimine-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline

Chloro-acetyl chloride (66 μ l) is joined 4-(3-chloro-2-fluoroanilino)-7-methoxyl group of being cooled to 0 ℃-6-[(3S)-piperidines-3-base oxygen base] quinazoline hydrochloride (350mg; Press described in the embodiment 49 preparation) and methylene dichloride (10ml) solution of diisopropylethylamine (522 μ l) in, under room temperature, stirred the mixture 30 minutes.Add tetramethyleneimine (0.37ml),,, adopt methylene chloride (containing ammonia 7N) (97/3) wash-out then through the rapid column chromatography purifying with this solution stirring 1 hour.Merge and contain the part that requires product to some extent, evaporation obtains foam.This foam is dissolved in the methylene dichloride (5ml),, obtains title product (0.206g) by adding isohexane (50ml) crystallization; ¹H NMR spectrum:

(DMSO d ₆，100℃)1.50-1.72(m，5H)，1.83-1.95(m，2H)，2.08-2.18(m，1H)，2.40-2.58(m，4H)，3.18(d，1H)，3.37(d，1H)，3.48-3.56(m，1H)，3.58-3.64(m，1H)，3.68-3.77(m，1H)，3.89-3.93(m，1H)，3.95(s，3H)，4.51-4.59(m，1H)，7.23-7.31(m，2H)，7.40-7.48(m，1H)，7.57-7.64(m，1H)，7.90(s，1H)，8.41(br s，1H)，9.25(br s，1H)；

Mass spectrum: (M+H) ⁺514.

Embodiment 51

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N-methylamino-ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt and synthetic embodiment 43 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (0.28g; Described in embodiment 43 feedstock production, prepare) with the reaction of the ethanolic soln (5ml) of 33% methylamine, obtain title product, be foam (0.131g, 47%); ¹H NMR spectrum:

(CDCl ₃)1.91-2.22(m，4H)，2.22(s，3H)，2.70-2.90(m，1H)，3.28-3.40(m，2H)，3.44-3.54(m，2H)，3.97-4.09(m，4H)，4.47-4.51(d，1H)，4.60-4.66(t，1H)，7.06-7.20(m，2H)，7.24(s，1H)，8.07-8.13(m，1H)，8.57-8.70(m，3H)；

Mass spectrum: (M-H) ^-472.

Embodiment 52

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N, N-dimethylamino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt and synthetic embodiment 43 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } ethanolic soln (5ml) reaction of quinazoline (0.28g) and 33% dimethylamine, obtain title product, be foam (0.165g, 58%); ¹HNMR spectrum:

(CDCl ₃)1.91-2.01(m，1H)，2.04 2.11(m，2H)，2.14-2.22(m，1H)，2.33(s，6H)，3.02-3.22(dd，2H)，3.40-3.50(m，1H)，3.59-3.66(m，1H)，4.02(s，3H)，4.05-4.09(m，1H)，4.51-4.55(d，1H)，4.66-4.72(m，1H)，7.09-7.21(m，2H)，7.23(s，1H)，8.00-8.06(m，1H)，8.47(bs，1H)，8.62(s，1H)，8.68(s，1H)；

Mass spectrum: (M-H) ^-486.

Embodiment 53

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt and synthetic embodiment 43 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (0.28g) and tetramethyleneimine (2.5ml) reaction, obtain title product, be foam (0.151g, 50%); ¹HNMR spectrum:

(CDCl ₃)1.68-1.75(m，4H)，1.90-2.01(m，1H)，2.04-2.14(m，2H)，2.15-2.23(m，1H)，2.51-2.61(m，2H)，2.66-2.74(m，2H)，3.15-3.21(d，1H)，3.38-3.48(m，2H)，3.55-3.62(m，1H)，4.00-4.08(m，4H)，4.52-4.55(d，1H)，4.68-4.74(t，1H)，7.06-7.27(m，3H)，7.90-7.96(m，1H)，8.43(s，1H)，8.60(s，1H)，8.69(s，1H)；

Mass spectrum: (M-H) ^-512.

Embodiment 54

4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylene-dioxy tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group }-7-methoxyl group quinazoline

With 3,4-methylene radical dioxy base pyrrolidine hydrochloride (87mg) joins 4-(3-chloro-2-the fluoroanilino)-7-methoxyl group of stirring-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (0.25g; Press described in the embodiment 43 preparation) and acetonitrile (10ml) solution of diisopropylethylamine (0.2ml) in, with mixture heating up backflow 2 hours.Reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With organic layer salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is through column chromatography purification, methylene dichloride/Virahol/triethylamine (97/2/1 to the 95/4/1) wash-out that increases gradually with polarity.Vacuum-evaporation contains the part that requires product to some extent, obtains title product, is yellow solid (0.203g, 70%); ¹H NMR spectrum:

(CDCl ₃)1.92-2.22(m，4H)，2.54-2.61(m，2H)，3.05-3.15(m，2H)，3.26-3.38(q，2H)，3.42-3.47(m，1H)，3.58-3.65(m，1H)，4.00-4.10(m，4H)，4.47-4.55(m，3H)，4.65-4.72(m，1H)，4.84(s，1H)，5.02(s，1H)，7.11-7.22(m，2H)，7.24(s，1H)，7.96-8.02(m，1H)，8.38(s，1H)，8.61(s，1H)，8.63(s，1H)；

Mass spectrum: (M+H) ⁺558.

Raw material 3, being prepared as follows of 4-methylene radical dioxy base pyrrolidine hydrochloride:

With two dimethyl dicarbonate butyl ester (Boc ₂O, ethyl acetate 78.95g) (125ml) drips of solution be added to stirring, be cooled to 0 ℃ 3-pyrroline (25g; 65% purity contains tetramethyleneimine) and the mixed solution of ethyl acetate (125ml) in.In the dropping process, keep temperature of reaction between 5-10 ℃.The reaction mixture that obtains is warmed to ambient temperature overnight.With reaction mixture water, 0.1N aqueous hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and salt water washing in turn, through dried over mgso and evaporation.Obtain for colorless oil (62g) 2: 1 3-pyrroline-1-formic acid tertiary butyl ester [ NMR: (CDCl ₃) 1.45 (s, 9H), 4.1 (d, 4H), 6.75 (m, 2H)] and tetramethyleneimine-1-formic acid tertiary butyl ester [ NMR: (CDCl ₃) 1.5 (and s, 9H), 1.8 (br s, 4H), 3.3 (br s, 4H)] mixture.

Acetone (500ml) drips of solution of the above mixture that obtains is added to N-methylmorpholine- NIn the mixed solution of-oxide compound (28.45g), perosmic anhydride (1g) and water (500ml), during keep temperature of reaction to be lower than 25 ℃.Then at room temperature, reaction mixture was stirred 5 hours.Evaporating solvent distributes residue between ethyl acetate and water.With organic phase salt water washing, through dried over mgso, evaporation.Residue is through purification by silica gel column chromatography, and sherwood oil (b.p.40-60 ℃) that increases gradually with polarity and ethyl acetate mixed solution be as eluent, and again through purification by silica gel column chromatography, methylene dichloride that increases gradually with polarity and methyl alcohol mixed liquor are as eluent.Obtain 3,4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester is oily matter (34.6g); NMRSpectrum: (CDCl ₃) 1.45 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H), 3.6 (m, 2H), 4.25 (m, 2H).

With 3, DMF (400ml) solution of 4-dihydroxy pyrrolidine-1-formic acid tertiary butyl ester (34.6g) is cooled to 0-5 ℃, and gradation adding sodium hydride (60% mineral oil dispersion liquid, 0.375mol).Under 5 ℃, reaction mixture was stirred 1 hour.Add methylene bromide (15.6ml), under 5 ℃, reaction mixture was stirred 30 minutes.Reaction mixture is warmed to room temperature and stirred 16 hours.Evaporation DMF distributes residue between ethyl acetate and water.With organic phase water and salt water washing, through dried over mgso, evaporation.Residue is through purification by silica gel column chromatography, and sherwood oil (b.p.40-60 ℃) that increases gradually with polarity and ethyl acetate are as eluent.Obtain 3,4-methylene radical dioxy base tetramethyleneimine-1-formic acid tertiary butyl ester is colorless oil (19.77g); NMRSpectrum: (CDCl ₃) 1.45 (s, 9H), 3.35 (m, 2H), 3.75 (br s, 2H), 4.65 (m, 2H), 4.9 (s, 1H), 5.1 (s, 1H).

Virahol (150ml) solution of refrigerative 5M hydrogenchloride is joined ice bath refrigerative 3, in methylene dichloride (500ml) solution of 4-methylene radical dioxy base tetramethyleneimine-1-formic acid tertiary butyl ester (19.7g).Reaction mixture is warmed to room temperature and stirred 4 hours.Evaporating solvent grinds residue in ether.Filter collecting precipitation, with ether washing, drying.Obtain 3,4-methylene radical dioxy base pyrrolidine hydrochloride is beige solid (13.18g); NMRSpectrum: (DMSOd ₆) 3.15 (m, 2H), 3.35 (m, 2H), 4.65 (s, 1H), 4.8 (m, 2H), 5.1 (s, 1H).

Embodiment 55

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(1-methylpiperazine-4-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

Adopt and embodiment 43 described similar methods, make 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(chloracetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline (0.14g) and 1-methylpiperazine (5ml) reaction, obtain title product, be white foam shape thing (0.122g); ¹H NMR spectrum:

(CDCl3)1.91-2.01(m，1H)，2.04-2.12(m，2H)，2.17-2.23(m，1H)，2.25(s，3H)，2.34-2.45(m，3H)，2.49-2.59(m，2H)，2.62-2.72(m，2H)，3.08-3.26(q，2H)，3.40-3.51(m，2H)，3.54-3.61(m，1H)，4.00-4.08(m，4H)，4.50-4.56(m，1H)，4.67-4.74(m，1H)，7.10-7.24(m，2H)，7.23(s，1H)，7.91-7.97(m，1H)，8.38(s，1H)，8.60(s，1H)，8.66(s，1H)；

Mass spectrum: (M-H) ^-541.

Embodiment 56

4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(hydroxyacetyl) tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-6-[(3R)-tetramethyleneimine-3-base oxygen base]-7-methoxyl group quinazoline hydrochloride (0.25g; By preparation described in the embodiment 29) be dissolved in the mixed solution of methylene dichloride (10ml) and diisopropylethylamine (0.3ml).This solution is cooled to 4 ℃ in ice bath, adds alpha-Acetoxyacetyl chloride (0.069ml).The reaction mixture cooling was stirred 2 hours down, be allocated in then between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Separate organic layer, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is dissolved in the 7M alcohol system ammonia (10ml), the solution stirring that obtains is spent the night.Evaporating solvent, residue be through column chromatography purification, methylene chloride (saturated with ammonia) (98/2 to 92/8) the mixed solution wash-out that increases gradually with polarity.Evaporation contains the each several part that requires product to some extent, and residue is ground with ether, obtains title product, is light yellow solid (0.161g, 61%); ¹H NMR spectrum:

(DMSO-d ₆@393K，500MHz)2.10-2.40(m，2H)，3.50-3.70(m，3H)，3.70-3.85(m，1H)，3.95(s，3H)，4.05(s，2H)，5.15(s，1H)，7.15-7.30(m，2H)，7.30-7.45(m，1H)，7.50-7.70(m，1H)，7.85(s，1H)，8.40(s，1H)，9.20(bs，1H)；

Mass spectrum: (M+H) ⁺447.

Embodiment 57

6-[(3S)-1-ethanoyl piperidines-3-base oxygen base]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

Methylene dichloride (5ml) drips of solution of diacetyl oxide (42 μ l) is added to 4-(3-chloro-2-fluoroanilino)-7-methoxyl group stirring, under 0 ℃-6-[(3S)-piperidines-3-base oxygen base] quinazoline hydrochloride (0.175g, 0.4mmol; Press described in the embodiment 49 preparation) and methylene dichloride (20ml) solution of diisopropylethylamine (208 μ l) in, with mixture stirring 2 hours, be warmed to room temperature then.Reaction mixture is washed dry (MgSO with saturated sodium bicarbonate aqueous solution ₄), to filter, evaporation obtains white foam shape thing.With it through column chromatography purification, methylene chloride (100/0 to 95/5) the mixed solution wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is colourless foam shape thing (0.117g, 66%); ¹H NMR spectrum: (DMSO d ₆， @373K)

1.40-1.65(m，1H)，1.70-1.94(m，2H)，2.00(s，3H)，1.95-2.20(m，1H)，3.20-3.70(m，3H)，3.70-4.10(m，1H)，3.95(s，3H)，4.40-4.70(m，1H)，7.15-7.33(m，2H)，7.33-7.50(m，1H)，7.50-7.70(m，1H)，7.90(s，1H)，8.40(s，1H)，9.25(s，1H)；

Mass spectrum: (M+H) ⁺445.

Embodiment 58

Methylene dichloride (5ml) drips of solution of methylsulfonyl chloride (34 μ l) is added to 4-(3-chloro-2-fluoroanilino)-7-methoxyl group stirring, under 0 ℃-6-[(3S)-piperidines-3-base oxygen base] quinazoline hydrochloride (175mg; Press described in the embodiment 49 preparation) and methylene dichloride (20ml) solution of diisopropylethylamine (208 μ l) in.Reaction mixture is stirred 2 hours to room temperature.Reaction mixture is washed dry (MgSO with saturated sodium bicarbonate aqueous solution ₄), to filter, evaporation obtains foam.With it through column chromatography purification, methylene chloride mixed solution (100/0 to the 97/3) wash-out that increases gradually with polarity.Merge and contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is white foam shape thing (0.164g, 85%); ¹H NMR spectrum:

(DMSO d ₆)1.5-1.67(m，1H)，1.67-1.83(m，1H)，1.83-1.95(m，1H)，1.95-2.12(m，1H)，2.95(s，3H)，3.1-3.23(m，1H)，3.23-3.45(m，2H+H ₂O)，3.5-3.65(m，1H)，3.95(s，3H)，4.70(m，1H)，7.18-7.35(m，2H)，7.40-7.60(m，2H)，7.90(s，1H)，8.38(s，1H)，9.58(s，1H)；

Mass spectrum: (M+H) ⁺481.

Embodiment 59

With N, N-dimethylamino acetyl chloride hydrochloride (69mg) gradation joins 4-(3-chloro-2-fluoroanilino)-7-methoxyl group stirring, under 0 ℃-6-[(3S)-piperidines-3-base oxygen base] quinazoline hydrochloride (175mg; Press described in the embodiment 49 preparation) and methylene dichloride (25ml) solution of diisopropylethylamine (210 μ l) in.Reaction mixture is stirred 2 hours to room temperature.Reaction mixture is washed dry (MgSO with saturated sodium bicarbonate aqueous solution ₄), to filter, evaporation obtains foam.With it through column chromatography purification, the methylene chloride that increases gradually with polarity (saturated) (100/0 to 90/10) mixed solution wash-out with ammonia.Contain the each several part that requires product to some extent, vacuum-evaporation obtains title product, is white foam shape thing (0.152g, 78%); ¹H NMR spectrum: (DMSOd ₆@100 ℃)

1.40-1.65(m，1H)；1.75-1.95(m，2H)；2.00-2.30(m，7H)；3.05(dd，2H)；3.40-3.62(m，2H)；3.62-3.75(m，1H)；3.88(dd，1H)；3.95(s，3H)；4.45-4.65(m，1H)；7.15-7.30(m，2H)；7.30-7.47(m，1H)；7.50-7.7(m，1H)；7.88(s，1H)；8.40(s，1H)；9.25(s，1H)；

Mass spectrum: (M+H) ⁺488.

Embodiment 60

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(2-hydroxyl isobutyryl) tetramethyleneimine-2-yl] methoxyl group } quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2S)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (0.25g; By preparation described in the embodiment 31) be dissolved in the mixed solution of methylene dichloride (5ml) and diisopropylethylamine (0.3ml).This solution is cooled to 4 ℃ in ice/water-bath, adds 2-acetoxyl group butyryl chloride (0.085ml).The reaction mixture cooling was stirred 1 hour down, be allocated in then between methylene dichloride and the saturated sodium bicarbonate aqueous solution.Separate organic layer, use the salt water washing, through Na ₂SO ₄Drying is filtered, evaporation.Residue is dissolved in the 7M alcohol system ammonia (10ml), the solution stirring that obtains is spent the night.Evaporating solvent, residue be through column chromatography purification, methylene dichloride/Virahol/triethylamine mixed solution (97/2/1 to the 95/4/1) wash-out that increases gradually with polarity.Evaporation contains the each several part that requires product to some extent, and residue is ground with ether, obtains title product, is white solid (0.210g); ¹H NMR spectrum:

(CDCl ₃)1.57(s，6H)，1.85-2.30(m，4H)，3.55-3.75(m，1H)，3.75-3.90(m，1H)，3.90-4.20(m，5H)，4.53(d，1H)，4.7-4.85(m，1H)，7.05-7.20(m，2H)，7.25(s，1H)，8.15-8.35(m，2H)，8.50(s，1H)，8.67(s，1H)；

Mass spectrum: (M+H) ⁺489.

Embodiment 61

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[(2S)-1-methylpyrrolidin-2-base carbonyl] piperidines-3-base oxygen base } quinazoline

HATU (0.26g) is joined 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg; Press described in the embodiment 45 preparation), in DMF (7.5ml) solution of diisopropylethylamine (210 μ l) and N-methyl-L-proline(Pro) (0.120g), under the room temperature, with mixture stirring 2.5 hours.DMF is removed in decompression, residue is dissolved in the methylene dichloride (50ml), with saturated sodium bicarbonate (50ml) and water (50ml) washing.Through the rapid column chromatography purifying, with methylene chloride (saturated) (96/4) wash-out with ammonia.Evaporation contains the each several part that requires product to some extent, obtains foam.This foam being dissolved in the methylene dichloride (5ml), adding isohexane (50ml) crystallization, obtain title product, is the mixture (0.130g) of two kinds of diastereomers; ¹HNMR spectrum:

(DMSO d ₆)1.43-1.62(m，2H)，1.66-1.95(m，4H)，1.96-2.18(m，4H)，2.20-2.29(m，2H)，2.67-2.80(m，1H)，2.96(m，1H)，3.03-3.20(m，1H)，3.51-3.80(m，2H)，3.80-4.05(m，4H)，4.51-4.68(m，1H)，7.22-7.31(m，2H)，7.47-7.59(m，2H)，7.89(m，1H)，8.39(s，1H)，9.55(m，1H)；

Mass spectrum: (M+H) ⁺514.

Embodiment 62

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-[(N, N-formyl-dimethylamino methyl) piperidines-3-base oxygen base] quinazoline

2-chloro-N,N-dimethylacetamide (105mg) is joined in DMF (5ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg) and salt of wormwood (1.19g).Under the room temperature, reaction mixture was stirred 30 minutes, filter evaporating solvent.Through the rapid column chromatography purifying,, obtain foam with methylene chloride (96/4) wash-out.This foam is ground with ether and isohexane, obtain title product, be white solid (105mg); ¹H NMR spectrum:

(DMSO d ₆) 1.45 (m, 1H), 1.61 (m, 1H), 1.78 (m, 1H), 2.10 (m, 1H), 2.26 (m, 1H), 2.38 (m, 1H), 2.65-2.77 (m, 1H), 2.75 (s, 3H), 2.99 (s, 3H), 3.04 (m, 1H), 3.22 (s, 2H), 3.94 (s, 3H), 4.62 (m, 1H), 7.21 (s, 1H), 7.29 (m, 1H), 7.47-7.55 (m, 2H), 7.88 (s, 1H), 8.38 (s, 1H), 9.59 (s, 1H); Mass spectrum: (M+H) ⁺488.

Embodiment 63

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[1-(3,3-two fluoropyrrolidines-1-base ethanoyl) piperidines-3-base oxygen base] quinazoline

Chloro-acetyl chloride (47 μ l) is joined in methylene dichloride (10ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373 μ l), with reaction mixture stirring at room 1 hour.Add 3,3-difluoro pyrrolidine hydrochloride (Synthetic Letters, 1995; 1,55-57; 328mg), with this solution stirring 1 hour, use saturated sodium bicarbonate aqueous solution (10ml) washing then, through the rapid column chromatography purifying, methylene chloride (100/0 to the 95/5) wash-out with polarity increases gradually obtains foam.This foam is dissolved in the methylene dichloride (5ml), adds isohexane (50ml) crystallization, obtain title product (102mg); ¹H NMR spectrum:

(DMSO d ₆)1.45-1.57(m，1H)，1.73-1.95(m，2H)，1.98-2.18(m，2H)，2.18-2.33(m，1H)，2.63-2.75(m，1H)，2.77-2.85(m，1H)，2.85-2.99(m，1H)，3.04-3.19(m，1H)，3.21-3.29(m，1H)，3.37-3.50(m，2H)，3.52-3.70(m，2H)，3.77-3.99(m，4H)，4.63(m，1H)，7.21-7.29(m，2H)，7.47-7.57(m，2H)，7.87(d，1H)8.39(s，1H)，9.55(d，1H)；

Mass spectrum: (M+H) ⁺550.

Embodiment 64

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[[(3R)-3-hydroxyl pyrrolidine-1-yl] ethanoyl] piperidines-3-base oxygen base } quinazoline

Chloro-acetyl chloride (47 μ l) is joined in methylene dichloride (10ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373 μ l), will stir 1 hour under the mixture room temperature.Add (R)-(+)-3-pyrrolidinol (202mg), with this solution stirring 1 hour, use saturated sodium bicarbonate aqueous solution (10ml) washing then, through the rapid column chromatography purifying, methylene chloride (saturated with ammonia) (100/0 to 95/5) mixed solution wash-out with polarity increases gradually obtains foam.This foam being dissolved in the methylene dichloride (5ml), adding isohexane (50ml) crystallization, obtain title product, is the mixture (68mg) of two kinds of diastereomers; ¹H NMR spectrum:

(DMSO d ₆，100℃)1.52(m，2H)，1.87(m，3H)，2.09(m，1H)，2.38(m，1H)，2.61(m，1H)，2.77(m，1H)，3.18(m，1H)，3.36(d，1H)，3.53(m，2H，)，3.68(m，1H)，3.89(m，1H)，3.94(s，3H)，4.15(m，1H)，4.23(m，1H)，4.53(m，1H)，7.27(m，2H)，7.41(m，1H)，7.59(m，1H)，7.89(s，1H)，8.38(s，1H)，9.24(br s，1H)；

Mass spectrum: (M+H) ⁺530.

Embodiment 65

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(4-methyl-3-oxo piperazine-1-yl) ethanoyl] piperidines-3-base oxygen base } quinazoline

Chloro-acetyl chloride (47 μ l) is joined in methylene dichloride (10ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373 μ l), will stir 1 hour under the mixture room temperature.Add 1-methylpiperazine-2-ketone (195mg), with this solution stirring 1 hour, use saturated sodium bicarbonate aqueous solution (10ml) washing then, through the rapid column chromatography purifying, methylene chloride (100/0 to 95/5) wash-out with polarity increases gradually obtains foam.This foam is dissolved in the methylene dichloride (5ml), adds isohexane (50ml) crystallization, obtain title product (177mg); ¹H NMR spectrum:

(DMSO d ₆，100℃)1.57(m，1H)，1.91(m，2H)，2.08(m，1H)，2.67-2.85(m，5H)，3.08(s，2H)，3.18(m，3H)，3.32(d，J＝15Hz，1H)，3.47-3.60(m，2H)，3.71-3.83(m，2H，)，3.95(s，3H)，4.57(m，1H)，7.27(m，2H)，7.42(m，1H)，7.60(m，1H)，7.89(s，1H)，8.40(s，1H)，9.23(br s，1H)；

Mass spectrum: (M+H) ⁺557.

Embodiment 66

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{1-[(4-ethanoyl piperazine-1-yl) ethanoyl] piperidines-3-base oxygen base } quinazoline

Chloro-acetyl chloride (47 μ l) is joined in methylene dichloride (10ml) solution of 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(piperidines-3-base oxygen base) quinazoline dihydrochloride (250mg) and diisopropylethylamine (373 μ l), will stir 1 hour under the mixture room temperature.Add 1-ethanoyl piperazine (292mg); with this solution stirring 1 hour, use saturated sodium bicarbonate aqueous solution (10ml) washing then, through the rapid column chromatography purifying; methylene chloride mixed solution (100/0 to 95/5) wash-out with polarity increases gradually obtains foam.This foam is dissolved in the methylene dichloride (5ml), adds isohexane (50ml) crystallization, obtain title compound (73mg); ¹H NMR spectrum:

(DMSO d ₆，100℃)1.55(m，1H)，1.88(m，2H)，1.92(s，3H)，2.11(m，1H)，2.30-2.48(m，4H)，3.10(d，1H)，3.28(d，1H)，3.34(m，4H)，3.56(m，2H)，3.73(m，1H)，3.88(m，1H)，3.94(s，3H)，4.56(m，1H)，7.27(m，2H)，7.41(m，1H)，7.60(m，1H)，7.90(s，1H)，8.38(s，1H)，9.27(m，1H)；

Mass spectrum: (M+H) ⁺571.

Embodiment 67

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline

With 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(2R)-tetramethyleneimine-2-ylmethoxy] quinazoline hydrochloride (250mg; By preparation described in the embodiment 32), formic acid (5ml) and formaldehyde (the 37%w/v aqueous solution) mixed solution (2.5ml) be heated to 85 ℃ 1 hour.With reaction mixture vacuum-evaporation,, between ethyl acetate and saturated sodium bicarbonate aqueous solution, distribute then then with methylbenzene azeotropic.With organic layer salt water washing,, filter evaporation through dried over sodium sulfate.Residue is through the flash chromatography purifying then, and the methylene chloride (saturated with ammonia) that increases gradually with polarity is the mixed solution wash-out (98/2-94/6).Merge and contain the each several part that requires product to some extent, evaporation obtains colourless jelly, grinds with ether, filters, and vacuum-drying obtains title product, is white solid (0.15g); ¹HNMR spectrum:

(DMSO d ₆)1.55-1.83(m，3H)；1.95-2.10(m，1H)；2.20-2.35(m，1H)；2.45(s，3H)；2.68-2.85(m，1H)；2.93-3.10(m，1H)；3.92(s，3H)；3.92-4.15(m，2H)；7.19(s，1H)；7.20-7.30(m，1H)；7.40-7.55(m，2H)；7.81(s，1H)；8.36(s，1H)；9.57(s，1H)；

Mass spectrum: (M+H) ⁺417.

Embodiment 68

Medicinal compositions

The following describes the of the present invention representative pharmaceutical dosage form that is used for human treatment or prevention, these formulations limit (described active ingredient is called " compounds X ") by this paper:

(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 is 7.6)

Poly(oxyethylene glycol) 400 ... ... ... ... ... ... ... ... ... .4.5%w/v

Water for injection to 100%

Can prepare above-mentioned preparation by the ordinary method that pharmacy field is known.For example, by each component is mixed, subsequently this mixture compacting can be prepared described tablet in flakes.

Reference example 1

6-acetoxyl group-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline hydrochloride

With 6-acetoxyl group-4-chloro-7-methoxyl group quinazoline (press the described preparation of embodiment 25-5 among the WO 01/66099,6.00g, 23.8mmol) (3.46g 23.8mmol) is suspended in the Virahol (200ml) with 3-chloro-2-fluoroaniline.With this mixture 80 ℃ of following reflux 3 hours.Evaporating solvent with residue crystallization from acetonitrile, obtains the hydrochloride of product, is baby pink crystal (8.16g, 92%);

¹H NMR：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.

Reference example 2

4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group quinazoline

With 6-acetoxyl group-4-(3-chloro-2-fluoroanilino)-(reference example 1,8.72g 21.9mmol) are dissolved in the methyl alcohol (200ml) 7-methoxyl group quinazoline hydrochloride.Add strong aqua (15ml), stir down this solution is heated to 50 ℃ 2 hours, generation lacteous solid precipitation.Solid collected by filtration, with ether washing (3 * 200ml), under 60 ℃,, obtain pale solid product (5.40g, 77%) through Vanadium Pentoxide in FLAKES vacuum-drying;

¹H 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.

Reference example 3

The 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-(reference example 2,1870mg 5.85mmol) are dissolved among the DMA (50ml) 6-hydroxyl-7-methoxyl group quinazoline.Add (4-mesyloxy) piperidines-1-formic acid tertiary butyl ester (according to Chemical﹠amp; Pharmaceutical Bulletin 2001,49 (7), 822-829; 490mg 1.76mmol) and cesium fluoride (890mg, 5.85mmol preparation), stirs down, and mixed solution is heated to 85 ℃.When at interval 2 hours, 4 hours and 6 hours, in described reaction mixture, add above 4-mesyloxy piperidines-1-formic acid tertiary butyl ester and cesium fluoride of measuring.After in the end adding, continue heating 6 hours down in 85 ℃.Evaporating solvent distributes residue between DCM (150ml) and water (150ml).(4 * 100ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the DCM part that merges through dried over mgso, evaporation.Residue is through chromatography purification, with 0-2.5% (7: 1 dense NH of MeOH/ ₄The OH aqueous solution) DCM eluant solution.The each several part that merge to be fit to, evaporation obtains the product (2.40g, 58%, allow 2.3 normal residual DMA) into light brown foam;

¹HNMR：1.40(s，9H)，1.60-1.65(m，2H)，1.95-2.00(m，2H)，3.20-3.25(m，2H)，3.65-3.70(m，2H)，3.92(s，3H)，4.68(m，1H)，7.21(s，1H)，7.27(dd，1H)，7.47(ddd，1H)，7.51(dd，1H)，7.85(s，1H)，8.36(s，1H)，9.53(s，1H)；

Mass spectrum: 503.5,505.5.

Reference example 4

The 6-{[(1-tert-butoxycarbonyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-(reference example 2,700mg 2.19mmol) are dissolved among the DMA (35ml) 6-hydroxyl-7-methoxyl group quinazoline.Add salt of wormwood (1209mg, 8.76mmol) and 4-(toluene-4-sulfonyloxy methyl) piperidines-1-formic acid tertiary butyl ester (according to preparing described in the embodiment 1 among the WO 9427965; 808mg 2.19mmol), stirs mixed solution 4 hours down at 80 ℃.Evaporating solvent distributes residue between water (100ml) and DCM (100ml).(3 * 100ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the DCM part that the merges filter paper filtering by silicone-treated, evaporation obtains the product (1290mg, 98%) into brown solid;

¹H NMR：1.20(m，2H)，1.39(s，9H)，1.82(m，2H)，2.03(br.m，1H)，2.70-2.85(br.m，2H)，3.93(s，3H)，3.95-4.05(br.m，2H)，3.98(d，2H)，7.19(s，1H)，7.26(dd，1H)，7.46(dd，1H)，7.50(dd，1H)，7.76(s，1H)，8.35(s，1H)，9.57(s，1H)；

Mass spectrum: 517.3,519.3.

Reference example 5

6-{[2-(1-tert-butoxycarbonyl) piperidin-4-yl] oxyethyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

With 4-(3-chloro-2-fluoroanilino)-(reference example 2,500mg 1.56mmol) are dissolved among the DMA (25ml) 6-hydroxyl-7-methoxyl group quinazoline.Add salt of wormwood (864mg, 6.26mmol) and 4-[2-(mesyloxy) ethyl] piperidines-1-formic acid tertiary butyl ester is (according to preparing described in the embodiment 20 among the US 5252586; 504mg 1.64mmol), stirs mixed solution 16 hours down at 60 ℃.Evaporating solvent distributes residue between water (100ml) and DCM (100ml).(3 * 100ml) extract, and extracting solution and DCM is also laminated with DCM with water layer.With the DCM part that the merges filter paper filtering by silicone-treated, evaporation obtains the product (830mg, 100%) into the brown foam;

¹H NMR：1.00-1.18(m，2H)，1.38(s，9H)，1.65-1.80(m，5H)，2.65-2.75(m，2H)，3.92(s，3H)，3.93(m，2H)，4.15(t，2H)，7.18(s，1H) 7.26(dd，1H)，7.46(dd，1H)，7.51(dd，1H)，7.77(s，1H)，8.36(s，1H)，9.54(s，1H)；

Mass spectrum: 531.6,533.6.

Claims

1. the quinazoline derivant of a formula I or its pharmacy acceptable salt:

Wherein:

G ¹And G ²Independent separately is halogeno-group;

X ¹Be direct key or O;

R ¹Be selected from hydrogen and (1-6C) alkyl, wherein said (1-6C) alkyl optional by one or more can be identical or different the following substituting group that is selected from replace: hydroxyl and halogeno-group and/or amino, nitro, carboxyl, cyano group, halogeno-group, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyl, (2-6C) alkyloyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino, the alkanoylamino of N-(1-6C) alkyl-(2-6C), (1-6C) alkoxy carbonyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) the alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C);

X ²Be [CR ²R ³] _m, wherein m is the integer of 1-6,

R ²And R ³Independently be selected from hydrogen, hydroxyl, (1-4C) alkyl and hydroxyl (1-4C) alkyl separately;

Q ¹Be (3-7C) cycloalkyl or heterocyclic radical, wherein Q ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; acryl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (2-6C) alkenyl thio; (2-6C) alkynes sulfenyl; (1-6C) alkyl sulphinyl; (2-6C) alkenyl sulfinyl; (2-6C) alkynyl sulfinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (2-6C) alkynyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; (2-6C) alkyloyl; (2-6C) alkanoyloxy; (2-6C) alkanoylamino; the alkanoylamino of N-(1-6C) alkyl-(2-6C); sulfamyl; N-(1-6C) alkylsulfamoyl group; N; N-two-[(1-6C) alkyl] sulfamyl; (1-6C) alkane sulfuryl amino; the alkane sulfuryl amino of N-(1-6C) alkyl-(1-6C); formamyl (1-6C) alkyl; N-(1-6C) alkyl-carbamoyl (1-6C) alkyl; N; N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl; sulfamyl (1-6C) alkyl; N-(1-6C) alkylsulfamoyl group (1-6C) alkyl; N; N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl; (2-6C) alkyloyl (1-6C) alkyl; (2-6C) alkanoyloxy (1-6C) alkyl; (2-6C) alkanoylamino (1-6C) alkyl; N-(1-6C) alkyl-(2-6C) alkanoylamino (1-6C) alkyl and (1-6C) alkoxy carbonyl (1-6C) alkyl, the perhaps group of following formula:

Q ²-X ³-

X wherein ³Be CO and Q ²Be heterocyclic radical,

And Q wherein ²Optional have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group, hydroxyl, (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkyl sulphonyl,

And Q wherein ¹In any (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl and (2-6C) alkyloyl is optional has a following substituting group that is selected from that one or more can be identical or different: halogeno-group; hydroxyl alkyl and/or optional having is selected from following substituting group with (1-6C): cyano group; nitro; carboxyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; hydroxyl (1-6C) alkoxyl group; (1-4C) alkoxyl group (1-6C) alkoxyl group; (2-6C) alkyloyl; (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more can be identical or different optional having: cyano group, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group and (1-2C) alkoxyl group (1-4C) alkoxyl group

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group; and can on any available theheterocyclic nitrogen atom, choose wantonly to have and be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl; prerequisite is that described ring can be therefore by not quaternized

And wherein be present in by R as substituting group ^aAnd R ^bAny (1-4C) alkyl on the ring that the nitrogen-atoms that links to each other with their forms or (2-4C) optional one or more substituting group that has of alkyloyl; they can be identical or different substituting group that is selected from halogeno-group and hydroxyl and/or optional having to be selected from (1-4C) alkyl and (1-4C) substituting group of alkoxyl group

And Q wherein ¹-X ²Any heterocyclic group in the-group is optional have 1 or 2 oxo (=O) or sulfo-(=S) substituting group.

2. according to the quinazoline derivant of the formula I of claim 1, each R wherein ¹, G ¹, G ², X ¹And X ²Have in the claim 1 and limit in all senses; And

Q ¹Be to have a 3-7 unit monocyclic heterocycles ring nitrogen heteroatom and optional 1 or 2 non-aromatics that is selected from nitrogen and sulfur heteroatom, saturated or fractional saturation, this ring is by carbon atom and radicals X on the ring ²-O-connects, and Q wherein ¹Choose wantonly and have 1; 2 or 3 can be identical or different be selected from following substituting group: halogeno-group; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; formamyl; acryl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl; (1-6C) alkoxyl group; (2-6C) alkenyloxy; (2-6C) alkynyloxy group; (1-6C) alkylthio; (2-6C) alkenyl thio; (2-6C) alkynes sulfenyl; (1-6C) alkyl sulphinyl; (2-6C) alkenyl sulfinyl; (2-6C) alkynyl sulfinyl; (1-6C) alkyl sulphonyl; (2-6C) alkenyl alkylsulfonyl; (2-6C) alkynyl alkylsulfonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkane sulfuryl amino, N-(1-6C) the alkane sulfuryl amino of alkyl-(1-6C), formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) alkanoylamino (1-6C) alkyl, the perhaps group of following formula of alkyl-(2-6C):

Q ²-X ³-

X wherein ³Be CO and Q ²Be heterocyclic radical, described heterocyclic radical is selected from morpholino and contains a nitrogen heteroatom and optional 1 or 2 heteroatomic 4,5 or 6 yuan of monocyclic heterocycles base that are selected from sulphur and nitrogen,

And Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) optional have that one or more can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group of alkyloyl: cyano group, nitro, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (1-4C) alkoxyl group (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl be selected from following substituting group substituting group that is selected from halogeno-group and hydroxyl and/or optional the having that one or more can be identical or different optional having: cyano group, nitro, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxyl group, hydroxyl (1-4C) alkoxyl group and (1-2C) alkoxyl group (1-4C) alkoxyl group

Prerequisite is to work as X ²Be [CH ₂] _m, m is the integer of 1-6, Q ¹For on the 1-position by (2-4C) alkyl or (2-5C) when the pyrrolidyl that replaces of alkyloyl or piperidyl, Q then ¹The 1-position on (2-4C) alkyl or (2-5C) alkyloyl do not replaced by 2-oxo morpholinyl.

3. according to the quinazoline derivant of the formula I of claim 1, each R wherein ¹, G ¹, G ², X ¹And X ²Have in the claim 1 and limit in all senses; And

Q wherein ¹In any (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl and (2-6C) optional have that one or more can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group of alkyloyl: cyano group, nitro, carboxyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl,

4. according to the quinazoline derivant of the formula I of claim 1, each R wherein ¹, G ¹, G ², X ¹And X ²Have in the claim 1 and limit in all senses; And

Q ¹Be 4, the 5 or 6 yuan of monocyclic heterocycles non-aromatics, saturated or fractional saturation that have 1 or 2 ring nitrogen heteroatom, this ring is by carbon atom and radicals X on the ring ²-O-connects, and Q wherein ¹Optional have 1 or 2 can be identical or different be selected from following substituting group: halogeno-group, cyano group, nitro, hydroxyl, formamyl, acryl, (1-6C) alkyl, (1-6C) alkylthio, (2-6C) alkenyl thio, (2-6C) alkynes sulfenyl, (1-6C) alkyl sulphinyl, (2-6C) alkenyl sulfinyl, (2-6C) alkynyl sulfinyl, (1-6C) alkyl sulphonyl, (2-6C) alkenyl alkylsulfonyl, (2-6C) alkynyl alkylsulfonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl, (2-6C) alkyloyl (1-6C) alkyl, (2-6C) alkanoyloxy (1-6C) alkyl, (2-6C) alkanoylamino (1-6C) alkyl and N-(1-6C) alkanoylamino (1-6C) alkyl, the perhaps group of following formula of alkyl-(2-6C):

Q ²-X ³-

X wherein ³Be CO, and Q ²Be heterocyclic radical, it is selected from morpholino, piperidyl, piperazinyl and pyrrolidyl,

And Q wherein ¹In any (1-6C) alkyl or (2-6C) alkyloyl optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group: cyano group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have one or more substituting group, it can be identical or different, be selected from the substituting group of halogeno-group and hydroxyl and/or optionally have one and be selected from the cyano group and (1-4C) substituting group of alkoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with them forms 4,5 or 6 yuan of rings that do not contain Sauerstoffatom; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl, (1-4C) alkyl and (1-3C) substituting group of alkylenedioxy group; and can on any available theheterocyclic nitrogen atom, choose wantonly to have and be selected from (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl; prerequisite is that described ring can be therefore by not quaternized

And wherein be present in by R as substituting group ^aAnd R ^bAny (1-4C) alkyl on the ring that the nitrogen-atoms that links to each other with their forms or (2-4C) alkyloyl is optional has the substituting group that is selected from halogeno-group and hydroxyl that one or more can be identical or different and/or be selected from (1-4C) alkyl and (1-4C) substituting group of alkoxyl group optional having

5. according to the quinazoline derivant of the formula I of claim 1, each R wherein ¹, G ¹, G ², X ¹And X ²Have in the claim 1 and limit in all senses; And

Q ¹Be selected from by a ring carbon atom and radicals X ²Pyrrolidyl and piperidyl that-O-connects, and wherein said pyrrolidyl or piperidyl are optional is selected from following substituting group by 1 or 2 and replaces: halogeno-group, cyano group, hydroxyl, formamyl, (1-6C) alkyl, (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) alkyloyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, formamyl (1-6C) alkyl, N-(1-6C) alkyl-carbamoyl (1-6C) alkyl, N, N-two-[(1-6C) alkyl] formamyl (1-6C) alkyl, sulfamyl (1-6C) alkyl, N-(1-6C) alkylsulfamoyl group (1-6C) alkyl, N, N-two-[(1-6C) alkyl] sulfamyl (1-6C) alkyl and (2-6C) alkyloyl (1-6C) alkyl, the perhaps group of following formula:

Q ²-X ³-

X wherein ³Be CO, and Q ²Be heterocyclic radical, it is selected from morpholino, piperidino-(1-position only), piperazine-1-base, tetramethyleneimine-1-base and tetramethyleneimine-2-base,

And Q wherein ¹In any (1-6C) alkyl or (2-6C) alkyloyl optional have 1 or 2 can be identical or different be selected from halogeno-group, hydroxyl and (1-6C) substituting group and/or optional the having of alkyl be selected from following substituting group: cyano group, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (2-6C) alkyloyl, (2-6C) alkanoyloxy and NR ^aR ^b, R wherein ^aBe hydrogen or (1-4C) alkyl, and R ^bBe hydrogen or (1-4C) alkyl, and R wherein ^aOr R ^bIn any (1-4C) alkyl optional have the substituting group that is selected from halogeno-group and hydroxyl that one or more can be identical or different and/or optionally have one and be selected from the cyano group and (1-4C) substituting group of alkoxyl group,

Perhaps R ^aAnd R ^bThe nitrogen-atoms that connects with their forms and is selected from tetramethyleneimine-1-base; the ring of piperidino-(1-position only) and piperazine-1-base; this ring on available ring carbon atom optional have 1 or 2 can be identical or different be selected from halogeno-group; hydroxyl; (1-4C) substituting group of alkyl and methylene radical dioxy base; and can on any available theheterocyclic nitrogen atom, choose wantonly to have and be selected from (1-4C) alkyl; (2-4C) alkyloyl and (1-4C) substituting group of alkyl sulphonyl; prerequisite is that described ring can be therefore by not quaternized

And Q wherein ¹-X ²Any heterocyclic group in the-group is optional to have 1 or 2 oxo (=O) substituting group.

6. according to the quinazoline derivant of each formula I in the aforementioned claim, G wherein ¹Be fluorine and G ²Be chlorine.

7. according to the quinazoline derivant of each formula I in the aforementioned claim, R wherein ¹-X ¹Be selected from hydrogen and (1-4C) alkoxyl group.

8. according to the quinazoline derivant of each formula I in the aforementioned claim, X wherein ²Be CH ₂

9. quinazoline derivant or its pharmacy acceptable salt according to the formula I of claim 1, it is selected from:

(1) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl)] quinazoline;

(2) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methyl piperidine-4-yl)] quinazoline;

(3) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(2-methoxy ethyl) piperidin-4-yl] methoxyl group } quinazoline;

(4) 4-(3-chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl) piperidin-4-yl] methoxyl group }-7-methoxyl group-quinazoline;

(5) 6-{[1-(carbamyl ylmethyl) piperidin-4-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline

(6) 4-(3-chloro-2-fluoroanilino)-6-{[1-(cyano methyl) piperidin-4-yl] methoxyl group }-7-methoxyl group quinazoline;

(7) methoxyl group 4-(3-chloro-2-fluoroanilino)-6-[(1-cyano group piperidin-4-yl)]-7-methoxyl group quinazoline;

(8) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(9) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{{ (2R)-1-methylsulfonyl tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(10) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(methylsulfonyl) tetramethyleneimine-3-yl] methoxyl group } quinazoline;

(11) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline;

(12) methoxyl group 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(1-methylpyrrolidin-3-yl)] quinazoline;

(13) 6-{[(2S)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(14) 6-{[(2R)-and 1-acetyl-pyrrolidine-2-yl] methoxyl group }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(15) methoxyl group 6-[(1-acetyl-pyrrolidine-3-yl)]-4-(3-chloro-2-fluoroanilino)-7-methoxyl group quinazoline;

(16) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(morpholino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(17) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(hydroxyacetyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(18) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N-methylamino-ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(19) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(N, N-dimethylamino ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(20) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(21) 4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylene radical dioxy base tetramethyleneimine-1-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group }-7-methoxyl group quinazoline;

(22) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(1-methylpiperazine-4-base ethanoyl) tetramethyleneimine-2-yl] methoxyl group } quinazoline;

(23) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2S)-1-(2-hydroxyl isobutyryl) tetramethyleneimine-2-yl] methoxyl group } quinazoline; With

(24) 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[(2R)-1-methylpyrrolidin-2-yl] methoxyl group } quinazoline.

10. method of quinazoline derivant for preparing by the formula I of definition in the claim 1, this method comprises:

Method (a) makes the compound of formula II:

Formula II

R wherein ¹, X ¹, G ¹And G ²Have in the claim 1 and to limit in all senses, but need where necessary protect, and the compound reaction of formula III any functional group:

Q ¹-X ²-Lg

Formula III

Q wherein ¹And X ²Have in the claim 1 and to limit in all senses, but need where necessary protect, and Lg is replaceable group, after this remove any blocking group of existence by ordinary method to any functional group; Perhaps

Method (b) is modified according to the quinazoline derivant of the another kind of formula I of definition in the claim 1 or the substituting group in its pharmacy acceptable salt or with substituting group and is introduced wherein except that needing where necessary to protect any functional group,

After this remove any blocking group of existence by ordinary method; Perhaps

Method (c) makes compound and formula Q by the formula II of definition in the method (a) under the Mitsunobu condition ¹-X ²The compound reaction of-OH, wherein Q ¹And X ²Have in the claim 1 and to limit in all senses, but need where necessary protect any functional group,

After this remove any blocking group of existence by ordinary method; Perhaps

Method (d) makes wherein R ¹-X ¹For the quinazoline derivant cracking of the formula I of (1-6C) alkoxyl group, to prepare wherein R ¹-X ¹Formula I compound for hydroxyl; Perhaps

Method (e) is for preparing wherein X ¹Be the formula I compound of O, make formula I compound, wherein R ¹-X ¹Be OH and Q ¹, X ², G ¹And G ²Have in the claim 1 and to limit in all senses, but need where necessary protect, with formula R any functional group ¹The compound reaction of-Lg, wherein R ¹Has in the claim 1 and to limit in all senses, but need where necessary protect, and Lg is replaceable group any functional group,

After this remove any blocking group of existence by ordinary method; Perhaps

Method (f) is for preparing wherein Q ¹Or R ¹Contain (1-6C) alkoxyl group of (1-6C) alkoxyl group or replacement or (1-6C) the formula I compound of (1-6C) alkylamino of alkylamino or replacement, make wherein Q ¹Or R ¹Contain the quinazoline derivant alkylation of the formula I of suitable hydroxyl or primary amino or secondary amino group; Perhaps

Method (g) is for preparing wherein R ¹The formula I compound that is replaced by group T; wherein T is selected from (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, (1-6C) alkylthio, (1-6C) alkyl sulphinyl and (1-6C) alkyl sulphonyl, makes the compound of following formula V:

Formula V

Q wherein ¹, X ¹, X ², R ¹, G ¹And G ²Have in the claim 1 and to limit in all senses, but any functional group is protected when needing, and Lg is replaceable group, react with formula TH compound, the T definition is the same, when still needing any functional group is protected, and after this removes any blocking group of existence by ordinary method; Perhaps

Method (h) is by making the compound of following formula VI:

Formula VI

R wherein ¹, X ¹, X ², Q ¹Has in the claim 1 and to limit in all senses, but any functional group is protected when needing, and Lg is replaceable group, and the aniline reaction of formula VII:

Formula VII

G wherein ¹And G ²Have in the claim 1 and to limit in all senses, but any functional group is protected when needing,

After this remove any blocking group of existence by ordinary method; Perhaps

Method (i) is for preparing wherein Q ¹The formamyl or the group Q that have replacement ²-X ³-formula I compound, Q wherein ²Be by theheterocyclic nitrogen atom and X ³The nitrogen heterocycle that connects, and X ³Be CO, make as claim 1 definition and Q wherein ¹The formula I compound that has carboxyl is protected any functional group when still needing, with primary amine or secondary amine or formula Q ²The H group carries out coupling, wherein Q ²H is the heterocyclic radical that contains the NH group; After this remove any blocking group of existence by ordinary method;

And when the pharmacy acceptable salt of the quinazoline derivant that needs formula I, can adopt conventional method to obtain.

11. a pharmaceutical composition, said composition comprise as the quinazoline derivant of the defined formula I of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.

12. the quinazoline derivant of formula I or its pharmacy acceptable salt are used for producing purposes in the medicine of antiproliferative effect warm-blooded animal in preparation as defined above.