CN1882577A

CN1882577A - Quinazoline derivatives

Info

Publication number: CN1882577A
Application number: CN 200480033565
Authority: CN
Inventors: L·F·A·亨内奎恩; C·T·哈尔萨尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-09-16
Filing date: 2004-09-13
Publication date: 2006-12-20
Also published as: ZA200603039B; CN1882576A; ZA200602188B; GB0321621D0

Abstract

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

Description

Quinazoline derivant

The present invention relates to some new quinazoline derivant or its pharmacy acceptable salt with anti-tumor activity, or its pharmaceutically acceptable ester, therefore described compound can be used for the treatment of in the method for 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.

Present multiple treatment suppresses the compound of the synthetic and cell proliferation of DNA because of the scheme of the caused disease of unusual adjusting (as psoriasis and cancer) of cell proliferation has all adopted.Up to now, the compound that is used for this type of treatment is generally all toxic to various cells, but they may be useful for the enhancement of quick noble cells such as tumour cell.Just developing at present other method of these Cytotoxic antitumor drugs, for example the selective depressant of cell signaling approach.The inhibitor of these types may have and presents the usefulness that strengthens selectively acting to suppressing tumour cell, thereby may reduce the possibility of the therapy with unwanted side effect.

Eukaryotic cell is constantly reacted to many different extracellular signals, and these signals can make and link up (communication) between intravital each cell of machine.Physical responses widely in these Signal Regulation cells comprises propagation, differentiation, apoptosis and moves (motility).The extracellular signal is taked the form of various soluble factor, comprises somatomedin and paracrine factor and endocrine factor.By combining with the specificity transmembrane receptor, these parts interrelate extracellular signal and the interior signal transduction path of cell, thereby make the signal conduction stride across plasma membrane, and each cell is replied its extracellular signal generation.The conductive process of many these signals utilizes the reversing process of proteic phosphorylation, and proteic phosphorylation participates in promoting these different cell responses.The phosphorylation state of target protein is subjected to the adjusting of specificity kinases and Phosphoric acid esterase, and described kinases and Phosphoric acid esterase are responsible for the proteic adjusting by about 1/3rd in all albumen of mammalian genes group coding.Because phosphorylation is the important regulation mechanism in the signal conductive process, therefore, the distortion in these cells in the approach causes unusual cell growth and differentiation, impel cell transformation also (to see Cohen etc., Curr Opin ChemBiol, 1999 thus with regard to not at all surprising, 3, the commentary of 459-465).

Know generally that now many these type of Tyrosylprotein kinases are the constitutive activity form because of generation suddenlys change and/or cause the various human cell transformation when overexpression.Kinase whose these sudden changes and form overexpression be present in the most human tumor (see Kolibaba etc., Biochimica et Biophysica Acta, 1997, 133, the commentary of F217-F248).Because Tyrosylprotein kinase plays an important role in the hyperplasia of multiple tissue and differentiation, therefore in the new anti-cancer therapies of research, more attention is to concentrate on these enzymes.The enzyme of this family is divided into two groups-acceptor and non--receptor tyrosine kinase, promptly is respectively EGF acceptor and SRC family.From great deal of research results (comprising the human genome project), in human genome, identified about 90 kinds of Tyrosylprotein kinases, wherein 58 kinds is receptor type, and 32 kinds is non--receptor type.These Tyrosylprotein kinases can be divided into 20 kinds of receptor tyrosine kinases and 10 kinds of non--receptor tyrosine kinase subfamilies (Robinson etc., Oncogene, 2000, 19, 5548-5557).

In the mitogenetic signal conduction that activated cell duplicates, these receptor tyrosine kinases have special vital role.These macromole glycoprotein of crossing over cytoplasmic membrane have the born of the same parents of its ligands specific (as the Urogastron EGF of EGF acceptor) outer in conjunction with the territory.The combination of part causes the activation by the kinase enzymatic activity of the acceptor of the intracellular portion coding of this receptor.This activity makes the crucial tyrosine amino acid phosphorylation in the target protein, causes proliferation signal conduction passing through cytoplasmic membrane.

The erbB family of known receptor Tyrosylprotein kinase (it comprises EGFR, erbB2, erbB3 and erbB4) general with the propagation that advances tumour cell with survive relevant (see Olayioye etc., EMBO J., 2000, 19, 3159 commentary).The overexpression that mechanism is the acceptor on protein level that can realize is commonly referred to be the result of gene amplification.This point can in many common human cancers, observe (see Klapper etc., Adv.Cancer Res., 2000, 77, 25 commentary), for example mammary cancer (Sainsbury etc., Brit.J.Cancer, 1988, 58, 458; Guerin etc., Oncogene Res., 1988, 3, 21; Slamon etc. ., Science, 1989, 244, 707; KlijnDeng., Breast Cancer Res.Treat., 1994, 29, 73 and see Salomon etc., Grit.Rev.Oncol.Hematol., 1995, 19, 183 commentary), non--small 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), esophagus cancer (Mukaida etc., Cancer, 1991, 68, 142), gastrointestinal cancer, for example colon, rectum or cancer of the stomach (Bolen etc., Oncogene 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 that the erbB family that more people's tumor tissues is carried out receptor tyrosine kinase expresses, people expect that the popularity of this family and importance will further be established in future.

Because the imbalance of one or more in these acceptors generally believes that now many tumours have more aggressive clinically, and therefore relevant with patient's poor prognosis (Brabender etc., Clin. Cancer Res., 2001, 7, 1850; Ross etc., Cancer Investigation, 2001, 19, 554, Yu etc., Bioessays, 2000, 22.7, 673).Except these clinical discoveries, the erbB family of clinical preceding information resources prompting receptor tyrosine kinase is relevant with cell transformation.This comprises observes one or more erbB acceptors of many tumor cell line overexpressions, and observes EGFR or erbB2 has the ability that makes these cytopathys when transfection is in non--tumour cell.Because tumour spontaneously takes place in mammary gland the transgenic mice of overexpression erbB2, the potentiality of this tumorigenesis is further confirmed.In addition, some preclinical studies confirmed to resist-proliferation function can induce by remove one or more erbB activity with micromolecular inhibitor, dominant negative regulation agent (dominant negatives) or inhibiting antibody (see Mendelsohn etc., Oncogene, 2000, 19, 6550 commentary).Therefore, the inhibitor that has recognized that these receptor tyrosine kinases should have as the value of the selective depressant of mammalian cancer cells propagation (Yaish etc., Science, 1988, 242, 933, Kolibaba etc., Biochimica etBiophysica Acta, 1997, 133, F217-F248; Al-Obeidi etc., 2000, Oncogene, 19, 5690-5701; Mendelsohn etc., 2000, Oncogene, 19, 6550-6565).

Recently, small molecules EGFR tyrosine kinase inhibitor, Iressa (be also referred to as gefitinib, and ZD1834) have been approved for treatment late period non--small cell lung cancer.In addition, use at result's proof of the inhibition antibody of EGFR and erbB2 (being respectively c-225 and trastuzumab) be used for the treatment of clinically selection noumenal tumour (summary is seen Mendelsohn etc., 2000, Oncogene, 19, be useful 6550-6565).

Detected erbB receptor tyrosine kinase member's amplification and/or activity recently, thus the hint in some non--neoplasm diseases, for example psoriasis (Ben-Bassat, Curr.Pharm. Des., 2000, 6, 933; Elder etc., Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar etc., Int.Urol.Nephrol., 2000, 32, 73), atherosclerosis and restenosis (Bokemeyer etc., Kidney Int., 2000, 58, 549) in work.Therefore, the inhibitor of expectation erbB receptor tyrosine kinase will be used for the treatment of these and other non--malignant cell excess proliferative disease.

European patent application EP 566 226 discloses some and is the 4-anilinoquinazoline 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 disclose some to have receptor tyrosine kinase and suppresses active carrying on anilino substituting group and 6-and/or the 7-position in the 4-position and carry substituent quinazoline derivant.

European patent application EP 837 063 is disclosed in the 4-amido quinazoline derivatives that the aryl that carries the part that contains aryl or heteroaryl on the 6-of quinazoline ring or the 7-position replaces.Claim that described compound is used for the treatment of excess proliferative disease.

International Patent Application WO 97/30035 and WO 98/13354 are disclosed in some 4-anilinoquinazoline that replaces in the 7-position for 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 7-position carries some ester group.

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

WO 01/21596 discloses the purposes of some 4-anilinoquinazoline derivatives as aurora 2 kinase inhibitor.

WO 02/18351 and WO 02/18372 disclose some and it is believed that to by the inhibited 4-anilinoquinazoline compound that replaces in 6-and/or 7-position of tyrosine kinase mediated signal transduction.

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

At present, the applicant has found some astonishing quinazoline derivant with anti-tumor activity, and these quinazoline derivants are contained some optional alkyloyl that replaces or alkylsulfonyl in the 7-position substituting group replaces.Compound of the present invention also has good cell to be renderd a service, and good physical property, particularly solubleness, and this can provide advantage aspect patient described compound being mixed with medicine and passing to.Some compound of the present invention has good DMPK characteristic, for example high bioavailability and/or high free blood plasma level and/or favourable transformation period and/or favourable volume of distribution, and expect that such characteristic provides effect in the improved body, and can reduce the patient and be exposed to described compound the time in vivo mutability (with other EGFR tyrosine kinase inhibitor, for example gefitinib is relatively the time).

In addition, chemical compound lot of the present invention in hERG test be non-activity or have only weak activity.

Although do not wish compound disclosed by the invention only is defined as and have pharmacologically active by influencing a kind of single bioprocess, but, the applicant thinks that compound provided by the invention is to play antitumor action by one or more receptor tyrosine kinases that suppress erbB family, and described kinases is relevant with the signal conduction step of the propagation that causes tumour cell.Specifically, the applicant thinks that compound of the present invention provides antitumor action by suppressing the EGF receptor tyrosine kinase.

Usually, although compound of the present invention has less inhibition activity to other kinases (for example VEGF and KDR receptor tyrosine kinase), but they but have effective inhibition activity to erbB receptor tyrosine kinase family, and for example they can suppress EGF and/or erbB2 and/or erbB4 receptor tyrosine kinase.In addition, compound of the present invention has obviously better usefulness to EGFR Tyrosylprotein kinase comparison erbB2 Tyrosylprotein kinase.Therefore, might be to be enough to suppress the EGFR Tyrosylprotein kinase there be the dosage of obviously effect to give compound of the present invention to erbB2 (or other) Tyrosylprotein kinase.The selective inhibitory that is provided by compound of the present invention can provide by the tyrosine kinase mediated treatment of diseases of EGFR, alleviate simultaneously may with suppress the relevant unwanted side effect of other Tyrosylprotein kinase.

According to a first aspect of the invention, the invention provides the quinazoline derivant of formula I:

Wherein:

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

Q ²-X ³-

X wherein ³For direct key or be O, and Q ²Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And R wherein ¹Adjacent carbons on any (2-6C) alkylidene chain in the substituting group is optional to be inserted into the following group of being selected from of this chain separately: O, S, SO, SO ₂, N (R ³), CO, CH (OR ³), CON (R ³), N (R ³) CO, SO ₂N (R ³), N (R ³) SO ₂, CH=CH and C ≡ C, wherein R ³Be hydrogen or (1-6C) alkyl,

And R wherein ¹Any CH in the substituting group ₂The optional CH endways of=CH-or HC ≡ C-group ₂=or HC ≡ position on carry and be selected from following substituting group: halogeno-group, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or be selected from the group of following formula:

Q ³-X ⁴-

X wherein ⁴For direct key or be selected from CO and N (R ⁴) CO, wherein R ⁴Be hydrogen or (1-6C) alkyl, and Q ³Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

And wherein at R ¹Any CH in the substituting group ₂Or CH ₃Group, rather than the CH in the heterocyclic ring ₂Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more halogeno-groups or (1-6C) alkyl substituent or be selected from following substituting group on the group: hydroxyl, cyano group, amino, carboxyl, formamyl, sulfamyl, oxo base, sulfo-, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino and N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁵-Q ⁴

X wherein ⁵For direct key or be selected from O, S, SO, SO ₂, N (R ⁵), CO, CH (OR ⁵), CON (R ⁵), N (R ⁵) CO, SO ₂N (R ⁵), N (R ⁵) SO ₂, C (R ⁵) ₂O, C (R ⁵) ₂S and C (R ⁵) ₂N (R ⁵), R wherein ⁵Be hydrogen or (1-6C) alkyl, and Q ⁴Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And R wherein ¹Any heterocyclic radical in the last substituting group is optional to carry one or more (for example 1; 2 or 3) substituting group; described substituting group can be identical or different, is selected from halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; formyl radical; sulfydryl; sulfamyl; (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; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino and N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C), or be selected from the group of following formula:

-X ⁶-R ⁶

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

And R wherein ¹Optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical in the last substituting group;

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

Each R ²Can be identical or different, be selected from halo, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, sulfamyl, trifluoromethyl, (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, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) group of the alkyl sulfonyl-amino of alkyl-(1-6C) and following formula:

-X ⁷-R ⁸

X wherein ⁷For direct key or be selected from O and N (R ⁹), R wherein ⁹Be hydrogen or (1-6C) alkyl, and R ⁸For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, (2-6C) alkanoylamino-(1-6C) or (1-6C) alkyl of alkoxycarbonyl amino-(1-6C);

Q ¹Be 4,5,6 or 7 yuan of saturated or unsaturated monocyclic heterocycles bases of part, described heterocyclic radical contains 1 nitrogen heteroatom and optional contains 1 or 2 other heteroatoms that is selected from O, S and N, and described ring is connected on the Sauerstoffatom among the formula I by ring carbon atom;

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

Each W can be identical or different, the group that is selected from halogeno-group, trifluoromethyl, cyano group, nitro, hydroxyl, oxo, amino, formyl radical, sulfydryl, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base and is selected from following formula:

-X ⁸-R ¹⁰

X wherein ⁸For direct key or be selected from O, CO, SO ₂And N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, and R ¹⁰For the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), N-(1-6C) alkyl of alkylamino-(1-6C) or N, N-two-[(1-6C) alkyl] amino-(1-6C) alkyl;

X ¹Be selected from CO and SO ₂

X ²Group for following formula:

-(CR ¹²R ¹³) _p-(Q ⁵) _m-(CR ¹⁴R ¹⁵) _q-

Wherein m is 0 or 1, p be 0,1,2,3 or 4 and Q be 0,1,2,3 or 4,

Each R ¹², R ¹³, R ¹⁴And R ¹⁵Can be identical or different, be selected from hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and two-[(1-6C) alkyl] amino, and Q ⁵Be selected from (3-7C) cycloalkylidene and (3-7C) inferior cycloalkenyl group,

And X wherein ²Any CH in the group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more halogeno-groups or (1-6C) alkyl substituent or be selected from following substituting group on the group: hydroxyl, cyano group, amino, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

Z be selected from hydrogen, hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) group of the alkyl sulfonyl-amino of alkyl-(1-6C) and following formula:

Q ⁶-X ⁹-

X wherein ⁹For direct key or be selected from O, N (R ¹⁶), SO ₂And SO ₂N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-6C) alkyl, and Q ⁶Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-4C) alkyl, heterocyclic radical or heterocyclic radical-(1-4C),

Condition is to work as X ⁹During for direct key, Q ⁶Be heterocyclic radical,

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

And wherein the adjacent carbons in any (2-6C) alkylidene chain in the Z substituting group is optional is inserted into the following group of being selected from of this chain separately: O, S, SO, SO ₂, N (R ¹⁷), CO ,-C=C-and-C ≡ C-, wherein R ¹⁷Be hydrogen or (1-6C) alkyl,

And any CH in any Z group wherein ₂Or CH ₃Group, rather than the CH in the heterocyclic ring ₂Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more halogeno-groups or (1-6C) alkyl substituent or be selected from following substituting group on the group: hydroxyl, cyano group, amino, carboxyl, formamyl, sulfamyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (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, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino and N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C),

And wherein any heterocyclic radical in the Z substituting group is optional carries one or more (for example 1; 2 or 3) substituting group; described substituting group can be identical or different, is selected from halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; formyl radical; sulfydryl; (1-6C) alkyl; (2-6C) alkenyl; (2-6C) alkynyl; (1-6C) alkoxyl group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (2-6C) alkyloyl; (2-6C) alkyloyl oxygen base and the group that is selected from following formula:

-X ¹⁰-R ¹⁸

X wherein ¹⁰For direct key or be selected from O, CO, SO ₂And N (R ¹⁹), R wherein ¹⁹Be hydrogen or (1-4C) alkyl, and R ¹⁸For the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-4C), hydroxyl-(1-4C), (1-4C) alkoxyl group-(1-4C), cyano group-(1-4C), amino-(1-4C), N-(1-4C) alkyl of alkylamino-(1-4C) and N, NIt is-two-[(1-4C) alkyl] amino-(1-4C) alkyl,

And wherein any heterocyclic radical in the Z substituting group is optional carries 1 or 2 oxo substituting group, condition be described oxo substituting group not with described heterocyclic radical in the adjacent ring carbon atom of epoxy atom on;

Condition is:

(i) the 4-anilino group in formula I is 4-bromo-2-fluorobenzene amido or 4-chloro-2-fluorobenzene amido, R ¹Be hydrogen or (1-3C) alkoxyl group and X ¹During for CO, then a be 0 and Z be selected from hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) group of alkyl-(1-6C) alkyl sulfonyl-amino, and following formula: Q ⁶-X ⁹-; With

(ii) work as Q ¹During for piperidyl, then Z is a hydrogen;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

According to a further aspect in the invention, the invention provides the quinazoline derivant of formula I, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein R ¹, R ², W, X ¹, X ², a and b as defined above; With

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

-X ¹⁰-R ¹⁸

X wherein ¹⁰For direct key or be selected from O, CO, SO ₂And N (R ¹⁹), R wherein ¹⁹Be hydrogen or (1-4C) alkyl, and R ¹⁸For the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-4C), hydroxyl-(1-4C), (1-4C) alkoxyl group-(1-4C), cyano group-(1-4C), amino-(1-4C), N-(1-4C) alkyl of alkylamino-(1-4C) and N, N-two-[(1-4C) alkyl] amino-(1-4C) alkyl;

Condition is:

(i) the 4-anilino group in formula I is 4-bromo-2-fluorobenzene amido or 4-chloro-2-fluorobenzene amido, R ¹Be hydrogen or (1-3C) alkoxyl group, and X ¹During for CO, then a be 0 and Z be selected from hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) the group Q of alkyl-(1-6C) alkyl sulfonyl-amino, and following formula ⁶-X ⁹-; With

(ii) work as Q ¹During for piperidyl, Z is a hydrogen.

In a specific embodiments of the present invention, the quinazoline derivant of formula I as defined above is provided, or its pharmacy acceptable salt.

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 relating to the independent alkyl such as " propyl group ", only be to refer in particular to linear form, and when relating to the independent branched-chain alkyl such as " sec.-propyl ", only be to refer in particular to the side chain form, and when mentioning independent cycloalkyl such as " cyclopentyl ", only refer in particular to 5 yuan of rings.Similarly convention is applicable on other generic term that 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; With two-[(1-6C) alkyl] amino comprise dimethylamino, diethylin, 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 one or more unsymmetrical carbon, therefore can exist with optically active or racemic form, the present invention comprises any have above-mentioned active such optically active or racemic form in its definition.Be also to be understood that (R, any scalemic or racemic mixture are represented in name S) to chipal compounds, and (R) and (S) expression optically active enantiomorph.In name, there is not (R, S), (R) or (S) time, should be appreciated that this name refers to any scalemic or racemic mixture, wherein the scalemic mixture comprises the R and the S optically active enantiomorph of any relative proportion, and racemic mixture comprises 50: 50 R of ratio and S optically active enantiomorph.By standard technique of organic chemistry well known in the art, for example, can carry out the synthetic of optically active form by from the synthetic of optically active raw material or the fractionation by racemic form.Similarly, use the standard laboratory technology of mentioning hereinafter, can estimate above-mentioned activity.

Suitable group in the above-mentioned general group comprises those that list below.

As any one " Q " group (Q for example ², Q ⁴Or Q ⁶) when being (3-7C) cycloalkyl, promptly (3-7C) cycloalkyl in " Q " group or the R group is suitably for, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or dicyclo [2.2.1] heptyl, as any one " Q " group (Q for example ², Q ⁴Or Q ⁶) when being (3-7C) cycloalkenyl group, promptly (3-7C) cycloalkenyl group in " Q " group is suitably for, as cyclobutene base, cyclopentenyl, cyclohexenyl or cycloheptenyl.Should be appreciated that, for Q ⁵, (3-7C) used herein cycloalkylidene refers to divalence (3-7C) cycloalkyl linking group, described linking group can connect by different carbon atoms in (3-7C) cycloalkylidene ring, perhaps can connect by same carbon atom in (3-7C) cycloalkylidene ring.Therefore, for example, " cyclopropylidene " group comprises inferior ring the third-1, ring propylidene base (cyclopropylidene) group of 2-base and following formula:

Yet, relate to discrete (3-7C) cycloalkylidene, for example encircle the propylidene base, only refer to this concrete group.Similarly agreement is applicable to by Q ⁵(3-7C) inferior cycloalkenyl group of expression.

As any " Q " group (Q for example ², Q ³, Q ⁴Or Q ⁶) when being heterocyclic radical, what promptly the heterocyclic radical in " Q " group was suitably for non-aromatics saturated (ring system that promptly has maximum saturation) or fractional saturation (is that ring system keeps, but be not whole degrees of unsaturation) 3-10 unit's monocycle or dicyclo, described ring can have 5 of as many as and be selected from following heteroatoms: oxygen, nitrogen and sulphur, except as otherwise noted, described ring can be that carbon or nitrogen connect, Oxyranyle for example, oxetanyl, azetidinyl, tetrahydrofuran base, 1, the 3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl (oxepanyl), pyrrolinyl, pyrrolidyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl (homopiperidinyl), piperazinyl, high piperazinyl (homopiperazinyl), the dihydropyridine base, tetrahydro pyridyl, the dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base, Decahydroisoquinolinpreparation base or decahydroquinolyl, tetrahydrofuran base particularly, THP trtrahydropyranyl, pyrrolidyl, morpholinyl, 1,4-oxaza heptane base, the parathiazan base, 1,1-dioxo tetrahydrochysene-4 H-1,4-thiazinyl, piperidyl or piperazinyl, more especially tetrahydrofuran (THF)-3-base, tetrahydropyran-4-base, tetramethylene sulfide-3-base, tetrahydric thiapyran-4-group, tetramethyleneimine-1-base, tetramethyleneimine-2-base, tetramethyleneimine-3-base, morpholino, morpholine-2-Ji, piperidino-(1-position only), piperidin-4-yl, piperidines-3-base, piperidines-2-base or piperazine-1-base.Nitrogen in the heterocyclic radical or sulphur atom can be oxidized and be obtained corresponding N oxide compound 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.Have the substituent so suitable group of 1 or 2 oxo or sulfo-for for example, 2-oxo-pyrrolidine base, 2-sulfo-pyrrolidyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.

For Q ¹Suitable value be non--aromatics 4-7 saturated or fractional saturation unit monocycle, described monocycle has 5 heteroatomss that are selected from oxygen, nitrogen and sulphur at the most, condition is that at least one heteroatoms is a nitrogen, described ring is connected in Sauerstoffatom in the formula 1 by carbon atom.The value that is fit to comprises, for example, above-mentioned those heterocyclic radicals that contain at least one nitrogen-atoms of mentioning, for example azetidinyl, pyrrolinyl, pyrrolidyl, tetrahydrochysene-1,4-thiazinyl, 1,1-dioxo tetrahydrochysene-1,4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro-pyrimidine base, Decahydroisoquinolinpreparation base or decahydroquinolyl.

Q ¹Occurrence be non--4,5,6 or 7 yuan of monocyclic heterocycles bases of aromatics that carbon connects, described heterocyclic radical contains 1 nitrogen heteroatom and optional contains 1 or 2 other heteroatoms that independently is selected from oxygen, nitrogen and sulphur, and described heterocyclic radical can be a saturated or fractional saturation fully.More particularly, Q ¹Be 4,5 or 6 yuan of monocyclic heterocycles bases that carbon connects, described heterocyclic radical contains 1 nitrogen heteroatom and optionally contains 1 other heteroatoms that is selected from oxygen, nitrogen and sulphur, described heterocyclic radical can be fractional saturation or be preferably fully saturated.More particularly, Q ¹Be complete 4, the 5 or 6 yuan of saturated monocyclic heterocycles bases of monocycle that carbon connects, described heterocyclic radical contains 1 nitrogen heteroatom.By Q ¹Such group that is fit to of representative comprises top listed suitable heterocyclic radical, more especially azetidinyl, pyrrolidyl, piperidyl, piperazinyl, homopiperidinyl or high piperazinyl (all these groups are connected in Sauerstoffatom among the formula I by ring carbon atom), more especially, azetidine-3-base, tetramethyleneimine-3-base, piperidines-3-base or piperidin-4-yl, and azetidine-3-base more especially.

When " Q " group was the alkyl of heterocyclic radical-(1-6C), it was suitably for as heterocyclyl methyl, 2-heterocyclic radical ethyl and 3-heterocyclic radical propyl group.The present invention includes corresponding " Q " group that is fit to, for example when " Q " group is not the alkyl of heterocyclic radical-(1-6C), can have alkyl of (3-7C) cycloalkyl-(1-6C) or (3-7C) alkyl of cycloalkenyl group-(1-6C).

For any " R " group (R ¹-R ¹⁹), W, or X ¹, X ²Or the various groups in the Z group, suitable value comprises :-

For halogeno-group: be fluoro base, chloro base, bromo base and iodo base;

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

For (2-8C) alkenyl: vinyl, pseudoallyl, allyl group and but-2-ene base;

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

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

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

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

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

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

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

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

For two-[(1-6C) alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino-and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and tert-butoxycarbonyl;

For N-(1-6C) alkyl-carbamoyl: N-methylamino formyl radical, N-ethylamino formyl radical and N-propyl group formamyl;

For N, N-two-[(1-6C) alkyl] formamyl: N, N-formyl-dimethylamino, N-ethyl-N-methylamino formyl radical and N, N-diethylamino formyl radical;

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

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

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

For the alkanoylamino of N-(1-6C) alkyl-(2-6C): N-methyl kharophen and N-methyl-prop amido;

For N-(1-6C) alkylsulfamoyl group: N-methyl sulfamyl and N-ethyl sulfamyl;

For N, N-two-[(1-6C) alkyl] sulfamyl: N, N-dimethylamino alkylsulfonyl;

For (1-6C) alkyl sulfonyl-amino: methylsulfonyl amino and ethylsulfonylamino;

For N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C): N-methyl methylsulfonyl amino and N-methyl ethylsulfonylamino;

For (3-6C) alkenoyl amino: acrylamido, methacrylamido and crotonoyl amino;

For the alkenoyl amino of N-(1-6C) alkyl-(3-6C): N-methacrylamido and N-methyl butene amido;

For (3-6C) alkynes acyl amino: propiolyl amino;

For the alkynes acyl amino of N-(1-6C) alkyl-(3-6C): N-methyl propine amido;

For amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl and 3-aminopropyl;

For the alkyl of (1-6C) alkylamino-(1-6C): methylamino-methyl, ethylamino methyl, 1-methylamino-ethyl, 2-methylamino-ethyl, 2-ethylamino ethyl and 3-methylamino-propyl group;

For two-[(1-6C) alkyl] amino-(1-6C) alkyl: dimethylamino methyl, diethylamino methyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylamino-propyl;

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

For the alkyl of hydroxyl-(1-6C): hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

For the alkyl of (1-6C) alkoxyl group-(1-6C): methoxymethyl, ethoxyl methyl, 1-methoxy ethyl, 2-methoxy ethyl, 2-ethoxyethyl group and 3-methoxy-propyl;

For the alkyl of cyano group-(1-6C): cyano methyl, 2-cyano ethyl, 1-cyano ethyl and 3-cyano group propyl group;

For the alkyl of (1-6C) alkylthio-(1-6C): methylthiomethyl, ethylmercapto group methyl, 2-methylmercaptoethyl, 1-methylmercaptoethyl and 3-methylthio group propyl group;

For the alkyl of (1-6C) alkyl sulphinyl-(1-6C): methylsulfinyl methyl, ethyl sulfinyl methyl, 2-methylsulfinyl ethyl, 1-methylsulfinyl ethyl and 3-methylsulfinyl propyl group;

For the alkyl of (1-6C) alkyl sulphonyl-(1-6C): sulfonyloxy methyl ylmethyl, ethylsulfonyl methyl, 2-methyl sulphonyl ethyl, 1-methyl sulphonyl ethyl and 3-methyl sulphonyl propyl group;

For the alkyl of (2-6C) alkanoylamino-(1-6C): acetylamino methyl, propionamido methyl and 2-kharophen ethyl;

For the alkyl of the alkanoylamino of N-(1-6C) alkyl-(2-6C)-(1-6C): N-methyl acetylamino methyl, 2-(N-methyl kharophen) ethyl and 2-(N-methyl-prop amido) ethyl;

For the alkyl of (1-6C) alkoxycarbonyl amino-(1-6C): methoxycarbonyl amino methyl, ethoxy carbonyl amino methyl, tert-butoxycarbonyl amino methyl and 2-methoxycarbonyl amino-ethyl;

For the alkyl of (2-6C) alkyloyl oxygen base-(1-6C): acetoxy-methyl, 2-acetoxyl group ethyl and 2-propionyloxy ethyl;

For the alkyl of formamyl-(1-6C): carbamyl ylmethyl, 1-formamyl ethyl, 2-formamyl ethyl and 3-formamyl propyl group;

For the alkyl of (2-6C) alkyloyl-(1-6C): ethanoyl methyl and 2-ethanoyl ethyl;

For the alkyl of N-(1-6C) alkyl-carbamoyl-(1-6C): N-methyl-carbamoyl methyl, N-ethylamino formyl radical methyl, N-propyl group carbamyl ylmethyl, 1-(N-methyl-carbamoyl) ethyl, 1-(N-ethylamino formyl radical) ethyl, 2-(N-methyl-carbamoyl) ethyl, 2-(N-ethylamino formyl radical) ethyl and 3-(N-methyl-carbamoyl) propyl group;

For N, alkyl: the N of N-two [(1-6C) alkyl] formamyl-(1-6C), N-dimethylamino formyl radical methyl, N, N-diethylin formyl radical methyl, 2-(N, N-dimethylamino formyl radical) ethyl and 3-(N, N-dimethylamino formyl radical) propyl group;

For sulfamyl (1-6C) alkyl: sulfamyl methyl, 1-sulfamyl ethyl, 2-sulfamyl ethyl and 3-sulfamyl propyl group;

For N-(1-6C) alkylsulfamoyl group (1-6C) alkyl: N-methyl sulfamyl methyl, N-ethyl sulfamyl methyl, N-propyl group sulfamyl methyl, 1-(N-methyl sulfamyl) ethyl, 2-(N-methyl sulfamyl) ethyl and 3-(N-methyl sulfamyl) propyl group; With

For N; N two-(1-6C) alkylsulfamoyl groups (1-6C) alkyl: N; N-dimethylamino alkylsulfonyl methyl, N; N-diethyl amino alkylsulfonyl methyl, N-methyl-N-ethyl sulfamyl methyl, 1-(N; N-dimethylamino alkylsulfonyl) ethyl, 1-(N, N-diethyl amino alkylsulfonyl) ethyl, 2-(N, N-dimethylamino alkylsulfonyl) ethyl, 2-(N; N-diethyl amino alkylsulfonyl) ethyl and 3-(N, N-dimethylamino alkylsulfonyl) propyl group.

As previously mentioned, the Z in formula I is formula Q ⁶-X ⁹-group, and X ⁹Be SO ₂N (R ¹⁶) time, SO then ₂Group is connected in Q ⁶And nitrogen-atoms is connected in the X among the formula I ²Similarly agreement is applicable at this other used group.For example, work as X ²Be formula Q ⁵-(CR ¹⁴R ¹⁵) _mGroup the time, Q then ⁵Group is connected in group Z and the (CR of formula I ¹⁴R ¹⁵) _mX among the group connection mode I ¹Group.

Such as above definition, at for example R ¹Adjacent carbon atom on any (2-6C) alkylidene chain in the substituting group can be chosen wantonly on chain by inserting group, for example O, CON (R ³), N (R ³) or C ≡ C and separating.For example, insert C ≡ C group on the ethylidene chain in 2-morpholino oxyethyl group group and obtain 4-morpholino fourth-2-alkynyloxy group group, and for example, insert the CONH group on the ethylidene chain in 3-methoxy propoxy group and obtain, for example, 2-(2-methoxyl group kharophen) oxyethyl group group.Should be appreciated that term (2-6C) alkylidene chain refers to any CH ₂CH ₂Group is (for example at R ¹In) and comprise, for example at (1-6C) alkyl, (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkenyl oxy, (2-8C) alkynyl and (2-8C) alkylidene chain in the alkynyloxy base.For example at R ¹In oneself-insert N (CH between third and fourth carbon atom in 5-alkene oxygen base group ₃) group, obtain 3-(N-methyl-N-allyl amino) propoxy-group.

As previously mentioned, work as R ¹Any CH in the substituting group ₂The optional CH endways of=CH-or HC ≡ C-group ₂=or HC ≡ position on carry substituting group, formula Q for example ³-X ⁴-group, X wherein ⁴For for example, NHCO and Q ³Be the alkyl of heterocyclic radical-(1-6C), so the suitable R that forms ¹Substituting group comprises, for example, N-[heterocyclic radical-(1-6C) alkyl] formamyl vinyl groups, for example N-(2-tetramethyleneimine-1-base ethyl) formamyl vinyl or N-[heterocyclic radical-(1-6C) alkyl] formamyl ethynyl, for example N-(2-tetramethyleneimine-1-base ethyl) formamyl ethynyl.

When relating to " CH at this ₂Or CH ₃Group is at each described CH ₂Or CH ₃Optionally on the group have one or more halogeno-groups or (1-6C) alkyl substituent " time, so at each described CH ₂Be fit to have 1 or 2 halos or (1-6C) alkyl substituent on the group, and at each described CH ₂Be fit to have 1,2 or 3 this type of substituting group on the group

When relate to any " CH at this ₂Or CH ₃Group is at each described CH ₂Or CH ₃The optional substituting group that has in this definition on the group " time; the substituting group that is fit to that so so forms comprises, for example (2-6) alkyloyl (for example hydroxyacetyl, 2-hydroxyl propionyl and 2-maloyl group) of the alkylamino (for example 2-hydroxyl-3-piperidino-(1-position only) propyl group amino and 2-hydroxyl-3-morpholino propyl group amino) of the heterocyclic radical of alkoxyl group (as 2-hydroxyl-3-piperidino-(1-position only) propoxy-and 2-hydroxyl-3-morpholino propoxy-), hydroxyl-replacement of the heterocyclic radical of hydroxyl-replacements-(1-6C)-(1-6C) and hydroxyl-replacement.

When relate to " any CH at this ₂Or CH ₃Rather than the CH in the heterocyclic radical ₂Group, the optional substituting group that carries " time, should be appreciated that, such description proposed only be to be present in the CH in the alkyl group for example ₃Optional substituting group on the group comes with the substituting group difference on the carbon atom that can be present in heterocyclic radical.Therefore, should be appreciated that can choose wantonly yet and carry one or more substituting groups when describe described heterocyclic radical group at this, the substituting group that exists on other ring carbon atom in heterocyclic radical is not got rid of in this description.For example, if R ¹Be 3-(tetramethyleneimine-1-yl) propoxy-, and be described as herein at for example R ¹CH in the substituting group ₂Or CH ₃Group, rather than the CH in the heterocyclic radical ₂Group, optional hydroxyl substituent and the R of carrying ¹In any heterocyclic radical optional when carrying alkyl substituent, then Ren Xuan hydroxyl substituent may reside in the CH of propoxy- ₂On, obtain for example 2-hydroxyl-3-(tetramethyleneimine-1-yl) propoxy-group.Similarly, alkyl for example methyl may reside on the tetramethyleneimine basic ring, obtains for example 3-(3-methylpyrrolidin-1-yl) propoxy-group.Similarly, the propoxy-group can be replaced by oh group, and the tetramethyleneimine basic ring can be obtained for example 2-hydroxyl-3-(3-methylpyrrolidin-1-yl) propoxy-group by methyl substituted.

For avoiding query, when W is the oxo base, Q ¹In CH ₂Replaced by O, obtain C (O) group.

Should be appreciated that, referred in this Q ¹During for piperidin-4-yl for example, refer to that piperidine ring is connected in the Sauerstoffatom among the formula I.Piperidine ring in the 1-position by group Z-X ²-X ¹-further replace, and choose wantonly on one or more available piperidyl ring carbon atoms and carry one or more W substituting groups.

Should be appreciated that some formula I compound can exist with the form of solvate and non-solvent compound, for example, the form of hydrate.Should be appreciated that, the present invention includes the erbB receptor tyrosine kinase is demonstrated inhibiting all such solvate form thereof.

Be also to be understood that some formula I compound can show as polymorph, thereby the present invention includes the erbB receptor tyrosine kinase is demonstrated inhibiting all such forms.

Be also to be understood that all tautomeric forms that the present invention relates to formula I compound, they demonstrate restraining effect to the erbB receptor tyrosine kinase.

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

Refer to the ester of the quinazoline derivant of formula I at this used term " pharmaceutically acceptable ester ", it obtains described parent compound or its pharmacy acceptable salt through hydrolysis in vivo.Hydrolyzable ester can be used for changing or improving the physics and/or the pharmaco-kinetic properties of described parent compound, for example solvability in the body of formula I quinazoline.The suitable ester group that can be used for forming the prodrug of pharmaceutically acceptable ester is known, for example discussed in the document below, for example: Pro-drugs as Novel Delivery Systems, T.Higuchi and V.Stella, Vol.14, ACS Symposium Series, and edit at Edward B.Roche;

Bioreversible Carriers in Drug Design，American PharmaceuticalAssociation and Pergamon Press，1987；

Design of Prodrugs is edited by H.Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, and Vol.42, p.309-396, by editors (AcademicPress, 1985) such as K.Widder;

A Textbook of Drug Design and Development is edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 " Design and Application of Prodrugs ", and H.Bundgaard is (1991) p.113-191;

H.Bundgaard，Advanced Drug Delivery Reviews，8，1-38(1992)；

H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77,285 (1988); With

N.Kakeya etc., Chem Pharm Bull, 32,692 (1984).

The concrete pharmaceutically acceptable ester of the quinazoline derivant of formula I or its pharmacy acceptable salt be with formula I in carboxyl or particularly oh group (for example, when Z is hydroxyl) formed ester, described ester is giving warm-blooded animal, man-hour for example, can be in human or animal body through the parent quinazoline of hydrolysis production I.

For the carboxylic group among the formula I, suitable pharmaceutically acceptable ester comprises C _1-6Alkoxyl group methyl esters such as methoxymethyl ester; C _1-6Alkanoyloxy methyl esters such as new pentane acyloxy methyl esters; The phthalidyl ester; C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Alkyl ester such as 1-cyclohexyl-carbonyl oxygen base ethyl ester; 1,3-dioxolane-2-ketone group (dioxolen-2-only) methyl esters such as 5-methyl isophthalic acid, 3-dioxolane-2-ketone group methyl esters; And C _1-6Alkoxy-carbonyl oxy ethyl ester such as 1-methoxycarbonyl oxygen base ethyl ester, and can form on any carboxylic group in The compounds of this invention.

For the oh group in formula I or its pharmacy acceptable salt, suitable pharmaceutically acceptable ester comprises inorganic ester for example phosphoric acid ester, alpha-acyloxy alkyl oxide and related compound and the ester that derives from pharmaceutically acceptable aliphatic carboxylic acid, especially paraffinic acid, alkenoic acid, naphthenic acid and alkanedioic acid, wherein each alkyl or alkenyl part advantageously has no more than 6 carbon atoms, and can form on any oh group in The compounds of this invention, for example when Z be hydroxyl or when containing oh group.After administration, hydrolysis in the pharmaceutically acceptable ester experience body, the parent carboxyl/oh group in the cracking production I quinazoline derivant.

The example that can be used for forming the alpha-acyloxy alkyl oxide of pharmaceutically acceptable ester comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.The selection that forms group for the pharmaceutically acceptable ester of the oh group among the formula I (for example when Z is hydroxyl) comprise the benzoyl of (1-6C) alkyloyl, benzoyl, phenylacetyl, replacement and phenylacetyl, (1-6C) alkoxy carbonyl (generation alkyl carbonate), two-(1-4C) alkyl-carbamoyls and N-(two-(1-4C) alkylamino ethyls)- N-(1-4C) alkyl-carbamoyl (generation carbamate), two-(1-4C) alkylamino ethanoyl and carboxyl ethanoyl.Substituent example comprises chloromethyl or amino methyl, (1-4C) alkylamino methyl and two-((1-4C) alkyl) amino methyl on the benzoyl, and the morpholino or the Piperazino (piperazino) that are connected to benzoyl basic ring 3-or 4-position from theheterocyclic nitrogen atom by the methylene radical linking group.

Concrete pharmaceutically acceptable ester for formula I quinazoline derivant or its pharmacy acceptable salt in oh group (for example when Z be hydroxyl or when containing oh group) phosphoric acid ester of formation.More particularly, pharmaceutically acceptable ester comprises formula I quinazoline derivant, and the oh group among its Chinese style I forms the phosphoryl (npd is 1) of formula (PD1) or ester or its pharmacy acceptable salt of inferior phosphoryl (npd is 0):

Another kind of concrete pharmaceutically acceptable ester is a formula I quinazoline derivant, and the hydroxyl among its Chinese style I (for example when Z is hydroxyl) forms phosphoryl, the group of production (PD1), and wherein npd is 1.

The useful intermediates for preparing this ester comprises the compound that contains formula (PD1) group, the wherein arbitrary or independent quilt of two-OH group (1-4C) alkyl (this compound itself also is the purpose compound), phenyl or phenyl-(1-4C) alkyl (this phenyl group is optional independently to be selected from (1-4C) alkyl, nitro, halogen and (1-4C) the group replacement of alkoxyl group by 1 or 2) protection in (PD1).

Contain the pharmaceutically acceptable ester of group as the formula I quinazoline derivant of (PD1); phosphorylating agent (for example containing chlorine or dialkyl amido leavings group) reaction that can be by making formula I quinazoline derivant and appropriate protection, oxidation then (if desired) and go to protect and prepare.Suitable phosphorylating agent is known, and for example comprises the phosphoramidic acid ester cpds such as the N of protection, N-two-[(1-6C) alkyl]-phosphoramidate, N for example, the N-diethylamino di(2-ethylhexyl)phosphate tert-butyl ester.

Should be understood that the ester group in the formula I quinazoline derivant can form the pharmacy acceptable salt of ester group, this salt formation part of the present invention.When requiring the pharmacy acceptable salt of pharmaceutically acceptable ester, it is finished by the routine techniques that those of ordinary skills know.Therefore, for example, the compound ionizable (partly or entirely) that contains formula (PD1) group forms the salt with suitable quantity gegenion.For example, if the pharmaceutically acceptable ester prodrugs of formula I quinazoline derivant contains (PD1) group, have two HO-P-functional groups, they can form suitable salt with suitable gegenion separately.The acceptable acid addition salts of formula (PD1) group is the salt of alkali, for example an alkali metal salt such as sodium salt, alkaline earth salt such as calcium salt or magnesium salts, or organic amine salt triethylamine salt or three-(2-hydroxyethyl) amine salt for example.Therefore for example group (PD1) can form a sodium salt or two-sodium salt).

Concrete novel cpd of the present invention comprises, for example, and formula I quinazoline derivant or its pharmacy acceptable salt or pharmaceutically acceptable ester, wherein, unless otherwise indicated, each R ¹, R ², W, Q ¹, X ¹, X ², a, b and Z have any implication defined above or following (a) defined implication to (qqqq) each section :-

(a) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) alkynyloxy group or formula Q ²-X ³-group,

X wherein ³For direct key or be O, Q ²Be the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Adjacent carbons in any in the substituting group (2-6C) alkylidene chain is optional by being selected from following group insertion chain and separating: O, N (R ³), CON (R ³), N (R ³) CO, CH=CH and C ≡ C, wherein R ³Be hydrogen or (1-6C) alkyl,

R wherein ¹Any CH in the substituting group ₂The optional CH endways of=CH-or HC ≡ C-group ₂=or HC ≡ position have and be selected from following substituting group: formamyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or formula Q ³-X ⁴-group,

X wherein ⁴For direct key or be selected from CO and N (R ⁴) CO, wherein R ⁴Be hydrogen or (1-6C) alkyl, Q ³Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group removes the CH in the heterocyclic radical ring ₂Outside the group, choose wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from hydroxyl, amino, cyano group, formamyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, NThe substituting group of-two-[(1-6C) alkyl] formamyls, or be selected from formula-X ⁵-Q ⁴Group, X wherein ⁵For direct key or be selected from O, N (R ⁵), CON (R ⁵), N (R ⁵) CO and C (R ⁵) ₂O, wherein R ⁵Be hydrogen or (1-6C) alkyl, Q ⁴Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; substituting group can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, or be selected from formula-X ⁶-R ⁶Group:

X wherein ⁶For direct key or be selected from O and N (R ⁷), R wherein ⁷Be hydrogen or (1-6C) alkyl, R ⁶For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, formamyl-(1-6C), N-(1-6C) alkyl of alkyl-carbamoyl-(1-6C) and N, NThe alkyl of-two-[(1-6C) alkyl] formamyls-(1-6C),

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1 or 2 oxo substituting group;

(b) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy, (2-6C) alkynyloxy group or formula Q ²-X ³-group,

X wherein ³Be direct key or O, Q ²Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Any CH in the substituting group ₂The optional CH endways of=CH-or HC ≡ C-group ₂=or HC ≡ position have and be selected from following substituting group: formamyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl,

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group removes the CH in the heterocyclic radical ring ₂Outside the group, choose wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from hydroxyl, amino, cyano group, formamyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, NThe substituting group of-two-[(1-6C) alkyl] formamyls, or be selected from formula-X ⁵-Q ⁴Group, X wherein ⁵For direct key or be selected from O, N (R ⁵), CON (R ⁵), N (R ⁵) CO and C (R ⁵) ₂O, wherein R ⁵Be hydrogen or (1-6C) alkyl, Q ⁵Be the alkyl of heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; substituting group can be identical or different, be selected from halogen, trifluoromethyl, hydroxyl, amino, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkyloyl, or be selected from formula-X ⁶-R ⁶Group:

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

(c) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (2-6C) alkenyloxy and (2-6C) alkynyloxy group,

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group removes the CH in the heterocyclic radical ring ₂Outside the group, choose wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from hydroxyl, amino, cyano group, formamyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl and N, NThe substituting group of-two-[(1-6C) alkyl] formamyls;

(d) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group or formula Q ²-X ³-group, X wherein ³Be O, Q ²Be the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

R wherein ¹Adjacent carbons in any in the substituting group (2-6C) alkylidene chain is optional by being selected from following group insertion chain and separating: O and N (R ³), R wherein ³Be hydrogen or (1-4C) alkyl,

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group removes the CH in the heterocyclic radical ring ₂Outside the group, choose wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from hydroxyl, amino, cyano group, (1-6C) alkoxyl group, the amino substituting group of (1-6C) alkylamino and two-[(1-6C) alkyl],

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; substituting group can be identical or different, be selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls and (2-6C) alkyloyl,

(e) R ¹Be selected from hydroxyl, (1-6C) alkoxyl group or formula Q ²-X ³-group, X wherein ³Be O, Q ²Be the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of azetidine-3-base-(1-4C), azetidine-1-base-(2-4C), tetramethyleneimine-2-base-(1-4C), tetramethyleneimine-3-base-(1-4C), tetramethyleneimine-1-base-(2-4C), piperidines-2-base-(1-4C), piperidines-3-base-(1-4C), piperidin-4-yl-(1-4C), piperidino-(1-position only)-(2-4C), Piperazino-(2-4C) or morpholino-(2-4C)

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group removes the CH in the heterocyclic radical ring ₂Outside the group, choose wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from hydroxyl, (1-4C) alkoxyl group, amino, the amino substituting group of (1-4C) alkylamino and two-[(1-4C) alkyl],

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; substituting group can be identical or different, be selected from halogen, hydroxyl, amino, formamyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxyl group, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, N-(1-4C) alkyl-carbamoyl, N, N-two-(1-4C) alkyl] formamyl and (2-4C) alkyloyl,

R wherein ¹Optional 1 oxo substituting group (the preferred R that has of any heterocyclic radical group in the last substituting group ¹Any oxo group on the middle morpholino group is positioned at 3 or 5 on the morpholino ring);

(f) R ¹Be selected from the alkoxyl group of hydrogen, hydroxyl, (1-4C) alkoxyl group, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C) alkoxyl group or formula Q ²-X ³-group,

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

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1,2 or 3 substituting group; substituting group can be identical or different; be selected from amino and (2-4C) alkyloyl of halogen, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl]

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1 oxo substituting group;

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

R wherein ¹Adjacent carbons in any in the substituting group (2-6C) alkylidene chain is optional by being selected from following group insertion chain and separating: O, NH, N (CH ₃), CH=CH and C ≡ C,

Work as R ¹During for vinyloxy group, allyloxy, second alkynyloxy group or 2-third alkynyloxy group, R ¹The optional CH endways of substituting group ₂=or HC ≡ position have and be selected from following substituting group: N-(2-dimethyl aminoethyl) formamyl, N-(3-dimethylaminopropyl) formamyl, methylamino methyl, 2-methylamino ethyl, 3-methylamino propyl group, 4-methylamino butyl, dimethylaminomethyl, 2-dimethyl aminoethyl, 3-dimethylaminopropyl and 4-dimethylamino butyl, or formula Q ³-X ⁴-group:

X wherein ⁴For direct key or be NHCO or N (CH ₃) CO, Q ³Be tetramethyleneimine-1-ylmethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 4-tetramethyleneimine-1-base butyl, tetramethyleneimine-2-ylmethyl, 2-tetramethyleneimine-2-base ethyl, 3-tetramethyleneimine-2-base propyl group, the morpholino methyl, 2-morpholino ethyl, 3-morpholino propyl group, 4-morpholino butyl, the piperidino-(1-position only) methyl, 2-piperidino-(1-position only) ethyl, 3-piperidino-(1-position only) propyl group, 4-piperidino-(1-position only) butyl, piperidines-3-ylmethyl, 2-piperidines-3-base ethyl, the piperidin-4-yl methyl, 2-piperidin-4-yl ethyl, piperazine-1-ylmethyl, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group or 4-piperazine-1-base butyl

R ¹In the substituting group, connect any CH of 2 carbon atoms ₂Group (removes the CH in the heterocyclic radical ring ₂Group is outer) or connect any CH of carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from following substituting group: hydroxyl, amino, methoxyl group, oxyethyl group, methyl sulphonyl, methylamino and dimethylamino,

R wherein ¹Any heterocyclic radical group in the last substituting group is chosen wantonly and is had 1 or 2 substituting group; substituting group can be identical or different; be selected from fluorine, chlorine, trifluoromethyl, hydroxyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamyl, methyl, ethyl, n-propyl, sec.-propyl and methoxyl group, R ¹Any piperidines-3-ylmethyl, piperidin-4-yl methyl or piperazine in the substituting group-1-base group is optional to carry out with 2-methoxy ethyl, 3-methoxy-propyl, 2-amino-ethyl, 3-aminopropyl, 2-methylamino ethyl, 3-methylamino propyl group, 2-dimethyl aminoethyl, 3-dimethylaminopropyl, ethanoyl or propionyl N-replace,

(h) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (3-7C) cycloalkyl-oxygen base and (3-7C) alkoxyl group of cycloalkyl-(1-6C),

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent on the group, or be selected from following substituting group: hydroxyl, cyano group, amino, carboxyl, formamyl, sulfamyl, oxo, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (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, N-(1-6C) alkylsulfamoyl group and N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl amino and N-(1-6C) the alkyl sulfonyl amino of alkyl-(1-6C);

(i) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (3-7C) cycloalkyl-oxygen base and (3-7C) alkoxyl group of cycloalkyl-(1-6C),

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more fluoro or chloro substituting group on the group, or be selected from following substituting group: hydroxyl, amino, (1-4C) alkoxyl group, (1-4C) alkylamino and two-[(1-4C) alkyl] amino;

(j) R ¹Be selected from hydrogen, hydroxyl, (1-6C) alkoxyl group, (3-7C) cycloalkyl-oxygen base and (3-7C) alkoxyl group of cycloalkyl-(1-6C),

R wherein ¹Adjacent carbons in any in the substituting group (2-6C) alkylidene chain is optional to be inserted in the chain and is separated by the O atom,

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more fluoro or chloro substituting group on the group, or be selected from the hydroxyl and (1-4C) substituting group of alkoxyl group;

(k) R ¹Be selected from the alkoxyl group of alkoxyl group of the alkoxyl group of the alkoxyl group of the alkoxyl group of the alkoxyl group of hydrogen, (1-6C) alkoxyl group, cyclopropyl-(1-4C), cyclobutyl-(1-4C), cyclopentyl-(1-4C), cyclohexyl-(1-6C), tetrahydrofuran base-(1-4C) and THP trtrahydropyranyl-(1-4C)

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more fluoro or chloro substituting group on the group, or be selected from the hydroxyl and (1-3C) substituting group of alkoxyl group;

(l) R ¹Be selected from hydrogen, (1-6C) alkoxyl group, cyclo propyl methoxy and 2-cyclopropyl oxyethyl group,

R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more fluoro or chloro substituting group on the group, or be selected from the substituting group of hydroxyl, methoxyl group and oxyethyl group;

(m) R ¹Be selected from methoxyl group, oxyethyl group, propoxy-, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2-ethoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy, 2-(tetramethyleneimine-1-yl) oxyethyl group, 3-(tetramethyleneimine-1-yl) propoxy-, 2-piperidino-(1-position only) oxyethyl group, 3-piperidino-(1-position only) propyl group, 2-Piperazino oxyethyl group, 3-Piperazino propoxy-, 2-morpholino oxyethyl group and 3-morpholino propoxy-;

(n) R ¹Be selected from hydrogen, methoxyl group, oxyethyl group, propoxy-, isopropoxy, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2-ethoxy ethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoro ethoxy;

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

(p) R ¹Be selected from hydrogen and (1-3C) alkoxyl group (R specifically ¹Be (1-3C) alkoxyl group such as methoxyl group, oxyethyl group and isopropoxy);

(q) R ¹Be hydrogen;

(r) R ¹Be methoxyl group;

(s) each R ²Can be identical or different, be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkyloyl, (2-6C) alkanoyloxy and formula-X ⁷-R ⁸Group,

X wherein ⁷For direct key or be selected from O and N (R ⁹), R wherein ⁹Be hydrogen or (1-6C) alkyl, R ⁸For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halogen-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl;

(t) each R ²Can be identical or different, be selected from halogen, hydroxyl, amino, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

(u) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, iodo base, cyano group, hydroxyl, trifluoromethyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl and (1-4C) alkoxyl group;

(v) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, (1-4C) alkyl, (2-4C) alkenyl and (2-4C) alkynyl;

(w) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, iodo base, cyano group, formamyl, hydroxyl, trifluoromethyl, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, vinyl, allyl group, ethynyl, 1-proyl, 2-propynyl, N-methylamino formyl radical, N-ethylamino formyl radical and N, the N-formyl-dimethylamino;

(x) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, iodo base, cyano group, hydroxyl, trifluoromethyl, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, vinyl, allyl group, ethynyl, 1-proyl and 2-propynyl;

(y) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, cyano group, hydroxyl, trifluoromethyl, methyl, ethyl, methoxyl group, oxyethyl group and ethynyl;

(z) each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base and ethynyl;

(aa) each R ²Can be identical or different, be selected from halogeno-group (specifically fluoro base, chloro base and bromo base);

(bb) b is 1,2 or 3, one R ²Position (3-) between in formula 1 on the anilino group;

(cc) b is 1,2 or 3, each R ²Can be identical or different, as the definition in any above (s) to (aa):

(dd) b is 1,2 or 3, one R ²Position (3-) is halogeno-group between in formula 1 on the anilino group, when b is 2 or 3, and other R ²Group can be identical or different, as the definition in any above (s) to (aa);

(ee) b is 1,2 or 3, each R ²Can be identical or different, be halogen, one of them R ²Position (3-) between on the anilino in formula I;

(ff) b is 1 or 2, each R ²Can be identical or different, be halogeno-group (specifically fluoro base, chloro base or bromo base), one of them R ²Be position (3-) between on the anilino group, other R ²Ortho position on the anilino group (2-) or contraposition (4-);

(gg) b is 1 or 2, one R ²(3-) position is chloro base or bromo base (specifically being the chloro base), another R when b is 2 between the anilino group in formula 1 ²Group is selected from fluoro base, chloro base and bromo (specifically being the fluoro base);

(hh) among the formula I on the quinazoline ring 4 anilino group be selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromobenzene amido and 3-acetylenylbenzene amido;

(ii) among the formula I on the quinazoline ring 4 anilino group be selected from 3-chloro-4-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromobenzene amido, 3-toluidine and 3-acetylenylbenzene amido;

(jj) among the formula I on the quinazoline ring 4 anilino group be 3-chloro-4-fluoroanilino;

(kk) among the formula I on the quinazoline ring 4 anilino group be 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino (more particularly, anilino is a 3-chloro-2-fluoroanilino);

(ll) Q ¹Be selected from azetidinyl, pyrrolidyl, piperidyl and homopiperidinyl, wherein Q ¹Be the carbon that is connected in the Sauerstoffatom among the formula I, the condition of reaching is when Z is piperidyl, and then Z is a hydrogen;

(mm) Q ¹Be selected from azetidine-3-base, tetramethyleneimine-3-base, piperidines-3-base and piperidin-4-yl, condition is to work as Q ¹During for piperidines-3-base or piperidin-4-yl, then Z is a hydrogen;

(nnn) Q ¹Be selected from tetramethyleneimine-3-base, piperidines-3-base and piperidin-4-yl, condition is to work as Q ¹During for piperidines-3-base or piperidin-4-yl, then Z is a hydrogen;

(ooo) Q ¹For piperidin-4-yl and Z are hydrogen;

(ppp) Q ¹Be azetidine-3-base;

(qqq) each W can be identical or different, is selected from halogeno-group, trifluoromethyl, hydroxyl, oxo, (1-6C) alkyl, (1-6C) alkoxyl group and is selected from the group of following formula:

-X ⁸-R ¹⁰

X wherein ⁸Be direct key or O, R ¹⁰Be alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C) or (1-6C) alkyl of alkoxyl group-(1-6C);

(rrr) each W can be identical or different, is selected from halogeno-group, hydroxyl, oxo base, (1-6C) alkyl and (1-6C) alkoxyl group;

(sss) each W can be identical or different, is selected from halogeno-group (particularly fluoro base), hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group;

(ttt) a be 0,1 or 2 and each W can be identical or different, as the definition in any (qqq) to (sss);

(uuu) a be 0 or 1 and W such as any (qqq) to (sss) in definition;

(vvv) a is 0;

(www) Q ¹Be piperidin-4-yl, a is 0 or 1, and Z is the definition among hydrogen and W such as any (qqq) to (sss);

(www) Q ¹Be azetidine-3-base, a is that 0 or 1 (preferred 0) and W are (1-4C) alkyl;

(xxx) X ¹Be CO;

(yyy) X ¹Be SO ₂

(zzz) X ²Group for following formula:

-(CR ¹²R ¹³) _p-(Q ⁵) _m-(CR ¹⁴R ¹⁵) _q-wherein m is 0 or 1, and p is 0,1,2,3 or 4, and q is 0,1,2,3 or 4,

Each R ¹², R ¹³, R ¹⁴And R ¹⁵Can be identical or different, be selected from hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and two-[(1-6C) alkyl] amino, Q ⁵Be selected from (3-7C) cycloalkylidene and (3-7C) inferior cycloalkenyl group,

X wherein ²Any CH in the group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogeno-groups or (1-6C) alkyl substituent on the group,

X ²In the substituting group, connect any CH of 2 carbon atoms ₂Any CH of group or connection carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from following substituting group: hydroxyl, cyano group, amino, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

(aaa) X ²Be selected from formula-(Q ⁵) _m-(CR ¹⁴R ¹⁵) _q-group and formula-(CR ¹²R ¹³) _q-(Q ⁵) _m-group, wherein m is 0 or 1, q is 1,2,3 or 4, and Q ⁵, R ¹², R ¹², R ¹⁴And R ¹⁵As defined above;

(bbb) X ²Be formula-Q ⁵-group, for example (3-7C) cycloalkylidene for example encircles the propylidene base;

(ccc) X ²Be selected from the cycloalkylidene of cyclopropylidene, inferior cyclobutyl, cyclopentylidene, cyclohexylidene, methylene radical-(3-6C), (3-6C) cycloalkylidene-methylene radical-, the cycloalkylidene of ethylidene-(3-6C) and (3-6C) cycloalkylidene-ethylidene-,

X wherein ²In any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogeno-groups or (1-6C) alkyl substituent on the group, or be selected from following substituting group: hydroxyl, amino, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

(ddd) X ²Be formula-(CR ¹²R ¹³) _q-group,

Q is 1,2,3 or 4 (particularly 1 or 2),

Each R ¹²And R ¹³Can be identical or different, be selected from hydrogen and (1-6C) alkyl,

X wherein ²In any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogenic substituents on the group,

X ²In the substituting group, connect any CH of 2 carbon atoms ₂Any CH of group or connection carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from following substituting group: hydroxyl, amino, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

(eee) X ²Be formula-(CR ¹²R ¹³) _q-group,

Q is 1,2 or 3,

X wherein ²Any CH in the group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogeno-group substituting groups on the group,

X ²In the substituting group, connect any CH of 2 carbon atoms ₂Any CH of group or connection carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from the hydroxyl and (1-6C) substituting group of alkoxyl group;

(fff) X ²Be formula-(CR ¹²R ¹³) _q-(CR ^12aaR ^13aa)-group,

Q is 1,2 or 3 (particularly 1 or 2, more especially 1),

Each R ¹², R ¹³And R ^13aaCan be identical or different, be selected from hydrogen and (1-6C) alkyl,

R ^12aaBe selected from amino, (1-6C) alkylamino and two-[(1-6C) alkyl] amino,

(ggg) X ²Be formula-(CR ¹²R ¹³) _q-group,

Q is 1,2,3 or 4 (particularly 1 or 2, more especially 1),

Each R ¹²And R ¹³Can be identical or different, be selected from hydrogen and (1-6C) alkyl, condition is X ²In at least one R ¹²Or R ¹³Group is (1-6C) alkyl,

(hhh) X ²Be selected from formula-(CR ¹²R ¹³)-,-(CR ¹²R ¹³CH ₂)-,-(CR ¹²R ¹³CH ₂CH ₂)-,-(CH ₂CR ¹²R ¹³)-and-(CH ₂CH ₂CR ¹²R ¹³)-group,

X wherein ²In any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogeno-group substituting groups on the group,

X ²In the substituting group, connect any CH of 2 carbon atoms ₂Any CH of group or connection carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from hydroxyl, amino, (1-6C) alkoxyl group, the amino substituting group of (1-6C) alkylamino and two-[(1-6C) alkyl];

(iii) X ²Be selected from formula-(CR ¹²R ¹³)-,-(CR ¹²R ¹³CH ₂)-,-(CR ¹²R ¹³CH ₂CH ₂)-,-(CH ₂CR ¹²R ¹³)-and-(CH ₂CH ₂CR ¹²R ¹³)-group,

Each R ¹²And R ¹³Can be identical or different, be selected from hydrogen and (1-6C) alkyl, condition is R at least ¹²Or R ¹³One of be side chain (1-6C) alkyl,

(jjj) X ²Be selected from formula-(CR ¹²R ¹³)-,-(CR ¹²R ¹³CH ₂)-,-(CR ¹²R ¹³CH ₂CH ₂)-,-(CH ₂CR ¹²R ¹³)-and-(CH ₂CH ₂CR ¹²R ¹³)-group,

Each R ¹²And R ¹³Can be identical or different, be selected from hydrogen and (1-6C) alkyl, condition is X ²In R at least ¹²Or R ¹³One of be branched-chain alkyl, wherein this branched-chain alkyl is preferably selected from sec.-propyl, isobutyl-, sec-butyl and the tertiary butyl,

X wherein ²In any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more fluoro or chloro substituting group on the group,

X ²In the substituting group, connect any CH of 2 carbon atoms ₂Any CH of group or connection carbon atom ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have on the group and be selected from the hydroxyl and (1-3C) substituting group of alkoxyl group;

(kkk) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-,-(CR ¹²R ¹³)-,-(CR ¹²R ¹³CH ₂)-and-(CH ₂CR ¹²R ¹³)-group,

Each R wherein ¹²And R ¹³Can be identical or different, be selected from alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C) and (1-4C) alkyl of alkoxyl group-(1-4C), condition is R ¹²And R ¹³Can not be hydrogen simultaneously;

(lll) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-group,

Each R wherein ^12aCan be identical or different, be selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of (1-4C) alkyl, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C),

And R wherein ^12bBe selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl]-amino, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C);

(mmm) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-and-(CH ₂CHR ^12b)-group,

R wherein ^12aBe selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C),

And R wherein ^12bBe selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of hydrogen, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C);

(nnn) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-group,

Each R wherein ^12aCan be identical or different, for (1-4C) alkyl,

And R wherein ^12bBe selected from amino, (1-4C) alkylamino and two-[(1-4C) alkyl]-amino;

(ooo) X ²Be selected from formula-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-group,

Each R wherein ^12aCan be identical or different, be in (1-4C) alkyl (particularly (1-3C) alkyl),

And R wherein ^12bBe selected from amino, (1-4C) alkylamino and two-[(1-4C) alkyl]-amino (R particularly ^12bBe selected from (1-4C) alkylamino and two-[(1-4C) alkyl]-amino, more especially two-[(1-3C) alkyl]-amino);

(ppp) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ¹²)-,-(CHR ¹²CH ₂)-and-(CH ₂CHR ¹²)-group,

R wherein ¹²Be selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C);

(qqq) X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12a)-,

Each R wherein ^12aCan be identical or different, be (1-4C) alkyl;

(rrr) X ²Be selected from formula-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12a)-(particularly, X ²For-(CHR ^12aThe group of)-),

Each R wherein ^12aCan be identical or different, be (1-4C) alkyl;

(sss) X ²Be selected from formula-(CH ₂) _q-group, wherein q is 1,2 or 3, particularly q is 1 or 2, more especially 1;

(ttt) Z be selected from hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) group of the alkyl sulfonyl-amino of alkyl-(1-6C) and following formula:

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

And any CH in the Z group wherein ₂Or CH ₃Group, rather than the CH in the heterocyclic ring ₂Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more halogeno-groups or (1-6C) alkyl substituent or be selected from following substituting group on the group: hydroxyl, cyano group, amino, carboxyl, formamyl, sulfamyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (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, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, N-(1-6C) alkanoylamino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkyl sulfonyl-amino and N-(1-6C) alkyl sulfonyl-amino of alkyl-(1-6C),

-X ¹⁰-R ¹⁸

(uuu) Z be selected from hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino and N-(1-6C) group of the alkyl sulfonyl-amino of alkyl-(1-6C) and following formula:

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

And wherein any heterocyclic radical in Z is saturated fully 4,5,6 or the 7-unit heterocyclic radical of monocycle, and it contains 1 or 2 heteroatoms that is selected from oxygen, nitrogen and sulphur,

-X ¹⁰-R ¹⁸

(vvv) Z is selected from the group of hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group and following formula:

Q ⁶-X ⁹-

X wherein ⁹For direct key or be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-6C) alkyl, and Q ⁶Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-4C) alkyl, heterocyclic radical or heterocyclic radical-(1-4C),

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

And 4,5,6 or 7-complete saturated or fractional saturation the unit monocyclic heterocycles base of wherein any heterocyclic radical in Z is monocycle non--aromatics, described heterocyclic radical contains 1 other heteroatoms that is selected from the heteroatoms of oxygen and nitrogen and is selected from oxygen, nitrogen and sulphur,

-X ¹⁰-R ¹⁸

(www) Z is selected from the group of hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group and following formula:

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

And wherein any heterocyclic radical in the Z substituting group is selected from tetrahydrofuran base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl (oxepanyl), pyrrolidyl, morpholinyl, piperidyl, homopiperidinyl, piperazinyl and high piperazinyl, described heterocyclic radical can be connected in the group that it connects by carbon or nitrogen

-X ¹⁰-R ¹⁸

(xxx) Z be selected from alkylamino, two-[(1-6C) alkyl] of the alkylamino of hydroxyl, amino, (1-6C) alkylamino, hydroxyl-(2-6C), (1-4C) alkoxyl group-(2-6C) amino, N-[hydroxyl-(2-6C) alkyl]- N-(1-6C) alkylamino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- N-(1-6C) alkylamino, two-[hydroxyl-(2-6C) alkyl]-amino, two-[(1-4C) alkoxyl group-(2-6C) alkyl] amino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- NThe alkoxyl group of-[hydroxyl-(2-6C) alkyl]-amino, (1-6C) alkoxyl group, hydroxyl-(2-6C), (1-4C) alkoxyl group-(2-6C) alkoxyl group, azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base, morpholino, the high piperidines-high piperazine of 1-base-1-base, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1, the group of 4-dioxane base and following formula:

Q ⁶-X ⁹-

X wherein ⁹Be selected from O and N (R ¹⁶), R wherein ¹⁶Be hydrogen or (1-4C) alkyl, and Q ⁶Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-4C) alkyl, heterocyclic radical or heterocyclic radical-(1-4C),

And Q wherein ⁶In any heterocyclic radical group be selected from tetrahydrofuran base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl, pyrrolidyl, morpholinyl, tetrahydrochysene-1,4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, described heterocyclic radical can be connected in the group that it connects by carbon or nitrogen

And condition is that Z is a heterocyclic radical, preferably can be by Q when m, p and q are 0 ⁶One of above-mentioned heterocyclic radical of expression (this heterocyclic radical preferably on carbon with X ¹Link to each other),

-X ¹⁰-R ¹⁸

(yyy) Z be selected from alkylamino, two-[(1-6C) alkyl] of the alkylamino of amino, (1-6C) alkylamino, hydroxyl-(2-6C), (1-4C) alkoxyl group-(2-6C) amino, N-[hydroxyl-(2-6C) alkyl]- N-(1-6C) alkylamino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- N-(1-6C) alkylamino, two-[hydroxyl-(2-6C) alkyl]-amino, two-[(1-4C) alkoxyl group-(2-6C) alkyl] amino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- N-[hydroxyl-(2-6C) alkyl]-amino, azetidine-1-base, tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base, morpholino, high piperidines-1-base and high piperazine-1-base,

And any CH in the Z group wherein ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more fluoro substituting groups on the group or be selected from following substituting group: hydroxyl, cyano group, amino, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino,

And wherein any heterocyclic radical in the Z substituting group is chosen wantonly and is carried one or more (for example 1,2 or 3) substituting group; described substituting group can be identical or different; be selected from halogeno-group; cyano group, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (2-4C) alkyloyl, (1-4C) alkylamino and two-[(1-4C) alkyl] amino

Condition is when m, p and q are 0, and then Z is one of the above-mentioned heterocyclic radical that can be represented by Z, for example tetramethyleneimine-1-base or piperidino-(1-position only) (preferred m+p+q sum is at least 1);

(zzz) Z is selected from the alkoxyl group of hydroxyl, (1-6C) alkoxyl group, hydroxyl-(2-6C), (1-4C) alkoxyl group-(2-6C) alkoxyl group, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, 1,3-dioxolanyl, 1, the group of 4-dioxane base, THP trtrahydropyranyl and following formula:

Q ⁶-X ⁹-

X wherein ⁹Be O, and Q ⁶Be the alkyl of the alkyl of (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-4C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-4C) alkyl, heterocyclic radical or heterocyclic radical-(1-4C),

And Q wherein ⁶In any heterocyclic radical be selected from tetrahydrofuran base, 1,3-dioxolanyl, 1,4-dioxane base, THP trtrahydropyranyl and oxepane alkyl,

And condition is that then Z is a heterocyclic radical when m, p and q are 0, and being preferably can be by Q ⁶(described heterocyclic radical preferably is connected in X by carbon to one of above-mentioned heterocyclic radical of expression ¹),

And wherein any heterocyclic radical in the Z substituting group is chosen wantonly and is carried one or more (for example 1,2 or 3) substituting group, described substituting group can be identical or different, be selected from halogeno-group, cyano group, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino and two-[(1-4C) alkyl] amino;

(aaaa) Z is selected from the group of hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group and following formula:

Q ⁶-X ⁹-

X wherein ⁹Be direct key and Q ⁶Be heterocyclic radical,

And condition is when m, p and q are 0, and then Z is that (preferred carbon is connected in X to heterocyclic radical ¹),

And wherein any heterocyclic radical in the Z substituting group is selected from azetidinyl, tetrahydrofuran base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl, pyrrolidyl, morpholinyl, piperidyl, homopiperidinyl, piperazinyl and high piperazinyl

And any CH in the Z group wherein ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more halogeno-groups or (1-6C) alkyl substituent or be selected from following substituting group on the group: hydroxyl and (1-6C) alkoxyl group,

And wherein any heterocyclic radical in the Z substituting group is optional carries one or more (for example 1; 2 or 3) substituting group; described substituting group can be identical or different; be selected from halogeno-group; trifluoromethyl; cyano group; nitro; hydroxyl; amino; formyl radical; (1-6C) alkyl; (2-6C) alkenyl; (2-6C) alkynyl; (1-6C) alkoxyl group; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino and (2-6C) alkyloyls

And wherein any azetidinyl among the Z, pyrrolidyl, piperidyl, homopiperidinyl, piperazinyl and high piperazinyl group are chosen wantonly and are carried the oxo substituting group;

(bbbb) Z be selected from alkylamino, two-[(1-6C) alkyl] of the alkylamino of hydroxyl, amino, (1-6C) alkylamino, hydroxyl-(2-6C), (1-4C) alkoxyl group-(2-6C) amino, N-[hydroxyl-(2-6C) alkyl]- N-(1-6C) alkylamino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- N-(1-6C) alkylamino, two-[hydroxyl-(2-6C) alkyl]-amino, two-[(1-4C) alkoxyl group-(2-6C) alkyl] amino, N-[(1-4C) alkoxyl group-(2-6C) alkyl]- NThe alkoxyl group of-[hydroxyl-(2-6C) alkyl]-amino, (1-6C) alkoxyl group, hydroxyl-(2-6C) and (1-4C) alkoxyl group of alkoxyl group-(2-6C),

And wherein the m+p+q sum is at least 1;

(cccc) Z is selected from hydroxyl, methoxyl group, oxyethyl group, the 2-hydroxyl-oxethyl, the 2-methoxy ethoxy, amino, methylamino-, ethylamino, N-(2-hydroxyethyl) amino, N-(2-methoxy ethyl) amino, dimethylamino, N-methyl-N-ethylamino, two-ethylamino, N-(2-hydroxyethyl)-N-methylamino-, N-(2-hydroxyethyl)-N-ethylamino, N, N-two-(2-hydroxyethyl) amino, N-(2-methoxy ethyl)-N-methylamino-, N-(2-methoxy ethyl)-N-ethylamino, tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base, morpholino, tetrahydrofuran base and THP trtrahydropyranyl;

And wherein any heterocyclic radical in Z is optional carries 1 or 2 substituting group, and described substituting group can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (2-4C) alkyloyl and (1-4C) alkoxyl group,

And condition is when m, p and q are 0, and Z is one of the above-mentioned heterocyclic radical that can be represented by Z, for example tetrahydrofuran base, tetramethyleneimine-1-base or piperidino-(1-position only) (preferred m+p+q sum is at least 1);

(dddd) Z is selected from tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base, morpholino, high piperidines-1-base, high piperazine-1-base (particularly Z is selected from tetramethyleneimine-1-base, piperidino-(1-position only), piperazine-1-base and morpholino),

And wherein the heterocyclic radical in Z is chosen wantonly and is carried one or more (for example 1,2 or 3) substituting group; it can be identical or different, be selected from fluoro base, chloro base, cyano group, hydroxyl, amino, formamyl, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls, ethanoyl, propionyl, 2-fluoro ethyl, 2-hydroxyethyl, 2-methoxy ethyl, cyano methyl, hydroxyacetyl, glycyl, methylamino-ethanoyl, (preferred m+p+q sum is at least 1 to ethylamino ethanoyl, dimethylamino ethanoyl and N-methyl-N-ethylamino ethanoyl;

(eeee) Z be selected from the alkoxyl group of hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, hydroxyl-(2-6C) and (1-4C) alkoxyl group-(2-6C) alkoxyl group, and m+p+q sum be at least 1;

(ffff) Z be selected from the alkoxyl group of hydroxyl, (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-4C) alkoxyl group-(2-4C) alkoxyl group, and m+p+q sum be at least 1 (preferably m+p+q is 1 or 2);

(gggg) Z is hydroxyl or (1-4C) alkoxyl group (particularly Z is a hydroxyl), and the m+p+q sum is at least 1 (preferably m+p+q is 1 or 2);

(hhhh) Z such as above-mentioned any (ttt) definition in (gggg),

And X wherein ²Be selected from-CH ₂-,-CH ₂CH ₂-,-(CR ¹²R ¹³)-,-(CR ¹²R ¹³CH ₂)-,-(CH ₂CR ¹²R ¹³)-and (3-6C) inferior cycloalkenyl group (for example cyclopropylidene for example encircles the propylidene base),

Each R wherein ¹²And R ¹³Can be identical or different, be selected from alkyl of hydrogen, (1-4C) alkyl, hydroxyl-(1-4C) and (1-3C) alkyl of alkoxyl group-(1-4C), condition is R ¹²And R ¹³Can not be hydrogen simultaneously,

And X wherein ¹Be CO;

(iiii) Z such as above (ttt) each definition in (gggg);

X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-(particularly, X ²For-(CHR ^12a)-),

Each R wherein ^12aCan be identical or different, be selected from the alkyl of (1-4C) alkyl, hydroxyl-(1-4C) and (1-3C) alkyl of alkoxyl group-(1-4C),

And X wherein ¹Be CO;

(jjjj) Z is selected from hydroxyl and (1-4C) alkoxyl group,

Each R wherein ^12aCan be identical or different, for (1-4C) alkyl,

And R wherein ^12bBe selected from hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino and two-[(1-4C) alkyl]-amino,

And X wherein ¹Be CO;

(kkkk) Z-X ²-X ¹Be hydroxyl-(2-4C) alkyloyl, for example hydroxyacetyl, 2-hydroxyl propionyl or 3-hydroxyl propionyl;

(llll) Z-X ²-X ¹Be (1-4C) alkoxyl group-(2-4C) alkyloyl, for example methoxyl group ethanoyl, 2-methoxy propyl acyl group or 3-methoxy propyl acyl group;

(mmmm) Z-X ²-X ¹Be selected from alkyloyl and two-[(1-4C) alkyl] of the alkyloyl of amino-(2-4C), (1-4C) alkylamino-(2-4C) amino-(2-4C) alkyloyl (Z-X for example ²-X ¹Be two-[(1-4C) alkyl] amino-ethanoyl, for example dimethylamino ethanoyl);

(nnnn) Z-X ²-be selected from tetrahydrofuran base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl, pyrrolidyl, morpholinyl, piperidyl, homopiperidinyl, piperazinyl and high piperazinyl, described heterocyclic radical is connected in carbonyl among the formula I by ring carbon atom

And group Z-X wherein ³In heterocyclic radical optional carry 1 or 2 substituting group, described substituting group can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl;

(oooo) Z-X ²-be selected from tetrahydrofuran base, 1,3-dioxolanyl, THP trtrahydropyranyl, 1,4-dioxane base, oxepane alkyl (Z-X for example ²Be tetrahydrofuran (THF)-2-base or the tetrahydropyrans-2-yl of selecting);

(pppp) Z-X ²-being selected from pyrrolidyl, morpholinyl, piperidyl, homopiperidinyl, piperazinyl and high piperazinyl, described heterocyclic radical is connected in X among the formula I by ring carbon atom ¹,

And group Z-X wherein ²In heterocyclic radical optional carry 1 or 2 substituting group, described substituting group can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl; With

(qqqq) Z-X ²Be selected from tetramethyleneimine-1-base, piperidino-(1-position only), morpholino, piperazine-1-base, high piperidines-1-base and high piperazine-1-base,

And group Z-X wherein ²In heterocyclic radical optional carry 1 or 2 substituting group, described substituting group can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl.

A quinazoline derivant that specific embodiments is formula I of the present invention, wherein:

R ¹Be selected from the group of alkoxyl group of the alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C) or following formula:

Q ²-X ³-

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

And R wherein ¹On substituting group in optional 1,2 or 3 substituting groups that carry of any heterocyclic radical; described substituting group can be identical or different; be selected from amino and (2-4C) alkyloyl of halogeno-group, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkyl sulphonyl, (1-4C) alkylamino, two-[(1-4C) alkyl]

And R wherein ¹On substituting group in any heterocyclic radical optional carry 1 oxo substituting group;

B is 1,2 or 3 (particularly b is 1 or preferred 2);

Each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base and (2-4C) alkynyl;

Q ¹Be selected from tetramethyleneimine-3-base and azetidine-3-base (preferred azetidine-3-yl);

A is 0 or 1 (preferred 0);

Each W can be identical or different, is selected from halogeno-group (as the fluoro base), hydroxyl, (1-3C) alkyl and (1-3C) alkoxyl group (occurrence of W is (1-3C) alkoxyl group);

X ¹Be CO;

X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-group,

Each R wherein ^12aCan be identical or different, be selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of (1-4C) alkyl, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C) (R particularly ^12aBe (1-4C) alkyl),

And R wherein ^12bBe selected from the alkyl of alkyl and two-[(1-4C) the alkyl]-amino of the alkyl of the alkyl of the alkyl of hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl]-amino, hydroxyl-(1-4C), (1-3C) alkoxyl group-(1-4C), amino-(1-4C), (1-4C) alkylamino-(1-4C)-(1-4C) (R particularly ^12bBe selected from amino, (1-4C) alkylamino and two-[(1-4C) alkyl]-amino);

Z is selected from alkoxyl group of hydroxyl, (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-4C) alkoxyl group of alkoxyl group-(2-4C), or

Z-X ²Be selected from tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidyl, piperidyl and morpholinyl, wherein Z-X ²Be connected in X by ring carbon atom ¹,

And wherein any heterocyclic radical in Z is optional carries one or two substituting groups, and it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl,

And wherein any azetidinyl, pyrrolidyl or the piperidyl in Z chosen wantonly and carried the oxo substituting group;

Condition is:

4-anilino group in formula I is 4-bromo-2-fluorobenzene amido or 4-chloro-2-fluorobenzene amido and R ¹During for (1-3C) alkoxyl group, then a is 0;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, R ¹Occurrence for being selected from the group of alkoxyl group of the alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C) or following formula:

Q ²-X ³-

And wherein at R ¹On substituting group in any heterocyclic radical optional carry 1 or 2 substituting group, described substituting group can be identical or different, is selected from halogeno-group, hydroxyl, amino, (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkylamino and two-[(1-4C) alkyl] amino.

In this embodiment, R ¹Another concrete value for being selected from alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-3C) alkoxy base, the more especially R of alkoxyl group-(2-4C) ¹Be selected from (1-4C) alkoxyl group, for example methoxyl group, oxyethyl group, isopropoxy, particularly R ¹Be methoxyl group.

In this embodiment, the occurrence of Z is for being selected from the hydroxyl and (1-4C) group of alkoxyl group (for example Z is hydroxyl, methoxy or ethoxy).

In this embodiment, the concrete 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido, 2-fluoro-5-chlorinated benzene amido, 3-bromobenzene amido and 3-acetylenylbenzene amido.More especially, in this embodiment, the 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido and 3-bromobenzene amido.More especially, described anilino group is 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and especially described anilino group is 3-chloro-2-fluorobenzene amido.

Another specific embodiment of the present invention is the quinazoline derivant of formula I, wherein:

R ¹Be (1-4C) alkoxyl group (for example methoxyl group, oxyethyl group or isopropoxy, particularly R are methoxyl group);

B is 1 or 2;

Each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base and ethynyl;

Q ¹Be azetidine-3-base;

A is 0 or 1 (preferred 0);

W is (1-3C) alkyl;

X ¹Be CO;

X ²Be selected from formula-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(CH ₂CHR ^12a)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12b)-,

Z-X ²Be selected from tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidyl, piperidyl and morpholinyl, it is connected in X by ring carbon atom ¹,

And wherein any heterocyclic radical among the Z is optional carries one or two substituting groups, and it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl;

Condition is:

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, the occurrence of Z is for being selected from the hydroxyl and (1-3C) group of alkoxyl group (for example Z is hydroxyl, methoxy or ethoxy).

In this embodiment, the concrete 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido, 2-fluoro-5-chlorinated benzene amido, 3-bromobenzene amido and 3-acetylenylbenzene amido.More especially in this embodiment, the 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido and 3-bromobenzene amido.More especially, described anilino group is 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and especially, the anilino group is 3-chloro-2-fluorobenzene amido.

B is 1 or 2;

Q ¹Be azetidine-3-base;

A is 0 or 1 (preferred 0);

W is (1-3C) alkyl;

X ¹Be CO;

X ²Be selected from formula-(CHR ^12a)-,-(CHR ^12aCH ₂)-and-(CH ₂CHR ^12a)-group, each R wherein ^12aCan be identical or different, be in (1-4C) alkyl (particularly (1-3C) alkyl);

And wherein any heterocyclic radical in Z is optional carries one or two substituting groups, and it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl;

Condition is:

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, the occurrence of Z is for being selected from the hydroxyl and (1-3C) group of alkoxyl group (for example methoxy or ethoxy).

In this embodiment, the concrete 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido, 2-fluoro-5-chlorinated benzene amido, 3-bromobenzene amido and 3-acetylenylbenzene amido.More especially, in this embodiment, the 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido and 3-bromobenzene amido.More especially, described anilino group is 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and especially, described anilino group is 3-chloro-2-fluorobenzene amido.

R ¹Be (1-4C) alkoxyl group (for example methoxyl group, oxyethyl group, isopropoxy, particularly methoxyl group);

4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido, 2-fluoro-5-chlorinated benzene amido, 3-bromobenzene amido and 3-acetylenylbenzene amido;

Z is hydroxyl or (1-4C) alkoxyl group (particularly Z is hydroxyl or methoxyl group);

Q ¹Be azetidine-3-base;

A is 0 or 1 (preferred 0);

W is (1-3C) alkyl;

X ¹Be CO;

X ²Be selected from formula-(CHR ^12a)-and-(CH ₂CHR ^12b)-,

R wherein ^12aBe (1-4C) alkyl (particularly (1-3C) alkyl, more especially methyl),

And R wherein ^12bBe selected from amino, (1-4C) alkylamino and two-[(1-4C) alkyl]-amino (R particularly ^12bBe selected from (1-3C) alkylamino and two-[(1-3C) alkyl]-amino, more especially two-[(1-3C) alkyl]-amino, more especially R ^12bBe methylamino-, and dimethylamino especially);

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, the concrete 4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido and 3-bromobenzene amido.More especially, described anilino group is 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and especially, described anilino group is 3-chloro-2-fluorobenzene amido.

4-anilino group among the formula I is selected from 3-chloro-4-fluorobenzene amido, 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido, 3-bromobenzene amido and 3-acetylenylbenzene amido;

Q ¹Be azetidine-3-base;

A is 0 or 1 (preferred 0);

W is (1-3C) alkyl;

X ¹Be CO;

Z-X ²Be selected from tetrahydrofuran base, THP trtrahydropyranyl, azetidinyl, pyrrolidyl, piperidyl and morpholinyl (Z-X particularly ²Be tetrahydrofuran base or pyrrolidyl), Z-X wherein ²Be connected in X by ring carbon atom ¹,

And wherein any heterocyclic radical in Z is optional carries one or two substituting groups, and it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, methyl, methoxyl group and ethanoyl;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, the concrete 4-anilino group among the formula I is selected from 3-bromo-2-fluorobenzene amido, 3-chloro-2-fluorobenzene amido and 3-bromobenzene amido.More especially, described anilino group is 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and especially, described anilino group is 3-chloro-2-fluorobenzene amido.

Another embodiment of formula I compound is the quinazoline derivant of formula Ia:

Wherein:

R ^1aBe selected from alkoxyl group of (1-3C) alkoxyl group, hydroxyl-(2-3C) and (1-3C) alkoxyl group of alkoxyl group-(2-3C) (R particularly ^1aBe methoxyl group);

R ^2bBe bromo or chloro (R particularly ^2bThe chloro base);

X ^2aBe selected from formula-(CHR ^12a)-and-(CH ₂CHR ^12b)-,

Z ¹Be selected from hydroxyl and (1-4C) alkoxyl group (Z particularly ¹Be hydroxyl or methoxyl group),

Or group Z ¹X ^2aBe selected from tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl and piperidyl, wherein Z ¹-X ^2aBe connected in carbonyl group by ring carbon atom,

And Z wherein ¹In any heterocyclic radical optional carry one or two substituting groups, it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl,

And work as Z ¹X ^2aDuring for pyrrolidyl or piperidyl, then pyrrolidyl or piperidyl are chosen wantonly and are carried the oxo substituting group;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In this embodiment, preferred Z ¹Be selected from hydroxyl and (1-4C) alkoxyl group (Z particularly ¹Be hydroxyl or methoxyl group, and hydroxyl especially).

In this embodiment, preferred X ^2aBe formula-(CHR ^12a)-group,

Another embodiment of formula I compound is the quinazoline derivant of formula Ib:

Wherein:

R ^1bBe selected from the group of alkoxyl group of the alkoxyl group of (1-4C) alkoxyl group, hydroxyl-(2-4C), (1-3C) alkoxyl group-(2-4C) or following formula:

Q ²-X ³-

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

X ^2bBe selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ¹²)-,-(CHR ¹²CH ₂)-and-(CH ₂CHR ¹²)-,

R wherein ¹²Be selected from alkyl of (1-3C) alkyl, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C); With

Z ²Be selected from alkoxyl group of hydroxyl, (1-3C) alkoxyl group, hydroxyl-(2-3C) and (1-3C) alkoxyl group of alkoxyl group-(2-3C);

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In one embodiment, in formula Ib, R ^1bBe selected from methoxyl group, oxyethyl group, 2-hydroxyl-oxethyl, 2-fluoro oxyethyl group, 2-methoxy ethoxy, 2-ethoxy ethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoro ethoxy (R particularly ^1bBe (1-3C) alkoxyl group, for example methoxyl group).

In another embodiment, in formula Ib, X ^2bBe selected from formula-CH ₂-,-CH ₂CH ₂-and-(CHR ¹²)-, be R wherein ¹²Be selected from alkyl of (1-3C) alkyl, hydroxyl-(1-3C) and (1-3C) alkyl of alkoxyl group-(1-3C) (R for example ¹²Be methyl).

In another embodiment, in formula Id, X ^2bBe selected from formula-CH ₂-and-(CHR ¹²)-, be R wherein ¹²Be (1-3C) alkyl (for example methyl).X for example ^2bBe selected from-CH ₂-and-CH (CH ₃)-, be X particularly ^2bFor-CH (CH ₃)-.

In another embodiment, in formula Id, Z ²Be selected from hydroxyl and (1-3C) alkoxyl group, particularly Z ²Be hydroxyl.

In another embodiment, in formula Id, group Z ²-X ^2b-be selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxy ethyl, (R)-1-methoxy ethyl.Group Z particularly ²-X ^2b-be the 1-hydroxyethyl, (S)-1-hydroxyethyl or (R)-1-hydroxyethyl more especially.

In another embodiment, in formula Id, R ^1bBe (1-3C) alkoxyl group, for example methoxyl group; With group Z ²-X ^2b-be selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxy ethyl, (R)-1-methoxy ethyl.Z particularly ²-X ^2bBe the 1-hydroxyethyl, more especially (S)-1-hydroxyethyl or (R)-1-hydroxyethyl.

Particular compound of the present invention is selected from the quinazoline derivant of following formula I for for example:

7-[(1-ethanoyl piperidin-4-yl) oxygen base]-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine;

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[1-(methyl sulphonyl) piperidin-4-yl] the oxygen base } quinazoline-4-amine;

(2S)-1-[3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) azetidine-1-yl]-1-oxo propan-2-ol;

(2R)-1-[3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) azetidine-1-yl]-1-oxo propan-2-ol;

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[(3R)-1-(methoxyl group ethanoyl) tetramethyleneimine-3-yl] the oxygen base } quinazoline-4-amine;

2-[(3R)-3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) tetramethyleneimine-1-yl]-2-oxo ethanol;

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-((3R)-and the 1-[(2-methoxy ethoxy) ethanoyl] tetramethyleneimine-3-yl } the oxygen base) quinazoline-4-amine;

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[(3R)-1-(3-methoxy propyl acyl group) tetramethyleneimine-3-yl] the oxygen base } quinazoline-4-amine;

3-[(3R)-3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) tetramethyleneimine-1-yl]-3-oxo third-1-alcohol; With

5-{[4-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) piperidines-1-yl] carbonyl } pyrrolidin-2-one;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

In specific embodiments of the present invention, the quinazoline derivant of formula I as herein described is provided, or its pharmacy acceptable salt.

Can be according to the known any methods availalbe that is used to prepare the chemofacies related compounds, preparation formula I quinazoline derivant or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.Suitable method comprises, for example, at WO94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO97/30034, WO 97/38994, WO01/66099, US 5,252,586, the method for explanation among EP 520 722, EP 566 226, EP 602 851 and the EP 635 507.When being used for preparation formula I quinazoline derivant, this method has constituted another aspect of the present invention, by and can below the alternative explanation of exemplary process, wherein unless otherwise indicated, R ¹, R ², X ¹, X ², Q ¹, W, a, b and Z have any implication defined above.Necessary raw material can use the organic chemistry standard method to obtain.In conjunction with the alternative and the appended examples of following exemplary process, the preparation method of this raw material is described.Perhaps, required raw material can by with the ordinary skill of organic chemistry filed in the similar method of described method obtain.

Method (a):

For X wherein ¹Preparation for the formula I compound of CO in the presence of suitable alkali, makes formula II quinazoline or its salt easily:

Wherein except that protecting any functional group if desired, R ¹, R ², W, a, b and Q ¹Has any implication defined above; Acid or its reactive derivatives coupling with formula III:

Z-X ²-COOH

III

Wherein except that protecting any functional group if desired, Z and X ²Has any implication defined above;

Perhaps

Method (b) in the presence of suitable alkali, makes the compound reaction of quinazoline or its salt (definition in the method (a) as mentioned) and the formula IV of formula II easily:

Z-X ²-X ¹-L ¹

IV

L wherein ¹Be replaceable group, Z, X ¹And X ²Has any implication defined above (except that protecting any functional group if desired);

Perhaps

Method (c) is for preparing wherein Z by nitrogen and X ²The formula I quinazoline derivant that links to each other in the presence of suitable alkali, makes formula V compound easily:

L wherein ²Be replaceable group, R ¹, R ², W, X ¹, X ², a, b and Q ¹Has any implication defined above (except that protecting any functional group if desired); With the compound reaction of formula ZH, wherein except that protecting any functional group if desired, Z defines as mentioned; Perhaps

Method (d)

For preparation has single-or the quinazoline derivant of two-(1-6C) alkylaminos, use formaldehyde or (2-6C) alkanal (alkanolaldehyde) (for example acetaldehyde or propionic aldehyde), reduction amination contains the corresponding formula I quinazoline derivant of N-H group; Perhaps

Method (e)

For preparing wherein R ¹Be the formula I quinazoline derivant of hydroxyl, cracking is R wherein ¹Formula I quinazoline derivant for (1-6C) alkoxyl group; Perhaps

Method (f)

For preparing wherein R ¹The formula I quinazoline derivant that links to each other with the quinazoline ring by Sauerstoffatom, by making formula VI compound:

Wherein except that protecting any functional group if desired, R ², W, X ¹, X ², Z, a, b and Q ¹Has any implication defined above; With formula R ^{1 '}The compound coupling of OH, wherein except that protecting any functional group if desired, radicals R ^{1 '}O is for above to R ¹One of group that links to each other with oxygen of definition (for example (1-6C) alkoxyl group or Q ²-O-);

Thereafter, (with any order) if desired:

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

(ii) remove any blocking group of existence by ordinary method; With

(iii) form pharmacy acceptable salt, or pharmaceutically acceptable ester.

More than Fan Ying actual conditions is as follows:

The condition of method (a)

Described coupled reaction is carried out in the presence of suitable coupler easily, for example carbodiimide or suitable peptide coupler, urea  coupler for example, phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea  (HATU) or Tetrafluoroboric acid O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea  (TBTU); Or carbodiimide such as dicyclohexylcarbodiimide, choose wantonly at catalyzer and for example carry out in the presence of dimethyl aminopyridine or 4-tetramethyleneimine and the pyridine.

Described coupled reaction reaction is carried out in the presence of appropriate base easily.Suitable alkali is, for example, organic amine alkali, pyridine, 2 for example, 6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, two-sec.-propyl ethamine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene, or for example basic metal or alkaline earth metal carbonate, for example yellow soda ash, salt of wormwood, cesium carbonate or lime carbonate.

This reaction is carried out in the presence of suitable inert solvent or thinner easily, for example ester as or ethyl acetate, halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin, ether such as tetrahydrofuran (THF) or 1, for example toluene or dipolar aprotic solvent be for example for 4-two  alkane, aromatic solvent N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or methyl-sulphoxide.This reaction is carried out in following temperature range easily, for example 0-120 ℃, easily or carry out near room temperature.

" reactive derivatives " of term formula III acid refers to produce with the reaction of formula II quinazoline the carboxylic acid derivative of corresponding amides.The reactive derivatives of suitable formula III carboxylic acid is that for example, carboxylic acid halides is for example by the acyl chlorides of acid with inorganic acyl chlorides (as thionyl chloride) reaction formation; Mixed anhydride, for example acid anhydride that forms by acid and chloro-formic ester (as isobutyl chlorocarbonate) reaction; Active ester, for example by acid with phenol (as Pentafluorophenol or N-hydroxybenzotriazole) ester of reaction formation; Or acyl azide, for example trinitride that forms by acid and trinitride (as diphenylphosphine acylazide thing) reaction; Acyl cyanide, for example acyl cyanide that forms by acid and nitrile (as diethyl phosphinylidyne nitrile) reaction.The reaction of the reactive derivatives of this carboxylic acid and amine (for example compound of formula II) is well known in the art, and for example they can be in the presence of alkali (for example above-mentioned alkali), reaction in suitable solvent (for example above-mentioned solvent).This reaction can be carried out under said temperature easily.

The preparation of the raw material of method (a)

Formula II quinazoline can obtain by ordinary method, for example described in the reaction process 1:

Reaction process 1

Wherein except that protecting any functional group if desired, R ¹, R ², Q ¹, W, a and b define as mentioned, removes any blocking group of existence subsequently by ordinary method, Pg is suitable hydroxy-protective group, Pg ¹Be suitable amido protecting group, L ³Be replaceable group.

Condition in the reaction process 1

The suitable hydroxy-protective group that step (i): Pg represents is well known in the art, comprises this paper following radicals, for example low-grade alkane acidyl group such as ethanoyl or benzyl.

Suitable replaceable group L ³For; for example; halogeno-group (specifically being the chloro base), alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, alkyl sulphinyl, aryl sulfonyl kia, alkyl sulphonyl, aryl sulfonyl, alkylsulfonyloxy or aryl-sulfonyl oxygen, for example chloro base, bromo base, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methylthio group, methylsulfonyl, mesyloxy or toluene-4-sulfonyloxy.Concrete replaceable group L ³Be the chloro base.

This reaction is carried out in the presence of acid easily.Suitable acid comprises, for example hydrogen chloride gas (being dissolved in suitable solvent for example ether or two  alkane easily) or hydrochloric acid.

Perhaps, L wherein ³For the formula IIa quinazoline derivant of halogeno-group (for example chloro base) can be when anacidity or the alkali and aniline reaction.In this reaction, halo leavings group L ³Displacement cause original position to form sour HL ³, and should the reaction autocatalysis.

Perhaps, the reaction of formula IIa quinazoline and aniline can be carried out in the presence of appropriate base.Suitable alkali is, for example, and organic amine alkali such as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, two-sec.-propyl ethamine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene, or basic metal or alkaline earth metal carbonate such as yellow soda ash, salt of wormwood, cesium carbonate or lime carbonate, or alkalimetal hydride such as sodium hydride, alkaline metal fluoride cpd such as cesium fluoride, or dimethyl silanyl ammonification basic metal such as hexamethyl dimethyl silanyl ammonification sodium.

Above-mentioned reaction is carried out in the presence of suitable inert solvent or thinner easily, for example alcohol or ester such as methyl alcohol, ethanol, Virahol or ethyl acetate, halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin, ether such as tetrahydrofuran (THF) or 1,4-two  alkane, aromatic solvent such as toluene or dipolar aprotic solvent as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone, methyl-sulphoxide or acetonitrile.Above-mentioned reaction is carried out in following temperature range easily, for example 0-250 ℃, easily at 40-80 ℃, perhaps preferably or reflux temperature near solvent (during use) under carry out.

Aniline and formula IIa compound maybe can use the ordinary method preparation for commercially available acquisition.

Step is (ii):

The method that use is known is gone protection.For example when Pg was benzyl group, it can be removed by handling formula IIb compound with suitable acid such as trifluoroacetic acid.Perhaps, the benzyl protection group can be removed by metal catalytic hydrogenation, for example by hydrogenation in the presence of carbon-containing palladium catalyst.Similarly, when Pg is a low-grade alkane acidyl group for example during ethanoyl, it can be removed by hydrolysis under alkaline condition, for example uses ammonia, easily as the methanol solution of ammonia.

Step (iiia):

Suitable amido protecting group Pg ₂Know, for example tert-butoxycarbonyl (BOC) group.

L ⁴Be suitable replaceable group, for example L ²In above-mentioned group, for example halogeno-group (specifically being chloro base or bromo base) or alkylsulfonyloxy (particularly mesyloxy) or aryl-sulfonyl oxygen (particularly toluene-4-sulfonyloxy or 4-nitrophenyl sulfonyloxy).

The reaction of formula IIc compound and formula IId compound is carried out in the presence of suitable alkali easily.Suitable alkali comprises the above-mentioned alkali in the step (i), for example cesium fluoride or salt of wormwood.This reaction is carried out in the presence of suitable inert solvent easily, for example, and dipolar aprotic solvent, for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone, methyl-sulphoxide or acetonitrile.Above-mentioned reaction is carried out in following temperature range easily, for example 0-250 ℃, easily at 40-80 ℃, perhaps preferably or near the reflux temperature of solvent (during use).

Step (iiib):

The alternative method of step (iiia) makes formula IIc compound and the coupling of formula IIe alcohol for using the Mitsunobu coupled reaction.Suitable Mitsunobu condition is known, and comprises, for example, in the presence of suitable tertiary phosphine and azoformic acid dialkyl, in organic solvent such as THF or suitable methylene dichloride, to react, temperature range is 0 ℃-100 ℃, for example 0 ℃-60 ℃, but suitably or near carrying out under the room temperature.Suitable tertiary phosphine comprises for example tri-n-butyl phosphine, or triphenylphosphine especially.Suitable azoformic acid dialkyl comprises, for example, and diethyl azodiformate (DEAD) or suitable tert-butyl azodicarboxylate (DTAD).The details of Mitsunobu reaction is included in Tet.Letts., and 31,699, (1990); The MitsunobuReaction, D.L.Hughes, Organic Reactions, 1992, Vol.42,335-656 and Progress in the Mitsunobu Reaction, D.L.Hughes, Organic Preparationsand Procedures International, 1996, Vol.28 is among the 127-164.

The compound of formula IId and IIe is what be commercially available, maybe can use the ordinary method preparation.

Step is (iv):

The method that use is known is removed amido protecting group Pg ₁For example work as Pg ₁During for the BOC group, by with suitable acid such as trifluoroacetic acid or salt acid treatment.

In the substituting approach of approach shown in the reaction process 1, can make not protection variant (being that Pg the is a hydrogen) reaction of the aniline formula IIa compound in the step (i), direct production IIc compound.

Formula II compound also can prepare according to reaction process 2:

Reaction process 2

Wherein except that protecting any functional group if desired, R ¹, R ², Q ¹, W, a, b, L ³And Pg ¹Any blocking group of existence is removed in definition subsequently by ordinary method as mentioned.

Condition in the reaction process 2

Step (i):

Coupling under the Mitsunobu condition described in reaction process 1 step (iiib).

Step is (ii):

This reaction is carried out in the presence of acid easily.Suitable acid comprises, for example hydrogen chloride gas (being dissolved in suitable solvent for example ether or two  alkane easily) or hydrochloric acid.This reaction is carried out in suitable inert solvent easily, for example described in the step of reaction process 1 (i).Easily, as the result of acidic conditions in the aniline coupled reaction, blocking group Pg ¹General original position is removed, and for example works as Pg ¹During for tert-butoxycarbonyl.Perhaps, blocking group can use ordinary method to remove after reaction.

Formula IIg quinazoline is what be commercially available, maybe can use the ordinary method preparation.

R wherein ¹For heterocyclic radical-(2-6C) the formula II quinazoline derivant of alkoxyl group (nitrogen of wherein said heterocyclic radical connects (2-6C) alkoxy base) can prepare according to reaction process 3:

Reaction process 3

Wherein except that protecting any functional group if desired, R ¹, R ², Q ¹, W, X ², L ¹, L ², a, b and Pg ¹Definition as mentioned, X ³' be (2-6C)-alkylidene group, Q ²For containing the heterocyclic radical of NH cyclic group, remove any blocking group of existence subsequently by ordinary method.

Step (i): L ¹And L ²Be the replaceable group of definition in the method (b), for example halogeno-group such as chloro base.With the reaction of formula IIj compound can with similarly carry out under the condition described in this paper method (b).

Formula IIj compound can be by using the standard method preparation, and for example the method described in the WO03/082831 obtains to have 2, the formula IIj compound of 3-dihalo aniline.By making 4-chloro-6-hydroxyl-7-methoxyl group quinazoline and suitable aniline coupling, can use similar approach preparation formula IIj compound.

Step is (ii): the condition described in similar this paper method (b).

Step is (iii): the cracking of methoxy group is carried out under the standard conditions of this reaction being used for, for example undertaken by handle formula IIm compound at elevated temperatures with pyridine hydrochloride , and for example 60-180 ℃, easily at about 170 ℃.

Step is (iv): coupling under the Mitsunobu condition described in reaction process 1 step (iiib).

Step (v): go protection to remove the Pg of amine protecting group group ¹, for example work as Pg ¹During for tert-butoxycarbonyl, undertaken by handle formula (IIo) compound with suitable acid such as trifluoroacetic acid.

The reaction conditions of method (b)

Suitable replaceable group L ¹Comprise for example halogeno-group such as chloro base.

This reaction is carried out in the presence of appropriate base easily, for example, easily in the presence of appropriate base, for example organic amine alkali such as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, two-sec.-propyl ethamine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene, or for example basic metal or alkaline earth metal carbonate such as yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate, or alkalimetal hydride such as sodium hydride, or dimethyl silanyl ammonification basic metal such as hexamethyl dimethyl silanyl ammonification sodium.

This reaction is carried out in the presence of suitable inert solvent or thinner easily, for example methylene dichloride, chloroform or tetracol phenixin of halogenated solvent for example, ether such as tetrahydrofuran (THF) or 1,4-two  alkane, aromatic solvent such as toluene or dipolar aprotic solvent as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or methyl-sulphoxide.

This reaction is carried out under 0 ℃-30 ℃ temperature suitably, at room temperature carries out easily.

When Z is hydroxyl, easily with the reaction of formula II compound in this oh group of protection.Suitable blocking group is known, for example alkyloyl group such as ethanoyl.Blocking group can removed for example basic hydrolysis in the presence of appropriate base such as sodium hydroxide with formula II compound reaction back by ordinary method.

Formula IV compound is the commercial compound, or they are known in the literature, or they can be by standard method preparation known in the art.

The reaction conditions of method (c):

L ²The suitable replaceable group of expression comprises for example halogen or sulfonyloxy group, for example chloro base, bromo base, sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy.Concrete group L ²Be the chloro base.

This reaction is carried out in the presence of appropriate base easily, the alkali of describing in for example a kind of method (b).

This reaction is carried out in the presence of suitable inert solvent or thinner easily, for example halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin, ether such as tetrahydrofuran (THF) or 1,4-two  alkane, ester such as ethyl acetate, aromatic solvent such as toluene or dipolar aprotic solvent as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or methyl-sulphoxide.

This reaction is carried out under 0 ℃-80 ℃ temperature suitably, at room temperature carries out easily.

The preparation of the raw material of method (c)

Formula V compound as raw material can pass through, and for example, in the presence of appropriate base, makes formula II quinazoline or its salt and the formula Va compound prepared in reaction of the above middle definition of method (a) easily:

L ²-X ²-X ¹-L ⁵

Va

X wherein ¹And X ²Definition as mentioned, L ²And L ⁵Be suitable replaceable group, condition is L ⁵Compare L ²More unstable.

L ²And L ⁵The suitable replaceable group of expression comprises for example halogeno-group such as chloro base.

This reaction in the presence of appropriate base, is carried out in suitable inert solvents or thinner easily, as above-mentioned definition to formula V quinazoline and the reaction of formula ZH compound.

Formula ZH compound and Va are the commercial compound, or they are known in the literature, or they can be by standard method preparation known in the art.

Easily, in the embodiment of method (c), by making the reaction of formula II quinazoline and formula Va compound, separate type V compound and products therefrom and formula ZH compound are reacted not then can be directly from formula II quinazoline preparation formula I quinazoline.This reaction allows to begin preparation formula I quinazoline from formula II quinazoline in the single reaction container.

The reaction conditions of method (d)

Method (d) can be used for the NH group in the alkylation formula I quinazoline derivant, for example when Z be amino or (1-6C) during alkylamino, or as group Z-X ²Have amino or (1-6C) during the alkylamino substituting group.Suitable reduction amination condition is well known in the art.For example, contain for generation NThe formula I quinazoline derivant of-methyl group, can make contain the N-H group respective compound in the presence of appropriate reductant with formaldehyde reaction.Appropriate reductant is, for example, hydride reducer such as formic acid, composite alkali aluminum hydride such as lithium aluminium hydride, or suitable alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, triethyl-boron sodium hydride, trimethoxy sodium borohydride and sodium triacetoxy borohydride.This reaction is carried out in suitable inert solvent or thinner easily, for example tetrahydrofuran (THF) and ether are used for stronger reductive agent such as lithium aluminium hydride, and for example methylene dichloride or protonic solvent such as methyl alcohol and ethanol are used for more weak reductive agent such as sodium triacetoxy borohydride and sodium cyanoborohydride.This reaction under acidic conditions, is carried out in the presence of suitable sour example hydrochloric acid or acetate suitably, also can use buffer reagent in reaction pH is maintained desired level.When reductive agent was formic acid, this reaction used the aqueous solution of formic acid to carry out easily.This is reflected in the following temperature range and carries out, for example-10-100 ℃, for example 0-50 ℃, easily or near carrying out under the room temperature.

Contain the NH group (for example when Z for amino or (1-6C) during alkylamino) formula I quinazoline derivant can be by using wherein a kind of method for preparing.For example make the amino acid coupling of formula II compound and suitable optional protection, remove any blocking group then by using method (a).

The reaction conditions of method (e)

Scission reaction can be carried out easily by any method that becomes known for this conversion.Especially suitable scission reaction is for to handle wherein R with alkali metal halide such as lithium iodide in the presence of 2 ¹Formula I quinazoline derivant for (1-6C) alkoxy base.We find, use 2 to be provided at selective splitting (1-6C) alkoxy base on the C6 position on the quinazoline ring.This reaction can be carried out in the presence of suitable inert solvents defined above or thinner.Yet reaction can only be used 2 to carry out easily and need not other solvents/diluents.This reaction is carried out in following temperature range suitably, and for example 10-170 ℃, preferably in the temperature that raises for example under 120-170 ℃, for example about 130 ℃.

The reaction conditions of method (f)

Coupled reaction is carried out under the Mitsunobu condition described in reaction process 1 step (iiib) easily.

The preparation of the raw material of method (f)

Can pass through as the formula VI compound of raw material, for example, use method (e) cracking formula I quinazoline derivant mentioned above and prepare, wherein R ¹Be for example methoxyl group.Perhaps, formula VI compound can use the ordinary method preparation.For example, work as X ¹During for CO, formula VI compound can use the method preparation described in the reaction process 4:

Reaction process 4

Wherein except that protecting any functional group if desired, R ¹, R ², Q ¹, W, X ², a, b, Pg and Pg ¹Any blocking group of existence is removed in definition subsequently by ordinary method as mentioned.

Condition in the reaction process 4

Step (i): with reaction process 3 steps (iii) described in similar cracking methoxy group under the condition.

Step (ii) Pg is suitable hydroxy-protective group defined above, for example alkyloyl such as ethanoyl.Group Pg can introduce under standard conditions, for example by making formula VIb compound and acetic anhydride.

Step is coupling under the Mitsunobu condition described in reaction process 1 step (iiib) (iii).

Step is (iv): go protection to remove blocking group Pg.For example, when Pg is ethanoyl,, for example use the methanol solution of ammonia by basic hydrolysis in alcohol.

Step (v): go protection to remove the Pg of amine protecting group group ¹, for example work as Pg ¹During for tert-butoxycarbonyl, by handle formula (VId) compound with suitable acid such as trifluoroacetic acid.

Step (vi): use described method of method (a) and sour Z-X ²-COOH coupling.

Formula I quinazoline derivant can be by using aforesaid method, and with the form acquisition of free alkali, perhaps, it also can obtain with the form of salt, acid salt.When hope obtains free alkali by the salt of formula I compound, described salt can be with suitable alkaline purification, for example, the carbonate of basic metal or alkaline-earth metal or oxyhydroxide (for example yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide), perhaps use ammonia treatment, for example use the methanol solution (for example methanol solution of 7N ammonia) of ammonia.

Generally speaking, the blocking group that is used for aforesaid method can be selected from any group that is suitable for protecting functional group to be protected that document is described or well known by persons skilled in the art, and can introduce blocking group by ordinary method.Can be by that describe in the document or well known by persons skilled in the artly be suitable for removing any method that makes things convenient for of waiting to remove blocking group; remove blocking group; select this method, make this method can remove described blocking group and the minimum that influences of other group in the molecule.

For simplicity, provide the example of concrete blocking group below, wherein " rudimentary " (as in low alkyl group) expression preferably has the group of 1-4 carbon atom.Should understand these examples and non exhaustive.The specific examples of the method for removing blocking group that provides equally, below is also also non exhaustive.The using method and the method for removing thereof of the blocking group of certainly, specifically not mentioning are also included within the scope of the invention.

Carboxy protective group can be into the aliphatic series of ester or the residue of aromatic grease group alcohol, perhaps is into the residue of the silanol of ester, and described pure and mild silanol preferably has 1-20 carbon atom.The example of carboxy protective group comprises straight chain and side chain (1-12C) alkyl (as the sec.-propyl and the tertiary butyl); Lower alkoxy-low alkyl group (as methoxymethyl, ethoxyl methyl and isobutoxy methyl); Low-grade acyloxy-low alkyl group (as acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl and oxy acid methyl neopentyl); Elementary alkoxy carbonyl oxygen base-low alkyl group (as 1-methoxycarbonyl oxygen base ethyl and 1-ethoxy carbonyl oxygen base ethyl); Aryl lower alkyl (as benzyl, 4-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl (as trimethyl silyl and tert-butyl dimetylsilyl); Three (low alkyl group) silyl-low alkyl group (as the trimethyl silyl ethyl); And (2-6C) alkenyl (as allyl group).Especially the method that is suitable for removing carboxy protective group comprises, as acid-, alkali-, metal-or enzyme-catalytic cracking.

The example of hydroxy-protective group comprises low alkyl group (as tert-butyl), low-grade alkenyl (as allyl group); Low-grade alkane acidyl (as ethanoyl); Elementary alkoxy carbonyl (as uncle-butoxy carbonyl); Lower alkanols allyloxycarbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Three (low alkyl group) silyl (as trimethyl silyl and tert-butyl dimetylsilyl) and aryl lower alkyl (as benzyl).

The example of amido protecting group comprises formyl radical, aryl lower alkyl (as benzyl, 4-methoxy-benzyl, the 2-nitrobenzyl and 2 of benzyl and replacement, 4-dimethoxy-benzyl and trityl group); Two-4-anisyl methyl and furyl methyl; Elementary alkoxy carbonyl (as uncle-butoxy carbonyl); Lower alkanols allyloxycarbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Low-grade alkane acidyl oxygen base alkyl (for example oxy acid methyl neopentyl); Trialkylsilkl (as trimethyl silyl and tert-butyl dimetylsilyl); The benzylidene of alkylidene group (as methylene radical) and benzylidene and replacement.

The proper method of removing hydroxyl and amido protecting group comprise as acid-, alkali-, metal-or the hydrogenation of enzyme-catalytic group hydrolysis (as the hydrolysis of 2-nitro benzyloxycarbonyl), group such as benzyl and photodissociation of group such as 2-nitro benzyloxycarbonyl.For example, the tert-butoxycarbonyl blocking group can be removed from amino through acid-catalyzed hydrolysis with trifluoroacetic acid.

About comprehensive guide of reaction conditions and reagent, the reader can be referring to AdvancedOrganic Chemistry, and the 4th edition, J.March edits, John Wiley ﹠amp; Sons 1992 publishes, can be referring to Protective Groups in OrganicSynthesis, the 2nd edition, editors such as T.Green, John Wiley ﹠amp about the guide of blocking group; Son publishes.

Should be appreciated that some Tong Guo the standard aromatics substitution reaction in the The compounds of this invention in the various ring substituents is introduced, or generates by conventional modified with functional group before or after aforesaid method, these are also included within the method for the present invention aspect.This reaction and modification comprise, for example, introduce substituting group, substituent reduction, substituent alkylation and substituent oxidation by the aromatics substitution reaction.The reagent and the reaction conditions that are used for this step are that chemical field is known.The specific examples of aromatics substitution reaction comprises with concentrated nitric acid introduces nitro, under the FriedelCrafts condition, introduces acyl group with for example carboxylic acid halides and Lewis acid (as aluminum chloride); Under the FriedelCrafts condition, introduce alkyl with alkylogen and Lewis acid (as aluminum chloride); With the introducing halogen group.

When the pharmacy acceptable salt that needs formula I quinazoline derivant, for example during acid salt, it can be by for example, uses ordinary method to make described quinazoline derivant and suitable acid-respons and obtain.

When needing the pharmaceutically acceptable ester of formula I quinazoline derivant, it can pass through, and for example uses the ordinary method described in the definition of the pharmaceutically acceptable ester of this paper, makes described quinazoline derivant and suitable acid or alcohol reaction and obtains.

As mentioned above, some compound of the present invention can contain one or more chiral centres, thereby can be used as steric isomer and exist and (for example work as Q ¹During for piperidines-3-base).Steric isomer can use routine techniques such as chromatography or fractional crystallization preparation.Enantiomer can be passed through the separation of racemic body, for example separates by fractional crystallization, fractionation or HPLC.Diastereomer can separate by the different physical propertys of diastereomer, for example separates by fractional crystallization, HPLC or flash chromatography.In addition, concrete steric isomer can prepare by chirality is synthetic from chiral raw material under the condition that does not cause racemization or epimerization, or by preparing with the chiral reagent derivatize.When separating concrete steric isomer, being separated to it does not suitably have other steric isomer substantially, for example contains and is less than 20%, especially is less than 10%, more particularly is less than other steric isomer of 5% weight.

In the chapters and sections of the preparation that above relates to formula I quinazoline derivant, term " inert solvent " refers to not the solvent with the mode that influences required product yield unfriendly and raw material, intermediate or product reaction.

Those skilled in the art should understand that, for alternatively, obtain compound of the present invention in mode more easily in some cases, each process steps referred to above can be carried out with different order, and/or each reaction can be carried out (being that chemical transformation can be carried out at above relevant with concrete reaction different intermediates) in the different steps of whole approach.

Some intermediate that is used for aforesaid method is new compound, and it constitutes further feature of the present invention.Others of the present invention provide formula II quinazoline derivant defined above or its salt, wherein:

A is 2;

Each R ²Can be identical or different, be halogeno-group (particularly being selected from fluoro base and chloro base), and R wherein ²Group is positioned at ortho position (2-) and a position (3-) on the aniline ring; With

Q ¹Be 4,5,6 or 7 yuan of saturated or unsaturated monocyclic heterocycles bases of part, described heterocyclic radical contains 1 nitrogen heteroatom and optional contains 1 or 2 other heteroatoms that is selected from O, S and N, and described ring is connected on the Sauerstoffatom among the formula I by ring carbon atom, and condition is that described heterocyclic radical group is not a piperidyl; Or its salt.Concrete formula II compound is that wherein said anilino group is the formula II compound of 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, and more especially, described anilino group is 3-chloro-2-fluorobenzene amido.In one embodiment, in formula II compound or its salt, R ¹Be (1-4C) alkoxyl group; Q ¹Be selected from azetidinyl and pyrrolidyl and be connected in Sauerstoffatom (the preferred Q of formula II by carbon ¹Be tetramethyleneimine-3-base or azetidine-3-base, more preferably Q ¹Be azetidine-3-yl); A is 0 or 1; W is positioned at Q when existing ¹In ring carbon atom on and be selected from (1-4C) alkyl, hydroxyl and (1-4C) alkoxyl group (preferred W is 0); With the anilino group among the formula II be 3-chloro-2-fluorobenzene amido or 3-bromo-2-fluorobenzene amido, more especially, described anilino group is 3-chloro-2-fluorobenzene amido.Formula II intermediate can be the salt form of intermediate.This salt need not to be pharmacy acceptable salt.For example, can be used for preparing the intermediate of non-pharmacy acceptable salt form, if for example this salt is used for preparation I compound.The salt of preferred formula II compound is the pharmacy acceptable salt that above defines about formula I quinazoline derivant.

Biology is measured

Before by their activity in vivo of xenotransplantation research evaluation, in not testing based on the protein tyrosine kinase mensuration of cell and based on the proliferation assay of cell, the inhibition activity of assessing compound.

A) protein tyrosine kinase phosphorylation assay

This test determination test compound suppresses to comprise the ability of phosphorylation of the peptide substrate of tyrosine by EGFR, erbB2 and erbB4 Tyrosylprotein kinase.

The reconstitution cell internal fragment of EGFR, erbB2 and erbB4 (searching number is respectively X00588, X03363 and L07868) is cloned and is expressed in baculovirus/Sf21 system.By with ice-cold dissolving damping fluid (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH 7.5,150mM NaCl, 10% glycerine, 1%Triton X-100,1.5mM MgCl ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA)) add proteinase inhibitor and handle these cells, then by the centrifuging clarification, by these cell preparation lysates.

By the ability of the synthetic peptide of its phosphorylation (by L-glutamic acid, L-Ala and tyrosine random copolymer), measure the formation type kinase activity of these recombinant proteins with 6: 3: 1 ratio formation.Specifically, the synthetic peptide of usefulness (0.2 μ g peptide in 200 μ l phosphate buffered saline (PBS) (PBS) solution, and 4 ℃ of following overnight incubation) wrap by Maxisorb ^Tm96 hole enzyme plates.At 50mMHEPES, among the pH 7.4, at room temperature wash plate is to remove any unnecessary non-binding synthetic peptide.By the peptide bag by plate in, at 100mM HEPES, pH 7.4, the Triphosaden (ATP) of each enzyme Km concentration, 10mM MnCl ₂, 0.1mM Na ₃VO ₄, in the 0.2mM DL-dithiothreitol (DTT) (DTT), 0.1%Triton X-100, the testing compound in dimethyl sulfoxide (DMSO) (DMSO) (final concentration 2.5%) is at room temperature hatched and is assessed the activity of EGFR or erbB2.Termination reaction is washed this plate with PBS-T (phosphate buffered saline (PBS) adds 0.5%Tween 20) subsequently by the liquid component of removing this test.

Detect the immobilization phosphorylated peptide product of this reaction by immunization method.At first, at room temperature, hatched this plate 90 minutes with the anti-Tyrosine O-phosphate primary antibody (4G10 is from UpstateBiotechnology) that derives from mouse.After the washing, the goat-anti mouse secondary antibody (NXA 931, from Amersham) that plate is puted together with horseradish peroxidase (HRP) was at room temperature handled 60 minutes up hill and dale.Again after the washing, with 2,2 '-azine-two (3-ethyl benzo thiazole phenanthroline-6-sulfonic acid) di-ammonium salts crystal (ABTS ^TM, from Roche) as substrate by the HRP activity in each hole of this plate of colorimetric estimation.

By reading to measure on the plate device absorbancy at 405nm place at Molecular Devices ThermoMax microplate, quantitatively colour developing and enzymic activity numerical value accordingly.Use IC ₅₀Value is represented the kinase inhibition to given compound.This can obtain the required compound concentration of 50% phosphorylation inhibition in this test by calculating and determine.Calculate the scope of phosphorylation by positive control value (carrier adds ATP) and negative control value (carrier deducts ATP).

B) mensuration of the KB cell proliferation of EGFR driving

This test determination testing compound suppresses the ability of KB cell (KB cell is from American type culture collection (ATCC)) propagation.

In containing the Dulbecco improvement Eagle substratum (DMEM) of 10% foetal calf serum, 2mM glutamine and non-essential amino acid, at 37 ℃, 7.5% CO ₂The air thermal preservation case in cultivate the KB cell.Use trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from original seed (stock) flask.Use hematimeter and measure cell density, and use trypan blue solution and calculate its viability, then at 37 ℃, 7.5%CO ₂Down, with every hole 1.25 * 10 ³The density of cell includes cell inoculation among the DMEM of serum, 1mM glutamine and non-essential amino acid of 2.5% charcoal absorption in 96 orifice plates, and it was left standstill 4 hours.

After being adsorbed on the plate, with described cell with or without epidermal growth factor (EGF) (final concentration 1ng/ml) and with or without the processing of certain the concentration range compound (final concentration 0.1%) in the methyl-sulphoxide (DMSO), hatched then 4 days.After incubation period, by adding 50 μ l bromination 3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium  (MTT) (storing solution 5mg/ml) measured cell quantity in 2 hours.Pour out MTT solution then, beat this plate gently, make cytolysis in the 100 μ l DMSO that add.

Use Molecular Devices ThermoMax microplate and read the plate device, read the absorbancy of dissolved cell at 540nm.Use IC ₅₀Value is represented inhibition of proliferation.This can obtain the required compound concentration of 50% propagation inhibition in this test by calculating and calculate.Calculate the scope of propagation by positive (carrier adds EGF) and negative (carrier deducts EGF) control value.

C) mensuration of clone's 24 phosphoric acid-erbB 2 cells

This immunofluorescence terminal point test determination test compound suppresses the ability of the phosphorylation of erbB2 in MCF 7 (mammary cancer) derived cell system, this clone be by with standard method with total length erbB2 gene transfection MCF7 cell, must be and express the proteic clone of total length wild-type erbB2 and obtain (be called hereinafter ' clone's 24 ' cell).

Under 37 ℃, at 7.5%CO ₂In the air incubator, in growth medium (the no phenol red Dulbecco improvement Eagle substratum (DMEM) that contains 10% foetal calf serum, 2mM glutamine and 1.2mg/ml G418), cultivate clone's 24 cells.By at PBS (phosphate buffered saline (PBS), pH 7.4, Gibco No.10010-015) in washing once, harvested cell from T 75 deposit flasks is used 2ml trypsin 1.25mg/ml then)/(0.8mg/ml) solution harvested cell of ethylenediamine tetraacetic acid (EDTA) (EDTA).The described cell of resuspending in growth medium.Measure cell density with hematimeter, calculate its viability with trypan blue solution then, then with the cell redilution in growth medium, and with every hole 1 * 10 ⁴The density of cell (among the 100 μ l), with its be inoculated in clear bottom 96 orifice plates (Packard, No.6005182) in.

After 3 days, from each hole, remove growth medium, replace the 100 μ l test media (the no phenol red DMEM that contains 2mM glutamine, 1.2mg/ml G418) that contain or do not contain the erbB inhibitor compound.Plate was put back to incubator 4 hours, in every hole, add the solution of 20% formaldehyde in PBS of 20 μ l then, plate was placed room temperature following 30 minutes.Remove this stationary liquid with the multiple tracks transfer pipet, in every hole, add 100 μ l PBS, remove with the multiple tracks transfer pipet then, in every hole, add 50 μ l PBS again.Sealing plate and under 4 ℃, be stored to many 2 weeks then.

At room temperature carry out immunostaining.With plate washing device with 200 μ l PBS/Tween 20 (by 1 bag of PBS/Tween dry mash (Sigma, No.P 3563) is joined the double distilled H of 1L ₂Make among the O) wash each hole once, add 200 μ l lock solution (the 5%Marvel drying defatted breast (Nestle) in PBS/Tween 20) then and hatched 10 minutes.Remove lock solution with plate washing device, add 200 μ l 0.5%Triton X-100/PBS then with saturatingization cell.After 10 minutes,, and then add 200 μ l lock solution and hatched 15 minutes with 200 μ l PBS/Tween, 20 wash plate.After removing this lock solution with plate washing device, in each hole, add in the 30 μ l lock solution (epi-position phosphoric acid-Tyr 1248, SantaCruz No.SC-12352-R), were hatched 2 hours then with the anti-phosphoric acid ErbB2 of the rabbit polyclonal IgG antibody of dilution in 1: 250.Remove this trie primary antibody solutions with plate washing device then, use plate washing device again with 200 μ l PBS/Tween, 20 washed twice.In every hole, add then 30 μ l be diluted at 1: 750 Alexa-Fluor 488 goat anti-rabbit igg secondary antibody in the lock solution (Molecular Probes, No.A-11008)., in this stage with black tail band seal, with plate lucifuge protection as far as possible from now on.Hatched each plate 45 minutes, and from the hole, removed secondary antibody solution then, use plate washing device again with 200 μ lPBS/Tween, 20 washed twice.In each plate, add 100 μ l PBS then, hatched 10 minutes, remove with plate washing device again.And then in every plate, add 100 μ l PBS, and no longer prolong then and hatch, remove with plate washing device.In every hole, add 50 μ l PBS then, plate is resealed with the black tail band, before analyzing, under 4 ℃, be stored to many 2 days.

Use Acumen Explorer Instrument (Acumen Explorer instrument) (AcumenBioscience Ltd.), a kind of can by laser scanning quantitative determination characteristics of image read the plate device, measure the fluorescent signal in every hole.Set this instrument and surpass the amount of the fluorescent object of predetermined threshold value, thereby the method for measuring the proteic phosphorylation state of erbB2 is provided with measurement.To import in the suitable software package (as Origin), by the fluorescence dose response data that every kind of compound obtains with the analysis that carries out curve fitting.Use IC ₅₀The inhibition of value representation erbB2 phosphorylation.This can measure by calculating the required compound concentration of phosphorylation signal 50% inhibition that obtains erbB2 in this test.

D) xenotransplantation is measured in the body

This test determination testing compound suppresses the ability of LoVo tumour (colorectum gland cancer is available from ATCC) growth in the female Swiss athymic mouse (AlderleyPark, nu/nu genotype).

Female Swiss athymic (nu/nu genotype) mouse is fed and is maintained in the AlderleyPark negative pressure disrupter (PFI Systems Ltd.).Mouse inhabits in the Fencing system, with 12 hours illumination/dark cycle, and provides quantity-unlimiting sterilization meals and water.Whole steps is all carried out with the mouse in 8 ages in week at least.By 1 * 10 in every animal subcutaneous injection 100 μ l serum free mediums ⁷Individual fresh culture cell is established the xenotransplantation of LoVo tumour cell (colorectum gland cancer is available from ATCC) in the donor mice aft rib.After implantation the 5th day, mouse is weaved into 7 groups at random, with compound or vehicle Control treatment, be administered once every day then with the 0.1ml/10g body weight.By measuring the bilateral of tumour with vernier callipers twice weekly, application of formula (length x width) * √ (length x width) * (π/6) and determine its volume, wherein length is the longest diameter of this tumour, width is corresponding vertical line.By the average change of compare group and treatment group gross tumor volume, the growth-inhibiting when calculating from the research beginning, and use statistical significance between two groups of Students t test evaluations.

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

Test (a) :-IC ₅₀In the scope of for example 0.001-1 μ M

Test (b) :-IC ₅₀In the scope of for example 0.001-5 μ M

Test (c) :-IC ₅₀In the scope of for example 0.01-5 μ M

Test (d) :-active in 1-200mg/kg/ days scope for example

Under the effective dose of test-compound of the present invention, in test (d), do not observe unacceptable toxicity on the physiology.Therefore, when giving formula I compound defined above or its pharmacy acceptable salt with the dosage range that hereinafter limits, expection does not produce the toxic action of trouble.

By way of example, use above-mentioned test (a) (to the inhibition of EGFR Tyrosylprotein kinase protein phosphorylation) and test (b) (KB raji cell assay Raji), the representative compounds described in this paper embodiment obtains the IC shown in the Table A down ₅₀The result:

Table A

The embodiment compound	The IC of test (a) (inhibition of EGFR Tyrosylprotein kinase protein phosphorylation) ₅₀(nM)	The IC of test (b) (the KB cell proliferating determining that EGFR drives) ₅₀(nM)
The embodiment compound			3	17	71
4	8	48	3	17	71
4	8	48	5	217	119
6[5]	41	397	5	217	119

Another aspect of the present invention provides 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 and is applicable to that the form that orally uses (for example is tablet, 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, gelifying agent, water-based or oily solution or suspension), be applicable to the form (as fine powder or liquid aerosol) of inhalation, be applicable to that form (as pulvis subtilis) that is blown into administration or the form that is applicable to parenteral admin (for example can be used for vein, subcutaneous, the sterile aqueous of intramuscular administration or oily solution perhaps are used for the suppository of rectal administration).

Can use various conventional pharmaceutical excipient well known in the art to prepare composition of the present invention through conventional method.Therefore, be used for liquid preparations for oral administration and can contain for example one or more tinting materials, sweeting agent, correctives and/or sanitas.

Combine with one or more vehicle with the amount of the active ingredient that produces single dose form must according to treated host and specifically route of administration change.For example, the preparation that is used for the human oral administration contains usually just like 0.5mg-0.5g active medicine (be more suitable for being 0.5-100mg, as be 1-30mg), the excipient composition that itself and suitable convenience are measured, and vehicle can be about 5%-98% of composition total weight.

Certainly, the principle of knowing according to medical field, when being used for the treatment of or prevent purpose, the dosage size of formula I quinazoline derivant should change according to the character of animal or disease of patient and severity, age and sex and route of administration.

When formula I quinazoline derivant being used for the treatment of or preventing purpose, generally give it and make the per daily dose scope be for example 0.1mg/kg-75mg/kg body weight, can divide administration for several times in case of necessity.Usually, when using the parenteral administration, should give lower dosage.Therefore, for example for intravenously administrable, normally used dosage range is for example 0.1mg/kg-30mg/kg body weight.Similarly, for inhalation, normally used dosage range is for example 0.05mg/kg-25mg/kg body weight.But the preferred oral administration is especially with the form of tablet.Typically, unit dosage contains the 0.5mg-0.5g that has an appointment compound of the present invention.

We find that compound of the present invention has antiproliferative properties, and for example anticancer property thinks that this specific character from its erbB family receptors tyrosine-kinase enzyme inhibition activity, especially suppresses EGF acceptor (erbB1) Tyrosylprotein kinase.In addition, some compound of the present invention has obviously better effectiveness to suppressing EGF receptor tyrosine kinase comparison other Tyrosylprotein kinase of inhibition (for example erbB2 receptor tyrosine kinase).This compound has enough effectiveness to suppressing the EGF receptor tyrosine kinase, makes them demonstrate few or obvious lower activity to other Tyrosylprotein kinase such as erbB2 simultaneously to be enough to suppress the amount use of EGF receptor tyrosine kinase.This compound can be used for selectivity and suppresses the EGF receptor tyrosine kinase, and can be used for effectively treating for example tumour of EGF driving.

Therefore, expect that compound of the present invention is used for the treatment of the disease or the medical conditions of or part mediation independent by erbB receptor tyrosine kinase (especially EGF receptor tyrosine kinase), promptly described compound is used in and produces erbB receptor tyrosine kinase restraining effect in the warm-blooded animal that needs this treatment.Therefore, compound of the present invention provides the method for treatment malignant cell, it is characterized in that suppressing one or more erbB family receptors Tyrosylprotein kinases.Specifically, The compounds of this invention can be used for producing antiproliferative and/or short apoptosis and/or anti-invasion effect, and it separately or the inhibition mediation of part by the erbB receptor tyrosine kinase.Specifically, expect that compound of the present invention is used for prevention or treatment to suppressing one or more erbB receptor tyrosine kinases (for example EGF and/or erbB2 and/or erbB4 receptor tyrosine kinase, especially responsive tumour EGF receptor tyrosine kinase), described kinases participates in driving the signal transduction step of these tumor cell proliferations and existence.Therefore expect compound of the present invention by antiproliferative effect is provided, be used for the treatment of psoriasis, benign prostatic hyperplasia (BPH), atherosclerosis and restenosis and/or cancer, specifically, be used for the treatment of the cancer of erbB receptor tyrosine kinase sensitivity.This optimum or malignant tumour can influence any tissue, comprise non-noumenal tumour such as leukemia, multiple myeloma or lymphoma, also comprise the cancer of noumenal tumour such as bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neuron, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva.

According to this aspect of the invention, provide formula I quinazoline derivant or its pharmacy acceptable salt or pharmaceutically acceptable ester as medicine.

According to this aspect of the invention, be provided in warm-blooded animal such as people, producing formula I quinazoline derivant or its pharmacy acceptable salt or the pharmaceutically acceptable ester of antiproliferative effect.

Therefore, according to this aspect of the invention, provide formula I quinazoline derivant or its pharmacy acceptable salt or the purposes of pharmaceutically acceptable ester in the preparation medicine as defined above, this medicine is used for producing antiproliferative effect warm-blooded animal such as people.

Further feature according to this aspect of the present invention, produce the method for antiproliferative effect among warm-blooded animal that the invention provides in the treatment of this kind of needs such as the people, this method comprises formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester that gives described animal effective dose.

According to another aspect of the present invention, the invention provides formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester purposes in the preparation medicine, this medicine is used for prevention or the treatment tumour responsive to inhibition erbB receptor tyrosine kinase (for example EGFR and/or erbB2 and/or erbB4 (especially EGFR) Tyrosylprotein kinase), and described kinases participates in causing the signal transduction step of tumor cell proliferation.

Further feature according to this aspect of the present invention, the invention provides the method for in warm-blooded animal such as people, preventing or treating tumour, described tumour is to suppressing one or more erbB family receptors Tyrosylprotein kinases (for example EGFR and/or erbB2 and/or erbB4 (especially EGFR) Tyrosylprotein kinase) sensitivity, described kinases participates in causing the signal transduction step of tumor cell proliferation and/or existence, and described method comprises formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester that gives described animal effective dose.

Further feature according to this aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt or pharmaceutically acceptable ester, it is used in warm-blooded animal such as people's prevention or the treatment tumour responsive to inhibition erbB receptor tyrosine kinase (for example EGFR and/or erbB2 and/or erbB4 (especially EGFR) Tyrosylprotein kinase), and described kinases participates in causing the signal transduction step of tumor cell proliferation.

According to another aspect of the present invention, the invention provides formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester purposes in the preparation medicine, described medicine is used for providing EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity warm-blooded animal such as people.

Further feature according to this aspect of the present invention, the invention provides the method that EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity are provided in warm-blooded animal such as people, this method comprises formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester that gives described animal effective dose.

Further feature according to this aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt or pharmaceutically acceptable ester, it is used for providing EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory activity warm-blooded animal such as people.

According to another feature of the present invention, the invention provides formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester purposes in the preparation medicine, described medicine is used for providing selectivity EGFR tyrosine kinase inhibitory activity warm-blooded animal such as people.

Further feature according to this aspect of the present invention, the invention provides the selectivity EGFR method of tyrosine kinase inhibitory activity is provided in warm-blooded animal such as people, described method comprises formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester that gives described animal effective dose.

According to the further feature of this aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt or pharmaceutically acceptable ester, it is used for providing selectivity EGFR tyrosine kinase inhibitory activity warm-blooded animal such as people.

" selectivity EGFR kinase inhibitory activity " refers to that formula I quinazoline derivant is more effective to suppressing other kinases of EGF receptor tyrosine kinase comparison inhibition.Specifically, some The compounds of this invention is more effective to suppressing other Tyrosylprotein kinase (for example other erbB receptor tyrosine kinase such as erbB2) than it to suppressing the EGF receptor kinase.Selectivity EGFR kinase inhibitor for example of the present invention is to suppress at least 5 times of erbB2 Tyrosylprotein kinase to the effectiveness that suppresses the EGF receptor tyrosine kinase, preferably at least 10 times, as in suitable mensuration from relative IC ₅₀Value is determined.For example, for given above-mentioned testing compound, by comparing the IC of KB raji cell assay Raji ₅₀The IC of value (the EGFR Tyrosylprotein kinase suppresses active mensuration) and clone's 24 phosphoric acid-erbB2 raji cell assay Raji ₅₀Value (the erb-B2 Tyrosylprotein kinase suppresses active mensuration).

According to another aspect of the present invention, the invention provides formula I quinazoline derivant defined above or its pharmacy acceptable salt or pharmaceutically acceptable ester in the purposes of preparation in the medicine, described medicine is used for treating cancer warm-blooded animal such as people and (for example is selected from leukemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neuron, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva cancer).

Further feature according to this aspect of the present invention, treat cancer among warm-blooded animal that the invention provides in this treatment of needs such as the people and (for example be selected from leukemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neuron, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva cancer) method, described method comprise formula I quinazoline derivant defined above or its pharmacy acceptable salt or the pharmaceutically acceptable ester that gives described animal effective dose.

According to another aspect of the present invention, the invention provides formula I compound or its pharmacy acceptable salt or pharmaceutically acceptable ester, it is used for treating cancer (for example being selected from the cancer of leukemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neuron, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva cancer) warm-blooded animal such as people.

As mentioned above, be used for the treatment of or prevent the required dosage size of disease specific must according to the host who is treated, route of administration and the severity of disease for the treatment of etc. change.

Antiproliferative treatment/tyrosine kinase inhibitory activity defined above can be used as the single therapy method and uses separately, perhaps except that quinazoline derivant of the present invention, also comprises with conventional operation, radiotherapy or chemotherapy combining.This embolic chemotherapy can comprise one or more following all kinds of antitumour drugs :-

(i) antiproliferative/antitumour drug that adopts in medical oncology and combination thereof are 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, vinblastine, vindesine and vinorelbine, and 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 downward modulation conditioning agent (for example 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 invasion and attack agent (as the inhibitor of inhibitors of metalloproteinase such as Marimastat and urokinase plasminogen activator function of receptors);

(iv) the somatomedin depressant of functions is drawn together growth factor antibodies, growth factor receptor antibody (for example, anti--erbB2 antibody trastuzumab [Herceptin as this type of inhibitor packages ^TM] and anti--erbB1 antibody Cetuximab [C225]), farnesyl tranfering enzyme inhibitor, mek inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, for example other inhibitor of epidermal growth factor family is (as EGFR family tyrosine kinase inhibitor, as 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 6-acrylamido N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example inhibitor of thrombocyte-deutero-growth factor family and for example inhibitor of pHGF family;

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

(vi) blood vessel injury agent, as combretastatin A4 and in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the disclosed compound of WO02/08213;

(vii) antisense therapy agent, the therapeutical agent of listed target above for example leading is as ISIS 2503, anti--agent of ras antisense therapy;

(viii) gene therapy method, comprise the method, GDEPT (gene-pacemaker enzyme prodrug therapy) method that for example replace aberrant gene (as unusual p53 or unusual BRCA1 or BRCA2), as use the method for Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and increase the method for patient to chemotherapy or radiotherapy (as to the drug-fast gene therapy of multiple medicine) tolerance;

(ix) immunotherapy method comprises method in the external and body that for example increases the patient tumors cell immunogenicity, as with cytokine (as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection, reduces the anergic method of T-cell; Use the method for the dendritic cell of transfection immunocyte such as cytokine-transfection; Use cytokine-transfection tumor cell line approach and use anti--Te to answer the method for antibody;

(x) cell cycle inhibitor comprises for example CDK inhibitor (as flavopiridol) and other cell cycle chechpoint inhibitor (as checkpoint kinase); Aurora kinase inhibitor and other relate to the inhibitor that mitotic division and endochylema move the kinases (for example mitotic kinesins) of regulation and control; And NSC 630176.

By simultaneously, order or each component of separately treating, can carry out this type of combination therapy.This type of joint product uses other interior medical active agent of amount ranges of interior compound of the present invention of aforesaid dosage range and approval.

According to an aspect of the present invention, the invention provides medicament production, other antitumour drug defined above that this product comprises the formula I quinazoline derivant of aforementioned definitions and is used for the cancer combination therapy.

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

In the following non-limiting Examples, the present invention is further specified now, unless otherwise indicated, in these embodiments:

(i) temperature with degree centigrade provide (℃); Operate under room temperature or the envrionment temperature and carry out, promptly in 18-25 ℃ temperature range, carry out;

(ii) organic solution is through anhydrous magnesium sulfate or dried over sodium sulfate; The evaporation of solvent is decompression (600-4000 pascal; 4.5-30mmHg) reach under the highest 60 ℃ bath temperature, use rotatory evaporator to carry out;

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

(iv) in general, reaction process is by TLC and/or analysis mode LCMS monitoring, and the reaction times that provides only is used for explanation;

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

(vi) providing yield and only be used for explanation, might not be by making great efforts the accessible yield of improving one's methods; More raw materials then repeats preparation if desired;

(vii) when providing, the NMR data are the form of the δ value of principal character proton, with respect to providing as 1,000,000/(ppm) parts of interior target tetramethylsilane (TMS), unless otherwise indicated, use full deuterium methyl-sulphoxide (DMSO-d ₆) as solvent, locate to measure at the operating frequency of used NMR instrument (300 or 400MHz); Use following abbreviation: s represents unimodal; D represents bimodal; T represents triplet; Q represents quartet; M represents multimodal; Br represents broad peak;

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

(ix) solvent ratio is with volume: volume (v/v) provides;

(x) mass spectrum (MS) carries out with positively charged ion or negatively charged ion pattern with Waters or Micromass electron spray(ES) LC-MS; Provide the m/z value; In general, only report the ion of indication gross (parent mass); Unless otherwise indicated, the mass ion of quoting is (MH) ⁺

(xi) synthetic with described in the embodiment of front when similar when what describe, the mmole of usage quantity is in equal proportions among the amount of use and the front embodiment;

(xii) fusing point (mp) is measured with the automatic fusing point instrument of Buchi B-545;

(xiii) unless otherwise indicated, the compound that contains asymmetric alternate c atoms is not split;

(xiv) use following abbreviation:

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

DIPEA: diisopropylethylamine;

DMA:N, the N-N,N-DIMETHYLACETAMIDE;

DMF:N, dinethylformamide;

DCM: methylene dichloride;

DMSO: methyl-sulphoxide

EtOAc: acetoacetic ester;

IPA: Virahol;

TFA: trifluoroacetic acid; With

THF: tetrahydrofuran (THF).

Embodiment 1

7-[(1-ethanoyl piperidin-4-yl) oxygen base]-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine

To be added drop-wise at the Acetyl Chloride 98Min. (64mg) in the methylene dichloride (5ml) in methylene dichloride (20ml) solution of N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-(piperidin-4-yl oxygen base) quinazoline-4-amine dihydrochloride (250mg) and diisopropylethylamine (300 μ l), so that the temperature of this mixture keeps＜5 ℃.This reaction mixture is warmed to room temperature, and places and spend the night.Use saturated sodium bicarbonate aqueous solution (50ml) washing then, through MgSO ₄Drying is filtered and evaporation obtains the white foam thing.Then with the product that obtains through column chromatography purification, with mixture (100/0-95/5) wash-out that increases the polar methylene chloride.Merge the part and the vaporising under vacuum that contain required product, obtain title compound, for being colourless foam thing (181mg); ¹ H NMR spectrum: (DMSO-d ₆) 1.50-1.65 (m, 1H), 1.65-1.80 (m, 1H), 1.91-2.15 (m, 2H), 2.04 (s, 3H), 3.20-3.33 (m, 1H), 3.33-3.47 (m, 1H), 3.65-3.80 (m, 1H), 3.85-4.02 (m, 1H), 3.95 (s, 3H), 4.90 (m, 1H), 7.30 (m, 1H), 7.35 (s, 1H), 7.40-7.60 (m, 2H), 7.82 (s, 1H), 8.39 (s, 1H), 9.60 (s, 1H); Mass spectrum: (M+H) ⁺445.

Be prepared as follows N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-(piperidin-4-yl oxygen base) quinazoline-4-amine dihydrochloride as starting raw material:

Dioxane (4.0ml) solution of 4.0M HCl is joined 7-(benzyl oxygen base)-4-chloro-6-methoxyl group quinazoline (preparation described in the embodiment in WO98/13354 1) (60g, 0.2mol) and 3-chloro-2-fluoro aniline (31.96g is 0.22mol) in the suspension of the stirring in acetonitrile (1200ml).This reaction mixture in 80 ℃ of heating 1 hour, is placed then and spent the night.Add acetonitrile (500ml), filter the precipitation that generates, (3 * 500ml) washing and vacuum-dryings obtain 7-(benzyl oxygen base)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate, are beige solid (85.45g, 96%) with acetonitrile; ¹ H NMR spectrum: (DMSO d ₆) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass spectrum: (M+H) ⁺410.

(85.45g, trifluoroacetic acid 0.192mol) (300ml) solution was in 80 ℃ of heating 1 hour with 7-(benzyl oxygen base)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate.This reaction mixture is evaporated to dried, makes residue be dissolved in methyl alcohol (200ml) again.Then this drips of solution is added in the saturated sodium bicarbonate aqueous solution (500ml) of stirring.Filter and collect the precipitation that generates, with acetonitrile washing and dry under vacuum.Then the solid that obtains is carried out heat (100 ℃) by the mixture with butanone (500ml) and MeOH (100ml) and grind purifying, filter and drying, obtain 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-alcohol, be Off-white solid (45g, 73%); ¹ H NMR spectrum: (DMSO d ₆): 3.98 (s, 3H), 7.10 (s, 1H), 7.25-7.30 (m, 1H), 7.40-7.50 (m, 1H), 7.50-7.60 (m, 1H), 7.80 (s, 1H), 8.30 (s, 1H), 9.55 (s, 1H), 10.32 (s, 1H); Mass spectrum: (M+H) ⁺320.

Make 4-[3-chloro-2-fluorobenzene amido]-(500mg 1.565mmol) is dissolved in DMA (20ml) to 6-methoxyl group quinazoline-7-alcohol.Add (4-methylsulfonyl oxygen base) piperidines-1-carboxylic acid tertiary butyl ester (436.6mg, 1.565mmol) and cesium fluoride (236.3mg, 1.565mmol), under the stirring with this mixture heating up to 60 ℃.After 18 hours, 4-methylsulfonyl oxygen phenylpiperidines-1-carboxylic acid tertiary butyl ester and the cesium fluoride with same amount joins in this reaction mixture once more, continues heating 18 hours again in 60 ℃.Evaporating solvent makes residue be allocated in saturated sodium bicarbonate aqueous solution (50ml) and EtOAc (between 2 * 50ml).Merge organism, through MgSO ₄Dry also evaporation.Make the product that obtains through column chromatography purification then, with mixture (100/0-0/100) wash-out that increases polar methylene dichloride/EtOAc.Merge part and the vaporising under vacuum contain required product, obtain 4-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) piperidines-1-carboxylic acid tertiary butyl ester, be colourless foam thing (757mg, 96%); ¹ H NMR spectrum: (DMSO-d ₆): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass spectrum: (M+H) ⁺503.

Trifluoroacetic acid (50ml) is joined 4-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) piperidines-1-carboxylic acid tertiary butyl ester (750mg, 1.49mmol) methylene dichloride (1ml) and the solution of triethyl silicane (1ml) in, with this solution stirring 1 hour.With this reaction mixture vapourisation under reduced pressure, make residue be dissolved in EtOAc (5ml) more then.Use 1M HCl/ ether (1ml) to handle this solution then, then handle, obtain white depositions with more ether (50ml).Collect the solid that generates, centrifugal subsequently, and dry under vacuum, obtain N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-(piperidin-4-yl oxygen base) quinazoline-4-amine dihydrochloride, be white solid (750mg); ¹ H NMR spectrum: (DMSO-d ₆): 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 3.15-3.50 (m, 4H), 4.15 (s, 3H), 5.02 (m, 1H), 7.48 (m, 1H), 7.60-7.85m, 3H), 8.35 (s, 1H), 8.85 (s, 1H), 9.56 (bs, 2H); Mass spectrum: (M+H) ⁺403.

Embodiment 2

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[1-(methyl sulphonyl) piperidin-4-yl] the oxygen base } quinazoline-4-amine

Adopt and the similar approach of in embodiment 1, describing, make methylsulfonyl chloride (43 μ l) and N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-(piperidin-4-yl oxygen base) quinazoline-4-amine dihydrochloride (220mg, 0.50mmol) reaction.The product that makes generation then is through column chromatography purification, with mixture (100/0-97/3) wash-out that increases the polar methylene chloride.Merge the part and the vaporising under vacuum that contain required product, obtain title compound, be colourless foam thing (145.6mg, 60.5%); ¹ H NMR spectrum: (DMSO-d ₆): 1.70-1.90 (m, 2H), 2.04-2.20 (m, 2H), 2.92 (s, 3H), and 3.10-3.25 (m, 2H), 3.35-3.45 (m, 2H), 3.95 (s, 3H), 4.83 (m, 1H), 7.30 (m, 1H), 7.34 (s, 1H), 7.40-7.60 (m, 2H), 7.83 (s, 1H), 8.40 (s, 1H), 9.65 (s, 1H); Mass spectrum: (M+H) ⁺481.

Embodiment 3

(2S)-1-[3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) azetidine-1-yl]-1-oxo propan-2-ol

(method (a))

HATU (0.102g) is joined in the solution of stirring of DMF (10ml) of 7-(azetidine-3-base oxygen base)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate (100mg), N-methylmorpholine (0.15ml) and L-lactic acid (0.024g), this mixture of stirring is 18 hours under room temperature.This reaction mixture is evaporated to dried, residue is allocated between ethyl acetate (20ml) and the water (10ml).Make organism through SiO then ₂The rapid column chromatography purifying is with mixture (0/100-10/90) wash-out that increases polar methyl alcohol and methylene dichloride.Merge suitable part and evaporation, obtain a kind of foam thing.Grind with ether/isohexane (1: 1), obtain title compound (0.073g) into white solid; ¹ H NMR spectrum: (DMSO d ₆) 1.20 (d, 3H), 3.80-3.95 (m, 1H), 3.97 (s, 3H), 4.15 (q, 1H), 4.27 (m, 1H), 4.41 (m, 1H), 4.80 (m, 1H), 5.12 (m, 1H), 5.25 (m, 1H), 6.95 (s, 1H), 7.27 (dd, 1H), 7.40-7.57 (m, 2H), 7.83 (s, 1H), 8.39 (s, 1H), 9.67 (s, 1H); Mass spectrum: (M+H) ⁺447.

Be prepared as follows 7-(azetidine-3-base oxygen base)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate starting raw material:

Under nitrogen atmosphere, with 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-alcohol (1.23g, 3.85mmol, as described in the preparation of the starting raw material of embodiment 1, preparing), triphenyl phosphine (1.51g, 5.78mmol) and 3-hydroxyl-azetidine-1-carboxylic acid tertiary butyl ester (1.0g, 5.78mmol, be commercially available, maybe can adopt known method preparation, for example make 1-(diphenyl methyl) aza-cyclobutane-3-alcohol hydrogenation (Synlett 1991, (11) 783-784)) methylene dichloride (25ml) solution be cooled to 0 ℃.(1.33g, methylene dichloride 5.78mmol) (5ml) solution are warmed to room temperature with this reaction mixture and stirred 18 hours to be added dropwise to azo-2-carboxylic acid's di-t-butyl ester then.Filter this mixture then, through column chromatography purification filtrate, with mixture (100/0-0/100) wash-out that increases polar methylene dichloride/EtOAc.Merge part and the vaporising under vacuum contain required product, obtain 3-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) azetidine-1-carboxylic acid tertiary butyl ester, be colourless foam thing (620mg); Matter Spectrum: (M+H) ⁺475.

Dioxane (20ml) solution of 4M HCl is joined 3-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) azetidine-1-carboxylic acid tertiary butyl ester (620mg, 1.30mmol) the stirred solution of acetonitrile (20ml) in, with this mixture heating up to 60 ℃.After 1 hour, filter and collect the precipitation that generates,, obtain 7-(azetidine-3-base oxygen base)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate, be white solid (334mg) with ether (20ml) washing and vacuum-drying; ¹ H NMR spectrum: (DMSO-d ₆): 4.05 (s, 3H), 4.0-4.25 (m, 2H), 4.4-4.55 (m, 2H), 5.3 (m, 1H), 7.3-7.42 (m, 2H), 7.52 (dd, 1H), 7.62 (dd, 1H), 8.55 (s, 1H), 8.83 (s, 1H), 9.4-9.7 (m, 2H), 12.05 (s, 1H); Mass spectrum: (M+H) ⁺375.

Embodiment 4

(2R)-1-[3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) azetidine-1-yl]-1-oxo propan-2-ol

(method (a))

Adopt with in the similar approach described in the embodiment 3, make D-lactic acid and 7-(the basic oxygen base of azetidine-3-)-N-(3-chloro-2-fluoro phenyl)-6-methoxyl group quinazoline-4-amine hydrochlorate coupling, obtain title compound; ¹ H NMR spectrum: (DMSO d ₆) 1.20 (d, 3H), 3.80-3.95 (m, 1H), 3.97 (s, 3H), 4.15 (q, 1H), 4.27 (m, 1H), 4.41 (m, 1H), 4.80 (m, 1H), 5.12 (m, 1H), 5.25 (m, 1H), 6.95 (s, 1H), 7.27 (dd, 1H), 7.40-7.57 (m, 2H), 7.83 (s, 1H), 8.39 (s, 1H), 9.67 (s, 1H); Mass spectrum: (M+H) ⁺447.

Embodiment 5

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[(3R)-1-(methoxyl group ethanoyl) tetramethyleneimine-3-yl] the oxygen base } quinazoline-4-amine

(method (a))

HATU (0.31g) is joined N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-[(3R)-tetramethyleneimine-3-base oxygen base] in methylene dichloride (10ml) solution of quinazoline-4-amine dihydrochloride (300mg), diisopropylethylamine (0.45ml) and methoxyacetic acid (0.086g), this mixture of stirring is 2.5 hours under room temperature.Add methylene dichloride (20ml), organic layer with aqueous sodium hydroxide solution (2M, 30ml) and water (30ml) wash.The product that generates with methyl alcohol (4%) and methylene dichloride (96%) wash-out, obtains a kind of foam thing through the rapid column chromatography purifying.Make its recrystallization by in ether (20ml), stirring, obtain title compound (0.142g) into white solid; ¹ H NMR Spectrum: (DMSO d ₆) 2.18 (m, 1H), 2.32 (m, 1H), 3.30 (s, 3H) ^*, 3.33 (s, 3H) ^*, 3.38-3.56 (m, 1H), 3.60-3.88 (m, 3H), 3.97 (s, 3H), 4.04 (s, 2H) ^*, 4.09 (s, 2H) ^*, 5.28 (m, 1H) ^*, 5.38 (m, 1H) ^*, 7.28 (m, 2H), 7.52 (m, 2H), 7.82 (s, 1H), 8.40 (s, 1H), 9.65 (br s, 1H); Mass spectrum: (M+H) ⁺461; Fusing point: 73-77 ℃.

^*The rotational isomer signal

Be prepared as follows as N-(3-chloro-2-fluoro the phenyl)-6-methoxyl group of starting raw material-7-[(3R)-tetramethyleneimine-3-base oxygen base] quinazoline-4-amine dihydrochloride:

Azo-2-carboxylic acid's di-t-butyl ester (5.41g) is added drop-wise to (3S)-3-hydroxyl pyrrolidine-1-carboxylic acid tertiary butyl ester (4.39g), 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-alcohol (5.00g is as preparing described in the preparation of the starting raw material of embodiment 1) and the mixture of triphenyl phosphine (6.16g) in methylene dichloride (115ml) in.Under room temperature with this solution stirring 1.5 hours.Mixture is through the rapid column chromatography purifying, with isohexane/acetone/triethylamine (82/17/1) wash-out, obtain (3R)-3-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) tetramethyleneimine-1-carboxylic acid tertiary butyl ester, for containing the yellow foam thing (11.40g) of some triphenyl phosphine oxide compounds, it can directly use; Mass spectrum: (M+H) ⁺489.

Dioxane (7.0ml) solution of 4.0M HCl is joined in the suspension of (3R)-3-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) tetramethyleneimine-stirring of 1-carboxylic acid tertiary butyl ester (11.40g) in acetonitrile (50ml).This reaction mixture is heated and places under this temperature and spend the night in 70 ℃.Filter white solid, obtain N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-[(3S)-tetramethyleneimine-3-base oxygen base] quinazoline-4-amine dihydrochloride, be solid (5.66g); ¹ H NMR spectrum: (DMSO d ₆) 2.28 (m, 1H), 2.40 (m, 1H), 3.25-3.75 (m, 4H), 4.04 (s, 3H), 5.35 (m, 1H), 7.35 (m, 1H), 7.53 (m, 1H), 7.61 (m, 2H), 8.59 (s, 1H), 8.84 (s, 1H), 9.60 (br s, 1H), 9.90 (br s, 1H); Mass spectrum: (M+H) ⁺389.

Embodiment 6

Employing is in the similar approach described in the embodiment 5, makes N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-[(3R)-tetramethyleneimine-3-base oxygen base] quinazoline-4-amine dihydrochloride and suitable carboxylic acid coupling, obtain the compound shown in the table 1:

Table 1

Explain:

In the table 1

Carbonyl group is connected to the point of nitrogen in piperidines-3-base group in the finger table 1.

In following note, in the NMR spectrum ^*Refer to the rotational isomer signal.

[1] 2-[(3R)-3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) tetramethyleneimine-1-yl]-2-oxo ethanol.After the coupled reaction,, obtain title compound, be white solid as at purified product described in the embodiment 5; ¹ H NMR spectrum: (DMSO d ₆)) 2.18 (m, 1H), 2.29 (m, 1H), 3.37-3.84 (m, 4H), 3.94 (s, 3H), 3.98-4.10 (m, 2H), 4.60 (m, 1H), 5.27 (m, 1H) ^*, 5.37 (m, 1H) ^*, 7.29 (m, 2H), 7.52 (m, 2H), 7.83 (s, 1H), 8.40 (s, 1H), 9.67 (br s, 1H); Mass spectrum: (M+H) ⁺447; Fusing point 210-213 ℃.

[2] N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-({ (3R)-1-[(2-methoxy ethoxy) ethanoyl] tetramethyleneimine-3-yl } the oxygen base) quinazoline-4-amine.After the coupled reaction,, obtain title compound (0.128g) into white solid as at purified product described in the embodiment 5; ¹ H NMR spectrum: (DMSO d ₆) 2.16 (m, 1H), 2.29 (m, 1H), 3.22 (s, 3H) ^*, 3.29 (s, 3H) ^*, 3.38-3.90 (m, 8H), 3.96 (s, 3H), 4.09 (s, 2H) ^*, 4.13 (s, 2H) ^*, 5.27 (m, 1H) ^*, 5.36 (m, 1H) ^*, 7.28 (m, 2H), 7.52 (m, 2H), 7.82 (s, 1H), 8.40 (s, 1H), 9.64 (br s, 1H); Mass spectrum: (M+H) ⁺505; Fusing point 75-79 ℃.

[3] N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[(3R)-1-(3-methoxy propyl acyl group) tetramethyleneimine-3-yl] the oxygen base } quinazoline-4-amine.After the coupled reaction,, obtain title compound, be white solid as at purified product described in the embodiment 5; (0.099g); ¹ H NMR spectrum: (DMSO d ₆) 2.25 (m, 2H), 2.54 (m, 2H), 3.21 (s, 3H) ^*, 3.27 (s, 3H) ^*, 3.40 (m, 1H), 3.52-3.90 (m, 5H), 3.96 (s, 3H), 5.27 (m, 1H) ^*, 5.33 (m, 1H) ^*, 7.28 (m, 2H), 7.52 (m, 2H), 7.83 (s, 1H), 8.40 (s, 1H), 9.63 (br s, 1H); Mass spectrum: (M+H) ⁺475; Fusing point 199-202 ℃.

[4] 3-[(3R)-3-(4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } the oxygen base) tetramethyleneimine-1-yl]-3-oxo third-1-alcohol.After the coupled reaction, make product,, obtain a kind of foam thing with methyl alcohol (5%) and methylene dichloride (95%) wash-out through the rapid column chromatography purifying.Make its recrystallization by in ether (20ml), stirring, obtain title compound (0.056g) into white solid; ¹ H The NMR spectrum: (DMSO d ₆) 2.25 (m, 2H), 2.57 (m, 2H), 3.39 (m, 1H), 3.53-3.77 (m, 5H), 3.95 (s, 3H), 4.50 (m, 1H), 5.28 (m, 1H) ^*, 5.33 (m, 1H) ^*, 7.28 (m, 2H), 7.52 (m, 2H), 7.84 (s, 1H), 8.40 (s, 1H), 9.69 (br s, 1H); Mass spectrum: (M+H) ⁺461; Fusing point 100-102 ℃.

[5] 5-{[4-({ 4-[3-chloro-2-fluorobenzene amido]-6-methoxyl group quinazoline-7-yl } oxygen base) piperidines-1-yl] carbonyl } pyrrolidin-2-one; ¹ H NMR spectrum: ((DMSO+CD ₃COOD): 1.64-1.89 (m, 2H); 1.89-1.99 (m, 1H); 2.04-2.23 (m, 4H); 2.31-2.43 (m, 1H); 3.32-3.54 (m, 2H); 3.73-3.86 (m, 1H); 3.89-3.98 (m, 1H); 4.03 (s, 3H); 4.94 (bs, 1H); 7.62 (dd, 1H); 7.41 (ddd, 1H); 7.50 (s, 1H); 7.58 (ddd, 1H); 7.68 (ddd, 1H); 8.12 (s, 1H); 8.92 (s, 1H); Mass spectrum: (M+H) ⁺514.

Embodiment 7

N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-{[1-(3-methylbutyryl base) piperidin-4-yl] the oxygen base } quinazoline-4-amine

(method (b))

With N-(3-chloro-2-fluoro phenyl)-6-methoxyl group-7-(piperidin-4-yl oxygen base) quinazoline-4-amine (500mg, 1.05mmol) and 4-Dimethylamino pyridine (128mg, 1.05mmol) in acetonitrile (2.5ml), stir, the adding diisopropylethylamine (0.366ml, 2.10mmol).Make this mixture be cooled to 0 ℃, be added dropwise to isoveryl chloride (0.160ml, acetonitrile 1.31mmol) (0.5ml) solution.Under this temperature, stirred this reaction mixture 0.5 hour then.Add entry (1.0ml) and potassium hydroxide (the 49%w/w aqueous solution of 0.641ml).Separate each layer, organic layer dilutes with ethyl acetate (2.5ml).Add entry, then add Glacial acetic acid (0.210ml).Stir this mixture and distribution.Through the dried over mgso organism, filter, concentrating under reduced pressure obtains title product (416mg, 81%), is white solid; ¹ H NMR spectrum: (DMSOd ₆) 0.92 (d, 6H); 1.61 (m, 2H); 2.01 (m, 3H); 2.23 (dd, 2H); 3.24 (m, 1H); 3.40 (m, 1H); 3.78 (m, 1H); 3.95 (m, 4H); 4.90 (m, 1H); 7.29 (dt, 1H); 7.35 (s, 1H); 7.51 (m, 2H); 7.83 (s, 1H); 8.39 (s, 1H); 9.63 (s, 1H); Mass spectrum: (M+H) ⁺487.

Embodiment 8

Pharmaceutical composition

The following representative drugs formulation of the present invention (activeconstituents is called " compounds X ") of this paper of explanation therapeutic in the people that can prepare or preventative use definition:

(a) tablet I mg/ sheet

Compounds X ... ... ... ... ... ... .100

Lactose Ph.Eur..................................182.75

Croscarmellose sodium ... ... ... ... ..12.0

Corn starch paste (5%w/v paste) ... ... ... ... 2.25

Magnesium Stearate ... ... ... ... ... ... 3.0

(b) injection I (50mg/ml)

Compounds X ... ... ... ... ... ... .5.0%w/v

The 1M sodium hydroxide solution ... ... ... ... ... 15.0%v/v

0.1M hydrochloric acid (regulating pH to 7.6)

Poly(oxyethylene glycol) 400 ... ... ... ... ... ... 4.5%w/v

Water for injection to 100%

Above-mentioned composition can prepare by the ordinary method that pharmaceutical field is known.For example, can pass through to mix each composition, and the mixture tablet forming is prepared tablet I.

Claims

1. the quinazoline derivant of a formula I:

Wherein:

Q ²-X ³-

Q ³-X ⁴-

-X ⁵-Q ⁴

-X ⁶-R ⁶

And R wherein ¹On substituting group in optional 1 or 2 oxo or the sulfo-substituting group of carrying of any heterocyclic radical;

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

-X ⁷-R ⁸

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

-X ⁸-R ¹⁰

X ¹Be selected from CO and SO ₂

X ²Group for following formula:

-(CR ¹²R ¹³) _p-(Q ⁵) _m-(CR ¹⁴R ¹⁵) _q-

Wherein m is 0 or 1, p be 0,1,2,3 or 4 and q be 0,1,2,3 or 4,

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

-X ¹⁰-R ¹⁸

Condition is:

(i) the 4-anilino group in formula I is 4-bromo-2-fluorobenzene amido or 4-chloro-2-fluorobenzene amido, R ¹Be hydrogen or (1-3C) alkoxyl group and X ¹During for CO, then a be 0 and Z be selected from hydroxyl, amino, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxyl group, (1-6C) alkyl sulphonyl, (1-6C) alkyl sulfonyl-amino, N-(1-6C) alkyl-(1-6C) alkyl sulfonyl-amino, and formula Q ⁶-X ⁹-group; With

(ii) work as Q ¹During for piperidyl, then Z is a hydrogen;

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

2. quinazoline derivant according to the formula I of claim 1, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

R ¹, R ², W, X ¹, X ², a and b such as in claim 1 definition; With

Q ⁶-X ⁹-

And condition is that then Z is a heterocyclic radical when m, p and q are 0,

-X ¹⁰-R ¹⁸

Condition is:

(ii) work as Q ¹During for piperidyl, Z is a hydrogen.

3. quinazoline derivant according to the formula I of claim 1 or claim 2, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

R ¹Be selected from the alkoxyl group of alkoxyl group of the alkoxyl group of the alkoxyl group of the alkoxyl group of the alkoxyl group of hydrogen, (1-6C) alkoxyl group, cyclopropyl-(1-4C), cyclobutyl-(1-4C), cyclopentyl-(1-4C), cyclohexyl-(1-6C), tetrahydrofuran base-(1-4C) and THP trtrahydropyranyl-(1-4C)

And R wherein ¹The optional Sauerstoffatom that is inserted into this chain of adjacent carbons on any (2-6C) alkylidene chain in the substituting group separates,

And R wherein ¹Any CH in the substituting group ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Carry one or more fluoro or chloro substituting group on the group, or be selected from following substituting group: hydroxyl and (1-3C) alkoxyl group.

4. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein R ¹Be (1-3C) alkoxyl group.

5. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

B is 1,2 or 3; With

Each R ²Can be identical or different, be selected from fluoro base, chloro base, bromo base, reach (2-4C) alkynyl.

6. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

B is 1 or 2, and a R ²Be positioned at formula I anilino between (3-) position and for chloro base or bromo base.

7. quinazoline derivant according to each formula I among the claim 1-4, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, the anilino of 4-position is selected from 3-chloro-2-bromobenzene amido, 3-chloro-2-fluorobenzene amido, 3-acetylenylbenzene amido and 3-bromobenzene amido on its Chinese style I quinazoline ring.

8. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

X ²Be selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ^12a)-,-(CHR ^12aCH ₂)-,-(C (R ^12a) ₂CH ₂)-,-(CH ₂C (R ^12a) ₂)-and-(CH ₂CHR ^12a)-,

Each R wherein ^12aCan be identical or different, be (1-4C) alkyl.

9. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

Q ¹Be azetidine-3-base;

A is 0 or 1; With

W is (1-3C) alkyl.

10. quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

Z be selected from the alkoxyl group of hydroxyl, (1-4C) alkoxyl group, hydroxyl-(2-4C) and (1-4C) summation of alkoxyl group-(2-4C) alkoxyl group, and m+p+q be at least 1.

11. the quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein X ¹Be CO.

12. the quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein group Z-X ²-X ¹Be selected from alkyloyl of hydroxyl-(2-4C) and (1-4C) alkyloyl of alkoxyl group-(2-4C).

13. the quinazoline derivant according to the formula I of claim 1, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, it has formula Ib:

Wherein:

Q ²-X ³-

X ^2bBe selected from formula-CH ₂-,-CH ₂CH ₂-,-(CHR ¹²)-,-(CHR ¹²CH ₂)-and-(CH ₂CHR ¹²)-

Z ²Be selected from alkoxyl group of hydroxyl, (1-3C) alkoxyl group, hydroxyl-(2-3C) and (1-3C) alkoxyl group of alkoxyl group-(2-3C).

14. the quinazoline derivant according to the formula I of claim 1, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, wherein:

R ¹Be (1-4C) alkoxyl group;

B is 1 or 2;

Q ¹Be azetidine-3-base;

A is 0;

W is (1-3C) alkyl;

X ¹Be CO;

X ²Be selected from formula-(CHR ^12a)-,-(CHR ^12aCH ₂)-and-(CH ₂CHR ^12a)-,

R wherein ^12aBe (1-4C) alkyl;

Z is selected from hydroxyl and (1-4C) alkoxyl group, or

And wherein any heterocyclic radical among the Z is optional carries one or two substituting groups, and it can be identical or different, is selected from fluoro base, chloro base, hydroxyl, (1-4C) alkyl, (1-4C) alkoxyl group and (2-4C) alkyloyl.

15. the quinazoline derivant according to the formula I of claim 1, it is selected from:

Or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

16. the quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt.

17. a medicinal compositions, it comprises the quinazoline derivant according to each formula I in the aforementioned claim, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, and pharmaceutically acceptable diluent or carrier.

18. the quinazoline derivant according to each formula I among the claim 1-16, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, it is as medicine.

19. according to the quinazoline derivant of each formula I among the claim 1-16, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester is used for producing purposes in the medicine of anti--proliferation function warm-blooded animal such as people in preparation.

20. quinazoline derivant according to each formula I among the claim 1-16, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester is used for preventing or treats those purposes to the medicine of the tumour that suppresses EGFR Tyrosylprotein kinase sensitivity in preparation, and described kinases participates in causing the signal transduction step of tumor cell proliferation.

21. quinazoline derivant according to each formula I among the claim 1-16, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester is used for providing purposes in the medicine of selectivity EGFR tyrosine kinase inhibitory activity warm-blooded animal such as people in preparation.

22. according to the quinazoline derivant of each formula I among the claim 1-16, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester, be used for purposes in the medicine of warm-blooded animal such as people's treatment cancer in preparation.

23. method that in the warm-blooded animal of this kind of needs treatment such as people, produces anti--proliferation function, this method comprises the quinazoline derivant according to each formula I among the claim 1-16 that gives described animal effective dose, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

24. method of in warm-blooded animal such as people, preventing or treating those to the tumour of inhibition EGFR Tyrosylprotein kinase sensitivity, described kinases participation causes the signal transduction step of the survival of tumor cell proliferation and/or tumour cell, this method comprises the quinazoline derivant according to each formula I among the claim 1-16 that gives described animal effective dose, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

25. one kind provides the selectivity EGFR method of tyrosine kinase inhibitory activity in warm-blooded animal such as people, this method comprises the quinazoline derivant according to each formula I among the claim 1-16 that gives described animal effective dose, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

26. in the warm-blooded animal of this kind of needs treatment such as people, treat method for cancer for one kind, this method comprises the quinazoline derivant according to each formula I among the claim 1-16 that gives described animal effective dose, or its pharmacy acceptable salt, or its pharmaceutically acceptable ester.

27. a method for preparing as the quinazoline derivant of formula I claimed in claim 1, it comprises:

Method (a):

For preparing wherein X ¹Be the formula I compound of CO, make formula II quinazoline or its salt:

R wherein ¹, R ², W, a, b and Q ¹Such as in claim 1 definition, except if desired the time, protecting any functional group, and acid or its reactive derivatives coupling of formula III:

Z-X ²-COOH

III

Wherein Z, X ¹And X ²Such as in claim 1 definition, except if desired the time, protecting any functional group;

Perhaps

Method (b) makes the compound reaction as the quinazoline of the formula II of definition in method (a) or its salt and formula IV:

Z-X ²-X ¹-L ¹

IV

L wherein ¹Be replaceable group, Z, X ¹And X ²Such as in claim 1 definition, except if desired the time, protecting any functional group;

Perhaps

Method (c) is for preparing wherein Z by nitrogen and X ²The formula I quinazoline derivant that links to each other makes formula V compound:

L wherein ²Be replaceable group, R ¹, R ², W, X ¹, X ², a, b and Q ¹Such as in claim 1 definition, except if desired the time, protecting any functional group, with the compound reaction of formula ZH, wherein Z as hereinbefore defined, except if desired the time, protecting any functional group; Perhaps

Method (d)

For preparation has single-or the quinazoline derivant of two-(1-6C) alkylaminos, use formaldehyde or (2-6C) alkanal, reduction amination contains the corresponding formula I quinazoline derivant of N-H group; Perhaps

Method (e)

Method (f)

R wherein ², W, X ¹, X ², Z, a, b and Q ¹Such as in claim 1 definition, except if desired the time, protecting any functional group, with formula R ^{1 '}The compound coupling of OH, wherein radicals R ^{1 '}O is to R in claim 1 ¹One of oxygen linking group of definition is except protecting any functional group if desired the time;

Thereafter, (with any order) if desired:

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

(ii) remove any blocking group of existence by ordinary method; With

(iii) form the pharmacy acceptable salt of formula I quinazoline derivant, or pharmaceutically acceptable ester.