HK1097840A - Quinazoline derivatives as tyrosine kinase inhibitors - Google Patents

Description

Quinazoline derivatives as tyrosine kinase inhibitors

The present invention relates to certain novel quinazoline derivatives, or pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof, which have anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, such as in the manufacture of medicaments for use in the prevention or treatment of solid tumour diseases in warm-blooded animals such as humans.

For diseases caused by abnormal regulation of cell proliferation such as psoriasis and cancer, various treatment regimens currently employ compounds that inhibit DNA synthesis and cell proliferation. To date, the compounds used in such treatments are generally toxic to cells, but their stronger effect on rapidly dividing cells such as tumor cells may be beneficial. Alternative approaches to these cytotoxic antineoplastic agents are currently being developed, such as selective inhibitors of cell signaling pathways. These types of inhibitors may have the potential to show increased selectivity of action against tumor cells, thus possibly reducing the probability of therapies with unwanted side effects.

Eukaryotic cells respond to many different extracellular signals that enable communication between cells within the body. These signal-regulated cellsIncluding proliferation, differentiation, apoptosis and migration. Extracellular signals take the form of a variety of soluble factors, including growth factors, paracrine factors, and endocrine factors. By binding to specific transmembrane receptors, these ligands link extracellular signals to intracellular signaling pathways, thus directing the signal across the plasma membrane and causing each cell to respond to its extracellular signals. Many of these signaling processes take advantage of the reversible process of protein phosphorylation, which is involved in promoting these diverse cellular responses. The phosphorylation state of the target protein is regulated by specific kinases and phosphatases responsible for the regulation of about one third of all proteins encoded by the mammalian genome. Since phosphorylation is an important regulatory mechanism in the signaling process, it is not surprising that aberrations in these intracellular pathways cause abnormal cell growth and differentiation, thereby causing cell deformation (see Cohen et al, Curr Opin Chem Biol，1999， 3Review in 459-465).

It is generally known that many of these tyrosine kinases are constitutively active forms due to mutations and/or cause transformation of a variety of human cells when overexpressed. These mutated and overexpressed forms of kinases are present in most human tumors (see Kolibaba et al, biochimicet Biophysica Acta, 1997,133review of F217-F248). Since tyrosine kinases play an important role in the proliferation and differentiation of various tissues, much attention has been focused on these enzymes in the study of new anti-cancer therapies. This family of enzymes is divided into two groups-receptor and non-receptor tyrosine kinases, the EGF receptor and SRC families, respectively. From a number of studies, including human genetic engineering, approximately 90 tyrosine kinases have been identified in the human genome, of which 58 are receptor-type and 32 are non-receptor-type. These tyrosine kinases can be divided into 20 receptor tyrosine kinases and 10 non-receptor tyrosine kinase subfamilies (Robinson et al,Oncogene，2000， 19，5548-5557)。

these receptor tyrosine kinases play a particularly important role in mitogenic signaling that triggers cell replication. These enzymes are macromolecular glycoproteins that span the plasma membrane of a cell and have an extracellular binding domain for their specific ligand (e.g., epidermal growth factor, EGF, for the EGF receptor). Binding of the ligand results in activation of the kinase enzyme activity of the receptor encoded by its intracellular proteins. This activity phosphorylates key tyrosine amino acids in target proteins, leading to the transduction of proliferative signals through the plasma membrane of cells.

It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3, and erbB4, are commonly involved in promoting the proliferation and survival of tumor cells (see Olayioye et al,EMBO J.，2000， 193159). One mechanism that can be achieved is overexpression of the receptor at the protein level, generally considered as a result of gene amplification. This is observed in many common human cancers (see klaper et al,Adv.Cancer Res.，2000， 7725), such as breast cancer (Sainsbury et al,Brit.J.Cancer，1988， 58458; guerin et al, in the case of a pharmaceutical composition,Oncogene Res.，1988， 321, 21; slamon et al, to which reference is made,Science，1989， 244，707；Klijnand the like,Breast Cancer Res.Treat.，1994， 2973 and see Salomon et al,Crit.Rev.Oncol.Hematol.，1995， 19review of 183); non-small cell lung cancer (NSCLC) includes adenocarcinoma (Cerny et al,Brit.J.Cancer，1986， 54265, respectively; reubi et al, supra,Int.J.Cancer，1990， 45269; the Rusch et al, in the name of Rusch,Cancer Research，1993， 532379; the Brabender et al,Clin.Cancer Res.，2001， 71850) and other lung cancers (Hendler et al,Cancer Cells，1989， 7347, of; the results of the Ohsaki et al,Oncol.Rep.，2000，7，603)；bladder cancer (in the case of Neal et al,Lancet1985, 366; chow, and the like,Clin.Cancer Res.，2001， 71957, ZHau et al,Mol Carcinog.， 3254); esophageal cancer (Mukaida et al,Cancer，1991， 68142); gastrointestinal cancers, such as colon, rectal or gastric cancers (Bolen et al,Oncogene Res.，1987， 1149; kapitanovic et al, and the like,Gastroenterology，2000，1121103; ross, etc., and the like,Cancer Invest.，2001， 19554); prostate cancer (Visakorpi et al,Histochem.J.，1992， 24481; the results of Kumar et al, 2000,3273; the Scher et al, supra,J.Natl.Cancer Inst.，2000， 921866); leukemia (leukemia, leukemia,Cell，1984， 371035, Martin-Subero et al, Cancer Genet Cytogenet.，2001， 127174); ovarian cancer (Hellstrom et al,Cancer Res.，2001， 612420); head and neck cancer (Shiga et al,Head Neck，2000， 22599) or pancreatic cancer (Ovotny et al,Neoplasma，2001， 48188). With the detection of erbB family receptor tyrosine kinase expression in more human tumor tissues, it is expected that the breadth and importance of this family will not be further established.

Because of the dysregulation of one or more of these receptors, it is now generally accepted that many tumors are more clinically aggressive and therefore associated with poor prognosis in patients (Brabender et al,Clin. Cancer Res.，2001， 71850; ross, etc., and the like,Cancer Investigation，2001， 19554, Yu et al,Bioessays，2000， 22.7,673). In addition to these clinical results, preclinical information sources suggest that erbB family receptor tyrosine kinases are involved in cellular transformation. This includes the observation of many tumorsCell lines overexpress one or more erbB receptors and EGFR or erbB2 was observed to have the ability to denature non-tumor cells when transfected into these cells. This tumorigenic potential has been further demonstrated since transgenic mice overexpressing erbB2 spontaneously develop tumors in the mammary gland. In addition, certain preclinical studies have demonstrated that antiproliferative effects can be induced by the removal of one or more erbB activities using small molecule inhibitors, dominant negative modulators or inhibitory antibodies (see Mendelsohn et al, Oncogene，2000， 19Review of 6550). Thus, it has been recognized that inhibitors of these receptor tyrosine kinases should have value as selective inhibitors of mammalian cancer cell proliferation (Yaish et al.Science，1988，242933, Kolibaba et al, Biochimica et Biophysica Acta, 1997,133F217-F248; Al-Obeidi et Al, 2000,Oncogene， 195690-; mendelsohn et al, 2000,Oncogene， 19，6550-6565)。

recently, the small molecule EGFR tyrosine kinase inhibitor Iressa (also known as gefitinib and ZD1834) has been approved for the treatment of advanced non-small cell lung cancer. Moreover, the results of using inhibitory antibodies against EGFR and erbB2 (c-225 and trastuzumab, respectively) demonstrated that they are clinically beneficial for treating selected solid tumors (see Mendelsohn et al, 2000,Oncogene， 196550 vs 6565).

Amplification and/or activity of ErbB receptor tyrosine kinase members has been ascertained, thus suggesting that in certain non-malignant proliferative diseases, such as psoriasis (Ben-basal,Curr.Pharm.Des.，2000， 6933; elder et al, Science, 1989,243811), Benign Prostatic Hyperplasia (BPH) (Kumar et al,Int.Urol.Nephrol.，2000， 3273), atherosclerosis and restenosis (Bokemeyer et al,Kidney Int.，2000， 58and 549). Thus, erbB receptor tyrosine kinase is expectedEnzyme inhibitors would be useful in the treatment of these and other non-malignant cell hyperproliferative diseases.

European patent application EP 566226 discloses certain 4-anilinoquinazolines which are inhibitors of receptor tyrosine kinases.

International patent applications WO 96/33977, WO 96/33978, WO 96/33979, WO96/33980, WO 96/33981, WO 97/30034, WO 97/38994 disclose certain quinazoline derivatives which carry an anilino substituent at the 4-position and a substituent at the 6-and/or 7-position and which have receptor tyrosine kinase inhibitory activity.

European patent application EP 837063 discloses aryl substituted 4-aminoquinazoline derivatives bearing an aryl or heteroaryl containing moiety at the 6-or 7-position on the quinazoline ring. The compounds are described as useful for treating hyperproliferative diseases.

International patent applications WO 97/30035 and WO 98/13354 disclose certain 4-anilinoquinazolines substituted at the 7-position which are inhibitors of vascular endothelial growth factor receptor tyrosine kinases.

WO 00/55141 discloses 6, 7-substituted 4-anilinoquinazoline compounds which are characterized in that the substituents carry certain ester groups in the 6-and/or 7-position.

WO 00/56720 discloses 6, 7-dialkoxy-4-anilinoquinazoline compounds for the treatment of cancer or allergic reactions.

WO 01/21596 discloses the use of certain 4-anilinoquinazoline derivatives as aurora 2 kinase inhibitors.

WO 02/18351 and WO 02/18372 disclose certain 4-anilinoquinazoline compounds substituted at the 6-and/or 7-position, which are described as having an inhibitory effect on signal transduction mediated by tyrosine kinases.

WO 02/41882 discloses 4-anilinoquinazoline compounds substituted in the 6-and/or 7-position by substituted pyrrolidinyl-alkoxy or piperidinyl-alkoxy groups.

We have found that certain quinazoline derivatives which are substituted at the 7-position with a substituent which comprises a certain substituted alkanoyl group surprisingly possess potent anti-tumour activity. The compounds of the invention also generally have high cellular potency and advantageous physical properties, particularly solubility, which may provide advantages in formulation and delivery of the compounds to patients. Many of the compounds of the invention have favorable DMPK properties, e.g., high bioavailability and/or high free plasma levels and/or favorable half-life and/or favorable volume of distribution, which are expected to provide improved in vivo efficacy and reduced inter-patient variability upon exposure to such compounds, as compared to other EGFR tyrosine kinase inhibitors, e.g., gefitinib.

In addition, many of the compounds of the invention are inactive or only weakly active in the hERG assay.

Although not wishing to indicate that the disclosed compounds are pharmacologically active by affecting only a single biological process, applicants believe that the compounds provided by the present invention act against tumours by inhibiting one or more receptor tyrosine kinases of the erbB family which are involved in the signalling steps leading to the proliferation of tumour cells. In particular, applicants believe that the compounds of the present invention provide anti-tumor effects by inhibiting EGFR tyrosine kinase.

Generally, although the compounds of the invention have less inhibitory activity against other kinases such as VEGF and KDR receptor tyrosine kinases, they have potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibiting EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases. Moreover, the compounds of the invention have significantly better potency than erbB2 tyrosine kinase in inhibiting EGFR tyrosine kinase. It is therefore possible to administer the compounds of the invention at a dose sufficient to inhibit EGFR tyrosine kinase without significant effect on erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds of the present invention may provide treatment of diseases mediated by EGFR tyrosine kinases while mitigating undesirable side effects that may be associated with inhibiting other tyrosine kinases.

In a first aspect the present invention provides a quinazoline derivative of the formula I:

wherein:

R¹selected from hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, or selected from the group of formula Q²-X³A group of (a) wherein X³Is a direct bond or O, Q²Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, S, SO₂、N(R³)、CO、CH(OR³)、CON(R³)、N(R³)CO、SO₂N(R³)、N(R³)SO₂CH ═ CH and C ≡ C where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂Either with a substituent selected from: halogen, carboxyl, carbamoyl, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, or selected from the formula Q³-X⁴A group of (a) wherein X³Is a direct bond or is selected from CO and N (R)⁴) CO, wherein R⁴Is hydrogen or (1-6C) alkyl, Q⁴Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

Wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thio, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino, or selected from the formula-X⁵-Q⁴The group of (a): wherein X⁵Is a direct bond or is selected from O, S, SO₂、N(R⁵)、CO、CH(OR⁵)、CON(R⁵)、N(R⁵)CO、SO₂N(R⁵)、N(R⁵)SO₂、C(R⁵)₂O、C(R⁵)₂S and C (R)⁵)₂N(R⁵) Wherein R is⁵Is hydrogen or (1-6C) alkyl, Q⁴Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

wherein R is¹Any of the above substituents optionally bears one or more (e.g., 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkylamino ]Amino, (1-6C) alkoxyA carbonyl group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]A carbamoyl group,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino, or selected from the formula-X⁶-R⁶In which X is⁶Is a direct bond or is selected from O, N (R)⁷) And C (O), wherein R⁷Is hydrogen or (1-6C) alkyl, R⁶Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, carboxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl, (1-6C) alkoxycarbonylamino- (1-6C) alkyl, carbamoyl- (1-6C) alkyl,N- (1-6C) alkylcarbamoyl- (1-6C) alkyl,N， NDi- [ (1-6C) alkyl]Carbamoyl- (1-6C) alkyl, (2-6C) alkanoyl- (1-6C) alkyl or (1-6C) alkoxycarbonyl- (1-6C) alkyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo or thioxo substituents;

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

each R²Which may be the same or different, is selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl, N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula-X⁷-R⁸In which X is⁷Is a direct bond or is selected from O and N (R)⁹) Wherein R is⁹Is hydrogen or (1-6C) alkyl, R⁸Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl or (1-6C) alkoxycarbonylamino- (1-6C) alkyl;

Q¹Is piperidinyl;

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

each W, which may be the same or different, is selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X⁸-R¹⁰The group of (a): wherein X⁸Is a direct bond or is selected from O, CO, SO₂And N (R)¹¹) Wherein R is¹¹Is hydrogen or (1-6C) alkyl, R¹⁰Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl,N- (1-6C) alkylamino- (1-6C) alkyl orN， NDi- [ (1-6C) alkyl]Amino- (1-6C) alkyl;

X¹selected from CO and SO₂；

X²Is a group of the formula:

-(CR¹²R¹³)_p-(Q⁵)_m-(CR¹⁴R¹⁵)_q-

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3 or 4,

each R¹²、R¹³、R¹⁴And R¹⁵May be the same or different and is selected from the group consisting of hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and di- [ (1-6C) alkyl]Amino group, Q⁵Selected from (3-7C) cycloalkylene and (3-7C) cycloalkenylene,

wherein X²Any CH in the radical₂Or CH₃Radicals at each of said CH₂Or CH₃Optionally bearing one or more halogen or (1-6C) alkyl substituents on the radical, or selected from hydroxy, cyano, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl ]A substituent of an amino group;

z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond or is selected from O, N (R)¹⁶)、SO₂And SO₂N(R¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl, or heterocyclyl- (1-4C) alkyl;

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein adjacent carbon atoms in any (2-6C) alkylene chain in the Z substituent are optionally separated by an intervening chain selected from: o, S, SO₂、N(R¹⁷) CO, -C ═ C-and-C ≡ C-, where R is¹⁷Is hydrogen or (1-6C) alkyl,

wherein any CH in any Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl ]Amino- (1-4C) alkyl; the conditions are as follows:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R is¹When it is hydrogen or (1-3C) alkoxy, a is 0, and Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a).

In a particular embodiment of the invention there is provided a quinazoline derivative of the formula I, as defined above, or a pharmaceutically-acceptable salt thereof.

In this specification, the generic term "alkyl" includes straight-chain and branched alkyl groups such as propyl, isopropyl and tert-butyl, and (3-7C) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However, references to an individual alkyl group such as "propyl" refer only to the straight chain version, and references to an individual branched alkyl group such as "isopropyl" refer only to the branched chain version, whereas references to an individual cycloalkyl group such as "cyclopentyl" refer only to the 5-membered ring. Similar convention applies to other generic terms, such as (1-6C) alkoxy including methoxy, ethoxy, cyclopropoxy and cyclopentyloxy; (1-6C) alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino; di- [ (1-6C) alkyl ]The amino group includes dimethylamino group, diethylamino group, amino group,N-cyclobutyl-N-methylamino andN-cyclohexyl-N-an ethylamino group.

It will be appreciated that certain compounds of formula I as defined above may exist in optically active or racemic forms due to having one or more asymmetric carbon atoms, and the present invention includes within its definition any such optically active or racemic forms which possess the above-mentioned activity. It is also understood that (R, S) in the name of chiral compounds represents any scalemic or racemic mixture, while (R) and (S) represent enantiomers. There is no (R, S), (R) or (S) in the nomenclature, it being understood that the nomenclature refers to any scalemic or racemic mixture, wherein a scalemic mixture comprises R and S enantiomers in any relative proportion, and a racemic mixture comprises R and S enantiomers in a 50: 50 ratio. The synthesis of the optically active form can be carried out by standard organic chemical techniques well known in the art, for example by spinning photoactive starting material synthesis or by resolution of the racemic form. Similarly, the above activities can be evaluated using standard laboratory techniques referred to below.

Suitable values for the above general groups include those listed below.

Any "Q" group (e.g. Q) for cycloalkyl (3-7C)²、Q⁴、Q⁶) Or (3-7C) cycloalkyl in the group "Q" or R, suitable values being, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1 ]]Heptyl for any "Q" group when it is (3-7C) cycloalkenyl (e.g. Q)²、Q⁴、Q⁶) Or (3-7C) cycloalkenyl in the "Q" group, suitable values being, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It should be understood that for Q⁵As used herein, (3-7C) cycloalkylene refers to a divalent (3-7C) cycloalkane linking group, which may be attached through different carbon atoms in the (3-7C) cycloalkylene ring, or may be attached through the same carbon atom in the (3-7C) cycloalkylene ring. Thus, for example, a "cyclopropene" group includes cycloprop-1, 2-ylidene and cyclopropylidene (cyclopropylidene) of the formula:

however, reference to a (3-7C) cycloalkylene group alone, such as cyclopropylidene, is intended to refer to that group only. Similar conventions apply to Q⁵(3-7C) Cycloalkenylene.

For Q in the case of heterocyclyl¹External 'Q' groups (e.g. Q)²、Q³、Q⁴Or Q⁶) Or heterocyclyl in "Q", suitable values are, for example, non-aromatic saturated (i.e., having maximum saturation) And degree) or a 3-to 10-membered monocyclic or bicyclic ring which is partially saturated (i.e., the ring system retains some, but not all, of the unsaturation), may have up to 5 heteroatoms selected from: oxygen, nitrogen and sulfur, which rings may be carbon-or nitrogen-linked, such as, unless otherwise indicated, oxetanyl, azetidinyl, tetrahydrofuryl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1, 4-thiazinyl, 1-dioxotetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyrimidyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl or decahydroquinolinyl, especially tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1, 4-oxazepanyl, Thiomorpholinyl-1, 1-dioxotetrahydro-4H-1, 4-thiazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrothiophen-3-yl, tetrahydrothiopyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl or piperazin-1-yl. The nitrogen or sulfur atom in the heterocyclic group may be oxidized to give the corresponding N oxide or S oxide, for example, 1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. Suitable values for such groups with 1 or 2 oxo-or thio-substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl, 2, 5-dioxoimidazolidinyl or 2, 6-dioxopiperidinyl.

Q¹Is piperidinyl, the group being attached to the oxygen of formula I through a ring carbon atom.

When the "Q" group is heteroaryl- (1-6C) alkyl, suitable values are, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention includes corresponding suitable values for the "Q" group, for example when heterocyclyl- (1-6C) alkyl is not present and (3-7C) cycloalkyl- (1-6C) alkyl or (3-7C) cycloalkenyl- (1-6C) alkyl is present.

Any "R" group (R)¹-R¹⁹) W or X¹、X²Or each of the Z groups, suitable values include: -

For halogen, fluorine, chlorine, bromine and iodine;

for a (1-6C) alkyl group: methyl, ethyl, propyl, isopropyl and tert-butyl;

for (2-8C) alkenyl: vinyl, isopropenyl, allyl, and but-2-enyl;

for (2-8C) alkynyl: ethynyl, 2-propynyl and but-2-ynyl;

for (1-6C) alkoxy: methoxy, ethoxy, propoxy, isopropoxy, and butoxy;

for (2-6C) alkenyloxy: vinyloxy and allyloxy;

for (2-6C) alkynyloxy: ethynyloxy and 2-propynyloxy;

for (1-6C) alkylthio: methylthio, ethylthio and propylthio;

for (1-6C) alkylsulfinyl: methylsulfinyl and ethylsulfinyl;

For a (1-6C) alkylsulfonyl group: methylsulfonyl and ethylsulfonyl;

for (1-6C) alkylamino: methylamino, ethylamino, propylamino, isopropylamino, and butylamino;

for di- [ (1-6C) alkyl ] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino;

for (1-6C) alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;

for N- (1-6C) alkylcarbamoyl: n-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl;

for N, N-di- [ (1-6C) alkyl ] carbamoyl: n, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl;

for (2-6C) alkanoyl: acetyl, propionyl, and isobutyryl;

for (2-6C) alkanoyloxy: acetoxy and propionyloxy;

for (2-6C) alkanoylamino: acetylamino and propionylamino;

for N- (1-6C) alkyl- (2-6C) alkanoylamino: n-methylacetamido and N-methylpropionylamino;

for N- (1-6C) alkylsulfamoyl: n-methylsulfamoyl and N-ethylsulfamoyl;

for N, N-di- [ (1-6C) alkyl ] sulfamoyl: n, N-dimethylsulfamoyl;

For a (1-6C) alkylsulfonylamino group: methanesulfonylamino and ethanesulfonylamino;

for N- (1-6C) alkyl- (1-6C) alkylsulfonylamino: n-methylmethanesulfonylamino and N-methylethylsulfonylamino;

for (3-6C) enoylamino: acrylamido, methacrylamido, and crotonamido;

for N- (1-6C) alkyl- (3-6C) alkenoylamino: n-methacrylamido and N-methylbutenamido;

for (3-6C) alkynoylamino: a propiolamido group;

for N- (1-6C) alkyl- (3-6C) alkynoylamino: n-methyl propiolamido;

for amino- (1-6C) alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl, and 3-aminopropyl;

for (1-6C) alkylamino- (1-6C) alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl;

for di- [ (1-6C) alkyl ] amino- (1-6C) alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl;

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

for hydroxy- (1-6C) alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

For (1-6C) alkoxy- (1-6C) alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;

for cyano- (1-6C) alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl;

for (1-6C) alkylthio- (1-6C) alkyl: methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 1-methylthioethyl and 3-methylthiopropyl;

for (1-6C) alkylsulfinyl- (1-6C) alkyl: methylsulfinylmethyl, ethylsulfinylmethyl, 2-methylsulfinylethyl, 1-methylsulfinylethyl and 3-methylsulfinylpropyl;

for (1-6C) alkylsulfonyl- (1-6C) alkyl: methylsulfonylmethyl, ethylsulfonylmethyl, 2-methylsulfonylethyl, 1-methylsulfonylethyl, and 3-methylsulfonylpropyl;

for (2-6C) alkanoylamino- (1-6C) alkyl: acetamidomethyl, propionylaminomethyl, and 2-acetamidomethyl;

for N- (1-6C) alkyl- (2-6C) alkanoylamino- (1-6C) alkyl: n-methylacetamidomethyl, 2- (N-methylacetamido) ethyl and 2- (N-methylpropionylamino) ethyl;

for (1-6C) alkoxycarbonylamino- (1-6C) alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl;

For (2-6C) alkanoyloxy- (1-6C) alkyl: acetoxymethyl, 2-acetoxyethyl and 2-propionyloxyethyl;

for carbamoyl- (1-6C) alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl;

for (2-6C) alkanoyl- (1-6C) alkyl: acetylmethyl and 2-acetylethyl;

for N- (1-6C) alkylcarbamoyl- (1-6C) alkyl: n-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1- (N-methylcarbamoyl) ethyl, 1- (N-ethylcarbamoyl) ethyl, 2- (N-methylcarbamoyl) ethyl, 2- (N-ethylcarbamoyl) ethyl and 3- (N-methylcarbamoyl) propyl;

for N, N-bis [ (1-6C) alkyl ] carbamoyl- (1-6C) alkyl: n, N-dimethylcarbamoylmethyl, N-diethylcarbamoylmethyl, 2- (N, N-dimethylcarbamoyl) ethyl and 3- (N, N-dimethylcarbamoyl) propyl;

for sulfamoyl (1-6C) alkyl: sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and 3-sulfamoylpropyl;

for N- (1-6C) alkylsulfamoyl (1-6C) alkyl: n-methylsulfamoylmethyl, N-ethylsulfamoylmethyl, N-propylsulfamoylmethyl, 1- (N-methylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl and 3- (N-methylsulfamoyl) propyl;

For N, N di- (1-6C) alkylsulfamoyl (1-6C) alkyl: n, N-dimethylsulfamoylmethyl, N-diethylsulfamoylmethyl, N-methyl, N-ethylsulfamoylmethyl, 1- (N, N-dimethylsulfamoyl) ethyl, 1- (N, N-diethylsulfamoyl) ethyl, 2- (N, N-dimethylsulfamoyl) ethyl, 2- (N, N-diethylsulfamoyl) ethyl and 3- (N, N-dimethylsulfamoyl) propyl.

As defined above, when Z in formula I is of formula Q⁶-X⁹A group of (A) X⁹Is SO₂N(R¹⁶) When, SO₂Group and Q⁶To the nitrogen atom of formula I²Are connected. Similar conventions apply to the other groups defined herein. For example, when X²Is of the formula Q⁵-(CR¹⁴R¹⁵)_pWhen a group of (1) is Q⁵The radical being bound to the Z radical in formula I, (CR)¹⁴R¹⁵)_pThe radical and X in formula I¹The groups are linked.

As defined above, e.g. R¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent may optionally be separated by intervening chains of groups such as O, CON (R)³)、N(R³) Or C ≡ C. For example, insertion of a C.ident.C group into the ethylene chain of a 2-morpholinoethoxy group results in a 4-morpholinobut-2-ynyloxy group, for example, insertion of a CONH group into the ethylene chain of a 3-methoxypropoxy group results in, for example, a 2- (2-methoxyacetylamino) ethoxy group. It is understood that the term (2-6C) alkylene chain refers to any CH ₂CH₂Radical (e.g. R)¹In (b), an alkylene chain such as (1-6C) alkyl, (1-6C) alkoxy, (2-8C) alkenyl, (2-8C) alkenyloxy, (2-8C) alkynyl and (2-8C) alkynyloxy is included. For example, at R¹With the interposition of N (CH) between the third and fourth carbon atoms of the 5-hexenyloxy group₃) The group gives 3- (N-methyl-N-allylamino) propoxy.

As defined above, when R¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂With substituents in position ≡ or HC ≡ e.g. of formula Q³-X⁴A group of (a) wherein X⁴Is, for example, NHCO, Q³When it is heterocyclyl- (1-6C) alkyl, the resulting compoundsAptitude R¹The substituents include, for example,N- [ Heterocyclyl- (1-6C) alkyl group]Carbamoylethenyl radicals such asN- (2-pyrrolidin-1-ylethyl) carbamoyl vinyl, orN- [ Heterocyclyl- (1-6C) alkyl group]Carbamoylethynyl radicals such asN- (2-pyrrolidin-1-ylethyl) carbamoylethynyl.

When reference is made herein to CH₂Or CH₃Radicals at each of said CH₂Or CH₃Optionally having one or more halogen or (1-6C) alkyl substituents on the radical, on each of said CH groups₂Suitably having 1 or 2 halogen or (1-6C) alkyl substituents on the radical, on each of said CH groups₃Suitably, there are 1, 2 or 3 such substituents on the radical.

When reference is made herein to CH₂Or CH₃Radicals at each of said CH₂Or CH₃When optionally substituted as defined herein on a group, suitable substituents so formed include, for example, hydroxy-substituted heterocyclyl- (1-6C) alkoxy (e.g., 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy), hydroxy-substituted heterocyclyl- (1-6C) alkylamino (e.g., 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino), and hydroxy-substituted (2-6) alkanoyl (e.g., hydroxyacetyl, 2-hydroxypropionyl, and 2-hydroxybutyryl).

When referred to herein as "any CH₂Or CH₃Group, CH in the heterocyclic group being excluded₂In addition to groups, optionally with substituents ", it is understood that this statement is made merely for the purpose of distinguishing CH groups which may be present, for example, in alkyl groups₃Optional substituents on the group and substituents which may be present on carbon atoms of the heterocyclic group. Thus, it will be understood that, while it is stated herein that the heterocyclyl group may optionally also bear one or more substituents, such description does not exclude other substituents present on ring carbon atoms in the heterocyclyl group. For example, if R¹Is 3- (pyrrolidin-1-yl) propoxy, as illustrated herein for example by R¹CH in the substituent ₂Or CH₃Group, CH in the heterocyclic group being excluded₂Optionally bearing, in addition to the radicals, a hydroxyl substituent, and R¹Any of the heterocyclyl groups in (a) optionally bears an alkyl substituent, then an optional hydroxy substituent may be present on the CH of the propoxy group₂Thus, for example, 2-hydroxy-3- (pyrrolidin-1-yl) propoxy is produced. Similarly, an alkyl group such as methyl may be present on the pyrrolidinyl ring, resulting in, for example, 3- (3-methylpyrrolidin-1-yl) propoxy. Similarly, the propoxy group may be substituted with hydroxy and the pyrrolidinyl ring may be substituted with methyl, yielding, for example, 2-hydroxy-3- (3-methylpyrrolidin-1-yl) propoxy.

For the avoidance of doubt, when W is oxo, Q¹CH in (1)₂Substitution with O yields a C (O) group.

It is to be understood that reference herein to Q is made¹Is, for example, piperidin-4-yl, means that the piperidine ring is attached to the oxygen in formula I. The piperidine ring being further substituted in the 1-position by a group Z-X²-X¹-substituted, optionally with one or more W substituents on one or more available piperidinyl ring carbon atoms.

It will be appreciated that certain compounds of formula I may exist in solvated as well as unsolvated forms, for example, hydrated forms. It is to be understood that the invention includes all such solvate forms which exhibit an inhibitory effect on erbB receptor tyrosine kinases.

It will also be appreciated that certain compounds of formula I may exhibit polymorphism and the present invention therefore includes all such forms which exhibit inhibitory effects on erbB receptor tyrosine kinases.

It will also be appreciated that the invention relates to all tautomeric forms of the compounds of formula I which exhibit inhibitory effects on erbB receptor tyrosine kinases.

Suitable pharmaceutically acceptable salts of the compounds of the formula I are, for example, acid addition salts of the compounds of the formula I, for example with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or maleic acid; or, for example, a salt of a compound of formula I with sufficient acidity, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

The term "pharmaceutically acceptable ester" as used herein refers to an ester of a quinazoline derivative of the formula I which hydrolyses in vivo to leave the parent compound or a pharmaceutically acceptable salt thereof. The in vivo hydrolysable esters of the quinazolines of formula I may be used to alter or improve the physical and/or pharmacokinetic properties, e.g. solubility, of the parent compound. Suitable ester groups useful in forming pharmaceutically acceptable ester prodrugs are well known, for example, as discussed below:

Pro-drugs as Novel Delivery Systems, t.higuchi and v.stella, vol.14 soft words ACS Symposium Series and in Edward b.roche, ed.;

bioreversible Carriers in Drug Design, American pharmaceutical Association and Pergamon Press, 1987;

design of Prodrugs, eds., H.Bundgaard, (Elsevier, 1985) and Methods in enzymology, Vol.42, p.309-396, K.Widder et al, (Academic Press, 1985);

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

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

bundgaard et al, Journal of Pharmaceutical Sciences, 77, 285 (1988);

kakeya et al, Chem Pharm Bull, 32, 692 (1984).

A pharmaceutically acceptable ester of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, is an ester with a carboxy or (especially) hydroxy group of formula I (for example when Z is hydroxy), which ester is hydrolysed in the human or animal body to produce the parent quinazoline of the formula I when administered to a warm-blooded animal such as man.

For the carboxyl group in formula I, suitable pharmaceutically acceptable esters include C_1-6Alkoxymethyl esters such as methoxymethyl ester; c _1-6Alkanoyloxymethyl esters such as pivaloyloxymethyl ester; 2-benzo [ c ]]Furanone ester; c_3-8Cycloalkoxy-carbonyloxy group C_1-6Alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1, 3-dioxol-2-ketomethyl esters such as 5-methyl-1, 3-dioxol-2-ketomethyl ester; and C_1-6Alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, may be formed at any of the carboxyl groups in the compounds of the present invention.

For the hydroxy groups in formula I or a pharmaceutically acceptable salt thereof, suitable pharmaceutically acceptable esters include inorganic esters such as phosphate esters, α -acyloxyalkyl ethers and related compounds and esters derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenoic, naphthenic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms, may be formed at any hydroxy group in the compounds of the invention, for example when Z is hydroxy or contains a hydroxy group. After administration, the pharmaceutically acceptable ester undergoes in vivo hydrolysis, cleavage to yield the parent carboxy/hydroxy group in the quinazoline derivative of the formula I.

Examples of α -acyloxyalkyl ethers which may be used to form pharmaceutically acceptable esters include acetoxymethoxy and 2, 2-dimethylpropionyloxymethoxy. For hydroxy groups in formula I (e.g., when Z is hydroxy), the selection of pharmaceutically acceptable ester forming groups include (1-6C) alkanoyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl, (1-6C) alkoxycarbonyl (to produce alkyl carbonate), di- (1-4C) alkylcarbamoyl and N- (di- (1-4C) alkylaminoethyl) -N- (1-4C) alkylcarbamoyl (yielding carbamate), di- (1-4C) alkylaminoacetyl, and carboxyacetyl. Examples of substituents on benzoyl include chloromethyl or aminomethyl, (1-4C) alkylaminomethyl and di- ((1-4C) alkyl) aminomethyl, and morpholino or piperazine linked from the ring nitrogen atom to the 3-or 4-position of the benzoyl ring through a methylene linking groupOxazino (piperazino).

A particular pharmaceutically acceptable ester is a phosphate ester formed with a hydroxy group (e.g. when Z is hydroxy or contains a hydroxy group) of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof. More specifically, pharmaceutically acceptable esters include quinazoline derivatives of the formula I wherein the hydroxy group in formula I forms a phosphoryl (npd is 1) or phosphorylidene (npd is 0) ester of the formula (PD1) or a pharmaceutically acceptable salt thereof:

another specific pharmaceutically acceptable ester is a quinazoline derivative of the formula I wherein the hydroxy group in formula I (e.g. when Z is hydroxy) forms a phosphoryl group, giving a group of the formula (PD1) wherein npd is 1.

Useful intermediates for preparing such esters include compounds containing a group of formula (PD1) wherein either or both-OH groups in (PD1) are independently protected by (1-4C) alkyl (which compound itself is also the compound of interest), phenyl or phenyl- (1-4C) alkyl (which phenyl group is optionally substituted by 1 or 2 groups independently selected from (1-4C) alkyl, nitro, halo and (1-4C) alkoxy).

Pharmaceutically acceptable esters of quinazoline derivatives of the formula I containing a group such as (PD1) may be prepared by reacting a quinazoline derivative of the formula I with a suitably protected phosphorylating agent, for example containing a chloro or dialkylamino leaving group, followed by oxidation (if necessary) and deprotection. Suitable phosphorylating agents are well known and include, for example, protected phosphoramidate compounds such as N, N-di- [ (1-6C) alkyl ] -phosphoramidates, for example di-tert-butyl N, N-diethylaminophosphate.

It will be appreciated that the ester group in the quinazoline derivative of the formula I may form a pharmaceutically acceptable salt of the ester group, such salt forming part of the present invention. When a pharmaceutically acceptable salt of a pharmaceutically acceptable ester is desired, it is accomplished by conventional techniques well known to those of ordinary skill in the art. Thus, for example, a compound containing a group of formula (PD1) may be ionised (partially or wholly), forming a salt with a suitable number of counterions. By way of example, if a pharmaceutically acceptable ester prodrug of a quinazoline derivative of the formula I contains a (PD1) group, there are two HO-P-functionalities, each of which may form a suitable salt with a suitable counter ion. Suitable salts of the group of formula (PD1) are salts of bases, for example alkali metal salts such as sodium salts, alkaline earth metal salts such as calcium or magnesium salts, or organic amine salts such as triethylamine or tris- (2-hydroxyethyl) amine salts. Thus, for example, the group (PD1) may form a mono-or di-sodium salt).

Specific novel compounds of the invention include, for example, quinazoline derivatives of the formula I or pharmaceutically-acceptable salts or pharmaceutically-acceptable esters thereof, wherein, unless otherwise indicated, each R¹、R²、W、Q¹、X¹、X²A, b and Z have any of the meanings defined hereinbefore or in the following paragraphs (a) to (nnnn): -

(a)R¹Selected from hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy or of formula Q²-X³A group of (a) wherein X³Is a direct bond or is O, Q²Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, N (R)³)、CON(R³)、N(R³) CO, CH ═ CH and C ≡ C, where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂Either with a substituent selected from: a carbamoyl group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl]Amino- (1-6C) alkyl or of formula Q³-X⁴A group of (a) wherein X⁴Is a direct bond or is selected from CO and N (R)⁴) CO, wherein R⁴Is hydrogen or (1-6C) alkyl, Q ³Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical, or from hydroxy, amino, cyano, carbamoyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl andN， Ndi- [ (1-6C) alkyl]A substituent of carbamoyl, or a substituent selected from the group consisting of formula-X⁵-Q⁴In which X is⁵Is a direct bond or is selected from O, N (R)⁵)、CON(R⁵)、N(R⁵) CO and C (R)⁵)₂O, wherein R⁵Is hydrogen or (1-6C) alkyl, Q⁴Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

wherein R is¹Any of the above substituents optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, or selected from the group consisting of formula-X⁶-R⁶The group of (a):

wherein X ⁶Is a direct bond or is selected from O and N (R)⁷) Wherein R is⁷Is hydrogen or (1-6C) alkyl, R⁶Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, carbamoyl- (1-6C) alkyl,N- (1-6C) alkylcarbamoyl- (1-6C) alkyl andN， N-bis- [ (1-6C)) Alkyl radical]Carbamoyl- (1-6C) alkyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo substituents;

(b)R¹selected from hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy or of formula Q²-X³A group of (a) wherein X³Is a direct bond or O, Q²Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, N (R)³)、CON(R³)、N(R³) CO, CH ═ CH and C ≡ C, where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂Either with a substituent selected from: a carbamoyl group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl ]Amino- (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical, or from hydroxy, amino, cyano, carbamoyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl andN， Ndi- [ (1-6C) alkyl]A substituent of carbamoyl, or a substituent selected from the group consisting of formula-X⁵-Q⁴In which X is⁵Is a direct bond or is selected from O, N (R)⁵)、CON(R⁵)、N(R⁵) CO and C (R)⁵)₂O, wherein R⁵Is hydrogen or (1-6C) alkyl, Q⁴Is heterocyclyl or heterocyclicA radical- (1-6C) alkyl radical,

wherein R is¹Any of the above substituents optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, or selected from the group consisting of formula-X⁶-R⁶The group of (a):

wherein X⁶Is a direct bond or is selected from O and N (R)⁷) Wherein R is⁷Is hydrogen or (1-6C) alkyl, R ⁶Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl]Amino- (1-6C) alkyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo substituents;

(c)R¹selected from the group consisting of hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy and (2-6C) alkynyloxy,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, N (R)³)、CON(R³)、N(R³) CO, CH ═ CH and C ≡ C, where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical, or from hydroxy, amino, cyano, carbamoyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl andN， Ndi- [ (1-6C) alkyl]A substituent of a carbamoyl group;

(d)R¹selected from hydrogen, hydroxy, (1-6C) alkoxy or of formula Q²-X³A group of (a) wherein X³Is O, Q²Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

Wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o and N (R)³) Wherein R is³Is hydrogen or (1-4C) alkyl,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical, or from hydroxy, amino, cyano, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]A substituent of the amino group, and a substituent of the amino group,

wherein R is¹Any of the above substituents optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl and (2-6C) alkanoyl,

wherein R is₁Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo substituents;

(e)R¹selected from hydrogen, hydroxy, (1-6C) alkoxy or of formula Q²-X³A group of (a) wherein X³Is O, Q ²Is azetidin-3-yl- (1-4C) alkyl, azetidin-1-yl- (2-4C) alkyl, pyrrolidin-2-yl- (1-4C) alkyl, pyrrolidin-3-yl- (1-4C) alkyl, pyrrolidin-1-yl-(2-4C) alkyl, piperidin-2-yl- (1-4C) alkyl, piperidin-3-yl- (1-4C) alkyl, piperidin-4-yl- (1-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o and N (R)³) Wherein R is³Is hydrogen or (1-4C) alkyl,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical, or from hydroxy, (1-4C) alkoxy, amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]A substituent of the amino group, and a substituent of the amino group,

wherein R is¹Any of the above substituents optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, carbamoyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl ]Amino group,N- (1-4C) alkylcarbamoyl,N， N-di- (1-4C) alkyl]Carbamoyl and (2-4C) alkanoyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bears 1 oxo substituent (preferably R)¹Any oxo group on the mesomorpholino group is located at the 3 or 5 position on the morpholino ring);

(f)R¹selected from hydrogen, hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³A group of (a) wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents optionally bearing 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino and (2-4C) alkanoyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 oxo substituent;

(g)R¹selected from the group consisting of hydrogen, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, 2-hydroxyethoxy, 2-fluoroethoxy, cyclopropylmethoxy, 2-cyclopropylethoxy, vinyloxy, allyloxy, ethynyloxy, 2-propynyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofurmethyloxy, tetrahydrofuran-3-ylmethoxy, 2- (tetrahydrofuran-2-yl) ethoxy, 3- (tetrahydrofuran-2-yl) propoxy, 2- (tetrahydrofuran-3-yl) ethoxy, 3- (tetrahydrofuran-3-yl) propoxy, tetrahydropyranylmethoxy, 2-tetrahydropyranylethoxy, isopropoxy, 2-hydroxyethoxy, cyclopropylmethoxy, cyclopentanylmethoxy, cyclopentanylethoxy, 2-propargyloxy, ethynyl, 2-hydroxyethoxy, 2-fluoroethyloxy, cyclopropylmethoxy, 2-cyclopropylmethoxy, 3-tetrahydropyranyl-propoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2- (1, 1-dioxotetrahydro-4-yl) -ethoxy H-1, 4-thiazin-4-yl) ethoxy, 3- (1, 1-dioxotetrahydro-4-yl)H-1, 4-thiazin-4-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, pyrrolidin-1-yl, pyrrolidin-1-ylpropoxy, piperidin-3-yloxy, piperidin-4-ylethoxy, piperidin-4-yloxy, Morpholino, piperidino and piperazin-1-yl,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, O,NH、N(CH₃) CH ═ CH and C ≡ C,

when R is¹In the case of vinyloxy, allyloxy, ethynyloxy or 2-propynyloxy, R¹The substituent being optionally at the terminal CH₂Either with a substituent selected from:N- (2-dimethylaminoethyl) carbamoyl,N- (3-dimethylaminopropyl) carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or of formula Q ³-X⁴-a group of (a):

wherein X⁴Is a direct bond or is NHCO or N (CH)₃)CO，Q³Is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, piperazine-2-ylpropyl, morpholino-2-morpholinopropyl, morpholino-methyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-piperidinobutyl, piperidinomethyl, 2-piperidin-3-ylethyl, piperidin-4-ylethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,

R¹of the substituents, any CH having 2 carbon atoms attached thereto₂Radical (removing CH in cyclyl ring₂External to the radical) or any CH attached to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries substituents selected from: hydroxy, amino, methoxy, ethoxy, methylsulfonyl, methylamino and dimethylamino,

wherein R is¹Any of the above substituents optionally bearing 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methyl, ethyl, n-butyl, n, N-propyl, isopropyl and methoxy, R¹Any piperidin-3-ylmethyl, piperidin-4-ylmethyl or piperazin-1-yl group of substituents is optionally carried out with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetyl or propionylN-a substitution of a group of formula (I),

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo substituents;

(h)R¹selected from the group consisting of hydrogen, hydroxy, (1-6C) alkoxy, (3-7C) cycloalkyl-oxy and (3-7C) cycloalkyl- (1-6C) alkoxy,

wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]A carbamoyl group,N- (1-6C) alkylsulfamoyl andN， Ndi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino and N- (1-6C) alkyl- (1-6C) alkylsulfonylamino;

(i)R¹selected from the group consisting of hydrogen, hydroxy, (1-6C) alkoxy, (3-7C) cycloalkyl-oxy and (3-7C) cycloalkyl- (1-6C) alkoxy,

wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluoro or chloro substituents on the group, or substituents selected from: hydroxy, amino, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl]An amino group;

(j)R¹selected from the group consisting of hydrogen, hydroxy, (1-6C) alkoxy, (3-7C) cycloalkyl-oxy and (3-7C) cycloalkyl- (1-6C) alkoxy,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an O atom inserted into the chain,

wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluoro or chloro substituents on the group, or substituents selected from hydroxy and (1-4C) alkoxy;

(k)R¹selected from the group consisting of hydrogen, (1-6C) alkoxy, cyclopropyl- (1-4C) alkoxy, cyclobutyl- (1-4C) alkoxy, cyclopentyl- (1-4C) alkoxy, cyclohexyl- (1-6C) alkoxy, tetrahydrofuranyl- (1-4C) alkoxy and tetrahydropyranyl- (1-4C) alkoxy,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an O atom inserted into the chain,

Wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃A group bearing one or more fluoro or chloro substituents, or substituents selected from hydroxy and (1-3C) alkoxy;

(l)R¹selected from hydrogen, (1-6C) alkoxy, cyclopropylmethoxy and 2-cyclopropylethoxy,

wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluoro or chloro substituents on the radical, or substituents selected from hydroxy, methoxy and ethoxy;

(m)R¹selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-difluoroethoxy, 2,2, 2-trifluoroethoxy, 2- (pyrrolidin-1-yl) ethoxy, 3- (pyrrolidin-1-yl) propoxy, 2-piperidinoethoxy, 3-piperidinopropyl, 2-piperazinoethoxy, 3-piperazinopropoxy, 2-morpholinoethoxy, and 3-morpholinopropoxy;

(n)R¹selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2, 2-difluoroethoxy and 2, 2, 2-trifluoroethoxy;

(o)R¹Selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-3C) alkoxy- (2-3C) alkoxy;

(p)R¹selected from hydrogen and (1-3C) alkoxy (in particular R)¹Is (1-3C) alkoxy such as methoxy, ethoxy and isopropoxy);

(q)R¹is hydrogen;

(r)R¹is methoxy;

(s) each R²May be the same or different and is selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X⁷-R⁸In which X is⁷Is a direct bond or is selected from O and N (R)⁹) Wherein R is⁹Is hydrogen or (1-6C) alkyl, R⁸Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl;

(t) each R²May be the same or different and is selected from the group consisting of halogen, hydroxy, amino, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]An amino group;

(u) each R²May be the same or different and is selected from fluorine and chlorineBromine, iodine, cyano, hydroxy, trifluoromethyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl and (1-4C) alkoxy;

(v) Each R²May be the same or different and is selected from fluoro, chloro, bromo, (1-4C) alkyl, (2-4C) alkenyl and (2-4C) alkynyl;

(w) each R²Which may be the same or different, is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, carbamoyl, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, 2-propynyl, N-methylcarbamoyl, N-ethylcarbamoyl and N, N-dimethylcarbamoyl;

(x) Each R²Which may be the same or different, is selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, and 2-propynyl;

(y) each R²Which may be the same or different, is selected from fluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and ethynyl;

(z) each R²May be the same or different and is selected from the group consisting of fluoro, chloro, bromo and ethynyl;

(aa) each R²Which may be the same or different, are selected from halogens (in particular fluorine, chlorine and bromine);

(bb) b is 1, 2 or 3, one R²Meta (3-) on the anilino group in formula 1;

(cc) b is 1, 2 or 3, each R²May be the same or different, as defined in any of(s) to (aa) above;

(dd) b is 1, 2 or 3, one R²In formula 1, the meta position (3-) on the anilino group is halogen, and when b is 2 or 3, the other R²The groups may be the same or different, as defined in any of(s) to (aa) above;

(ee) b is 1, 2 or 3, each R²May be the same or different and is halogen, wherein one R is²Meta (3-) on the anilino group;

(ff) b is 1 or 2, each R²Which may be identical or different, are halogen (in particular fluorine, chlorine or bromine), one of the radicals R being²In the meta position (3-) on the anilino group, the other R²Ortho (2-) or para (4-) on the anilino group;

(gg) b is 1 or 2, one R²In the meta position (3-) to the anilino group, chlorine or bromine (in particular chlorine), the other R when b is 2²The radicals are selected from fluorine, chlorine and bromine;

(hh) the anilino group at the 4-position on the quinazoline ring in formula I is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino, and 3-ethynylanilino;

(ii) the anilino group at the 4-position on the quinazoline ring in formula I is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino, 3-methylanilino and 3-ethynylanilino;

(jj) the anilino group at the 4-position on the quinazoline ring in formula I is 3-chloro-4-fluoroanilino;

(kk) the anilino group at the 4-position on the quinazoline ring in formula I is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino (more specifically the anilino group is 3-chloro-2-fluoroanilino);

(ll)Q¹selected from piperidin-3-yl and piperidin-4-yl;

(mm)Q¹is piperidin-4-yl;

(nn) each W, which may be the same or different, is selected from halogen, trifluoromethyl, hydroxy, oxo, (1-6C) alkyl, (1-6C) alkoxy and a group of formula-X⁸-R¹⁰In which X is⁸Is a direct bond or O, R¹⁰Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl or (1-6C) alkoxy- (1-6C) alkyl;

(oo) each W, which may be the same or different, is selected from halogen, hydroxy, oxo, (1-6C) alkyl and (1-6C) alkoxy;

(pp) each W, which may be the same or different, is selected from halogen (specifically fluorine), hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

(qq) a is 0, 1 or 2 and each W may be the same or different, as defined in any of (nn) to (pp);

(rr) a is 0 or 1 and W is as defined in any of (nn) to (pp);

(ss) a is 0;

(tt)Q¹is piperidin-4-yl, a is 0 or 1, W is as defined in any of (nn) to (pp);

(uu)X¹is CO;

(vv)X¹is SO₂；

(ww)X²Is a group of the formula:

-(CR¹²R¹³)_p-(Q⁵)_m-(CR¹⁴R¹⁵)_qwherein m is 0 or 1, p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3 or 4,

each R¹²、R¹³、R¹⁴And R¹⁵May be the same or different and is selected from the group consisting of hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and di- [ (1-6C) alkyl ]Amino group, Q⁵Selected from (3-7C) cycloalkylene and (3-7C) cycloalkenylene,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the radical,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries substituents selected from: hydroxy, cyano, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]An amino group;

(xx)X²selected from the group consisting of formula (Q)⁵)_m-(CR¹⁴R¹⁵)_qA group of formula (II) and a compound of formula (III) - (CR)¹²R¹³)_q-(Q⁵)_mA group of (A) wherein m is 0 or 1, Q is 1, 2, 3 or 4, Q⁵、R¹²、R¹³、R¹⁴And R¹⁵As defined above;

(yy)X²is of the formula-Q⁵A group of (E), for example (3-7C) cycloalkylene such as cyclopropylidene;

(zz)X²selected from the group consisting of cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, methylene- (3-6C) cycloalkylene, (3-6C) cycloalkylene-methylene-, ethylene- (3-6C) cycloalkylene and (3-6C) cycloalkylene-ethylene-,

wherein X²Any CH in (1)₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl ]An amino group;

(aaa)X²is of the formula- (CR)¹²R¹³)_q-a group of (a) or (b),

q is 1, 2, 3 or 4 (specifically 1 or 2),

each R¹²And R¹³Which may be the same or different, are selected from hydrogen and (1-6C) alkyl,

wherein X²Any CH in (1)₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries substituents selected from: a hydroxyl group,Amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]An amino group;

(bbb)X²is of the formula- (CR)¹²R¹³)_q-a group of (a) or (b),

q is 1, 2 or 3,

each R¹²And R¹³Which may be the same or different, are selected from hydrogen and (1-6C) alkyl,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-6C) alkoxy;

(ccc)X²is of the formula- (CR)¹²R¹³)_q-(CR^12aaR^13aa) -a group of (a) or (b),

q is 1, 2 or 3 (specifically 1 or 2, more specifically 1),

each R¹²、R¹³And R^13aaWhich may be the same or different, are selected from hydrogen and (1-6C) alkyl,

R^12aaselected from amino, (1-6C) alkylamino and di- [ (1-6C) alkyl ]An amino group, a carboxyl group,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries substituents selected from: hydroxy, amino, (1-6C) alkoxy, (1-6C) Alkylamino and di- [ (1-6C) alkyl]An amino group;

(ddd)X²is of the formula- (CR)¹²R¹³)_q-a group of (a) or (b),

q is 1, 2, 3 or 4 (specifically 1 or 2, more specifically 1),

each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen and (1-6C) alkyl, with the proviso that X²At least one R¹²Or R¹³The group is (1-6C) alkyl,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-6C) alkoxy;

(eee)X²selected from the group consisting of formula- (CR)¹²R¹³)-、-(CR¹²R¹³CH₂)-、-(CR¹²R¹³CH₂CH₂)-、-(CH₂CR¹²R¹³) -and- (CH)₂CH₂CR¹²R¹³) -a group of (a) or (b),

each R¹²And R¹³Which may be the same or different, are selected from hydrogen and (1-6C) alkyl,

wherein X²Any CH in (1)₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²Of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The radicals carrying a group selected from hydroxy, amino, (1-6C) alkoxy, (1-6C) alkaneAlkylamino and di- [ (1-6C) alkyl]A substituent of an amino group;

(fff)X²selected from the group consisting of formula- (CR)¹²R¹³)-、-(CR¹²R¹³CH₂)-、-(CR¹²R¹³CH₂CH₂)-、-(CH₂CR¹²R¹³) -and- (CH)₂CH₂CR¹²R¹³) -a group of (a) or (b),

each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen and (1-6C) alkyl, with the proviso that at least R¹²Or R¹³One is branched (1-6C) alkyl,

wherein X²Any CH in (1)₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃With radicals selected from hydroxy, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]A substituent of an amino group;

(ggg)X²selected from the group consisting of formula- (CR)¹²R¹³)-、-(CR¹²R¹³CH₂)-、-(CR¹²R¹³CH₂CH₂)-、-(CH₂CR¹²R¹³) -and- (CH)₂CH₂CR¹²R¹³) -a group of (a) or (b),

each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen and (1-6C) alkyl, with the proviso that X²In (A) at least R¹²Or R¹³One is a branched alkyl group, preferably selected from isopropyl, isobutyl, sec-butyl and tert-butyl,

wherein X²Any CH in (1)₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluorine radicals on the radical Or a chlorine substituent,

X²of the substituents, any CH having 2 carbon atoms attached thereto₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-3C) alkoxy;

(hhh)X²is selected from the formula-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³) -a group of (a) or (b),

wherein each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-4C) alkoxy- (1-4C) alkyl, provided that R¹²And R¹³Not all are hydrogen;

(iii)X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein each R^12aMay be the same or different and is selected from the group consisting of (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl,

wherein R is^12bSelected from hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di- [ (1-4C) alkyl]-amino, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl;

(jjj)X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein R is^12aSelected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl ]-amino- (1-4C) alkyl,

wherein R is^12bSelected from the group consisting of hydrogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl;

(kkk)X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein each R^12aWhich may be identical or different, are (1-4C) alkyl,

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-an amino group;

(lll)X²selected from the group consisting of formula- (CHR)^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein each R^12aWhich may be the same or different, is a (1-4C) alkyl group (specifically a (1-3C) alkyl group),

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino (in particular R)^12bSelected from (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino, more particularly di- [ (1-3C) alkyl]-an amino group);

(mmm)X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR¹²)-、-(CHR¹²CH₂) -and- (CH)₂CHR¹²) Group of (A) to (B)

Wherein R is¹²Selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl;

(nnn)X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12a) -a group of (a) or (b),

wherein each R^12aMay be the same or different and is a (1-4C) alkyl group;

(ooo)X²selected from the group consisting of formula- (CHR) ^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12a) - (particularly X)²Is- (CHR)^12a) -) of a group selected from the group consisting of,

wherein each R^12aMay be the same or different and is a (1-4C) alkyl group;

(ppp)X²is selected from the formula- (CH)₂)_q-wherein q is 1, 2 or 3, in particular q is 1 or 2, more in particular 1;

(qqq) Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a):

wherein X⁹Is a direct bond or is selected from O, N (R)¹⁶)、SO₂And SO₂N(R¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkeneA group, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein any heterocyclyl group in Z is a monocyclic fully saturated 4-, 5-, 6-or 7-membered heterocyclyl group containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulphur,

wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl ]Amino- (1-4C) alkyl;

(rrr) Z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy and of the formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond or is selected from O and N (R)¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein any heterocyclyl group in Z is a monocyclic non-aromatic fully or partially saturated 4-, 5-, 6-or 7-membered heterocyclyl group containing 1 heteroatom selected from oxygen and nitrogen and optionally further heteroatoms selected from oxygen, nitrogen and sulphur,

wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoylA base,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a) or (b),

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl ]Amino- (1-4C) alkyl;

(sss) Z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy and of the formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond or is selected from O and N (R)¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

provided that X is present at that time⁹Is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein any heterocyclyl group in Z is selected from the group consisting of tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl, which heterocyclyl group may be attached to the group to which it is attached, either on carbon or nitrogen,

wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃The gene carries one or more halogen or (1-6C) alkyl substituents, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X^10-R¹⁸The group of (a) or (b),

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl ]Amino- (1-4C) alkyl;

(ttt) Z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy and of the formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

provided that when m, p and q are all 0, Z is a heterocyclic group (preferably carbon and X)¹Are connected to each other),

wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl,

wherein any CH in the Z group₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents, or substituents selected from hydroxy and (1-6C) alkoxy,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ] amino and (2-6C) alkanoyl;

(uuu) Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, hydroxy- (2-6C)) Alkylamino, (1-4C) alkoxy- (2-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- [ hydroxy- (2-6C) alkyl group]- N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino, di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl and of formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Selected from O and N (R)¹⁶) Wherein R is¹⁶Is hydrogen or (1-4C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

wherein Q⁶Any heterocyclyl group in (a) is selected from tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, which heterocyclyl group may be attached to the group to which it is attached, either on carbon or on nitrogen,

Provided that when m, p and Q are all 0, Z is a heterocyclic group, preferably Q⁶One of the above-mentioned heterocyclic groups which may be indicated (the heterocyclic group is preferably on carbon with X)¹Are connected to each other),

wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxyYl, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl]Amino- (1-4C) alkyl;

(vvv) Z is selected from the group consisting of amino, (1-6C) alkylamino, hydroxy- (2-6C) alkylamino, (1-4C) alkoxy- (2-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- [ hydroxy- (2-6C) alkyl group]-N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino group,Di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl and homopiperazin-1-yl,

wherein any CH in the Z group₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluorine substituents on the group, or substituents selected from: hydroxy, cyano, amino, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl ]An amino group, a carboxyl group,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, cyano, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (2-4C) alkanoyl, (1-4C) alkylamino and di- [ (1-4C) alkyl ] amino,

with the proviso that when m, p and q are all 0, Z is one of the above-mentioned heterocyclic groups which Z may represent, for example pyrrolidin-1-yl or piperidino (preferably the sum of m + p + q is at least 1);

(www) Z is selected from the group consisting of hydroxy, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, 1, 4-dioxanyl, tetrahydropyranyl and of formula Q⁶-X⁹-a group of (a):

wherein X⁹Is O, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl, or heterocyclyl- (1-4C) alkyl, wherein any Q⁶The heterocyclyl radicals represented are preferably selected from tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, 1, 4-dioxanyl and tetrahydropyranyl,

with the proviso that when m, p and q are all 0, Z is selected from the group consisting of tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, 1, 4-dioxanyl, tetrahydropyranyl and oxepanyl,

Wherein any CH in the Z group₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more fluorine substituents on the group, or substituents selected from: hydroxy, cyano, amino, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]An amino group, a carboxyl group,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, cyano, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl ] amino;

(xxx) Z is selected from hydroxy, amino, (1-6C) alkylamino, hydroxy- (2-6C) alkylamino, (1-4C) alkoxy- (2-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- [ hydroxy- (2-6C) alkyl group]-N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino, di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy and (1-4C) alkoxy- (2-6C) alkoxy,

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

(yyy) Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl ] amino, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy and (1-4C) alkoxy- (2-6C) alkoxy, the sum of m + p + q being at least 1;

(zzz) Z is selected from hydroxy, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy), the sum of m + p + q being at least 1;

(aaaa) Z is selected from the group consisting of hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N- (2-hydroxyethyl) amino, N- (2-methoxyethyl) amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N- (2-hydroxyethyl) -N-methylamino, N- (2-hydroxyethyl) -N-ethylamino, N-di- (2-hydroxyethyl) amino, N- (2-methoxyethyl) -N-methylamino, N- (2-methoxyethyl) -N-ethylamino, pyrrolidin-1-yl, and mixtures thereof, Piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (2-4C) alkanoyl and (1-4C) alkoxy,

with the proviso that when m, p and q are all 0, Z is one of the above-mentioned heterocyclic groups which Z may represent, for example pyrrolidin-1-yl, tetrahydrofuranyl or piperidino (preferably the sum of m + p + q is at least 1);

(bbbb) Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl (specifically Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl and morpholino),

Wherein the heterocyclyl group in Z optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from fluoro, chloro, cyano, hydroxy, amino, carbamoyl, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino group,N- (1-4C) alkylcarbamoyl,N， NDi- [ (1-4C) alkyl]Carbamoyl, acetyl, propionyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyacetyl, aminoacetyl, methylaminoacetyl, ethylaminoacetyl, dimethylaminoacetyl and N-methyl-N-ethylaminoacetyl (preferably the sum m + p + q is at least 1);

(cccc) Z is selected from hydroxyl, (1-4C) alkoxy, tetrahydrofuranyl and tetrahydropyranyl

Wherein any tetrahydrofuranyl or tetrahydropyranyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl and (1-4C) alkoxy,

with the proviso that when m, p and q are all 0, Z is selected from tetrahydrofuranyl and tetrahydropyranyl (preferably the sum of m + p + q is at least 1);

(dddd) Z is hydroxy or (1-4C) alkoxy (specifically Z is hydroxy) and the sum of m + p + q is at least 1;

(eeee) Z is as defined in any of (qqq) to (dddd) above,

wherein X²Is selected from-CH₂-、-CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂)-、-(CH₂CR¹²R¹³) And (3-6C) cycloalkenylene (e.g.cyclopropylene such as cyclopropylidene),

wherein each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl, provided that R¹²And R¹³Not all of them are hydrogen,

wherein X¹Is CO;

(ffff) Z is as defined in any of (qqq) to (dddd) above;

X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) Group of (A), (B), (C), (²Is- (CHR)^12a)-)，

Wherein each R^12aWhich may be the same or different, are selected from (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl,

wherein R is^12bSelected from hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di- [ (1-4)C) Alkyl radical]-amino, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl; wherein X¹Is CO;

(gggg) Z is selected from hydroxy and (1-4C) alkoxy,

X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) Group of (A), (B), (C), (²Is- (CHR)^12a)-)，

Wherein each R^12aWhich may be identical or different, are (1-4C) alkyl,

wherein R is^12bSelected from hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl ]-an amino group,

wherein X¹Is CO;

(hhhh)Z-X²-X¹is hydroxy- (2-4C) alkanoyl, e.g. hydroxyacetyl, 2-hydroxypropionyl or 3-hydroxypropionyl, in particular Z-X²-X¹Is 2-hydroxypropionyl;

(iiii)Z-X²-X¹is (1-4C) alkoxy- (2-4C) alkanoyl, such as methoxyacetyl, 2-methoxypropionyl or 3-methoxypropionyl;

(jjjj)Z-X²-X¹selected from the group consisting of amino- (2-4C) alkanoyl, (1-4C) alkylamino- (2-4C) alkanoyl and di- [ (1-4C) alkyl]Amino- (2-4C) alkanoyl (e.g. Z-X)²-X¹Is di- [ (1-4C) alkyl]Amino-acetyl groups such as dimethylaminoacetyl);

(kkkk)Z-X²-is selected from tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinylPiperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, in which the heterocyclyl group is attached to the carbonyl group via a ring carbon atom,

wherein Z-X²The heterocyclyl group in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl;

(llll)Z-X²selected from tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl (e.g. Z-X) ²Selected from tetrahydrofuran-2-yl or tetrahydropyran-2-yl);

(mmmm)Z-X²-is selected from pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, in which formula I the heterocyclyl is bound to X through a ring carbon atom¹The connection is carried out in a connecting way,

wherein Z-X²The heterocyclyl group in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl;

(nnnn)Z-X²selected from the group consisting of pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, homopiperidin-1-yl and homopiperazin-1-yl,

wherein Z-X²The heterocyclyl group in (1) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl.

A particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or a pharmaceutically-acceptable ester thereof, wherein:

R¹selected from the group consisting of hydrogen, (1-6C) alkoxy, cyclopropyl- (1-4C) alkoxy, cyclobutyl- (1-4C) alkoxy, cyclopentyl- (1-4C) alkoxy, cyclohexyl- (1-6C) alkoxy, tetrahydrofuranyl- (1-4C) alkoxy and tetrahydropyranyl- (1-4C) alkoxy,

wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH ₂Or CH₃With one or more halogen substituents, or substituents selected from hydroxy and (1-4C) alkoxy;

b is 1, 2 or 3;

each R²Which may be the same or different, is selected from halogen (in particular fluorine, chlorine or bromine), cyano, hydroxy, trifluoromethyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl and (1-4C) alkoxy;

Q¹is piperidin-4-yl;

a is 0, 1 or 2;

each W, which may be the same or different, is selected from halogen (specifically fluorine), trifluoromethyl, hydroxy, oxo, (1-6C) alkyl, (1-6C) alkoxy and a group of formula-X⁸-R¹⁰The group of (a):

wherein X⁸Is a direct bond or O, R¹⁰Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl or (1-6C) alkoxy- (1-6C) alkyl;

X¹is CO;

z and X²Have any of the values defined above; with the following conditions:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R¹Is hydrogen or (1-3C) alkoxy, X¹When it is CO, then a is 0 and Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹A group of (a) wherein Q⁶-X⁹-as defined above.

In this embodiment, X²Specific values of (a) are groups selected from: (3-6C) cycloalkylene (e.g. cyclopropylidene), -CH ₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³)-，

Wherein each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl, provided that R¹²And R¹³Not all of them are hydrogen,

wherein X²In (3-6C) cycloalkylene group₂Radicals being optionally in each of said CH₂Or a group bearing one or more (1-4C) alkyl substituents, or substituents selected from hydroxy, (1-4C) alkoxy, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl.

In this embodiment, specific values of Z are groups selected from: hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy and of the formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond or is selected from O and N (R)¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein any heterocyclyl group in Z is selected from the group consisting of tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1, 4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl, which heterocyclyl group may be attached to the group to which it is attached either at carbon or nitrogen,

Wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂In addition to the radicals, optionallyEach of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl]Amino- (1-4C) alkyl.

Another specific value of Z in this embodiment is a group selected from: hydroxy, amino, (1-6C) alkylamino, hydroxy- (2-6C) alkylamino, (1-4C) alkoxy- (2-6C) alkylaminoDi- [ (1-6C) alkyl]Amino group,N- [ hydroxy- (2-6C) alkyl group]- N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino, di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl and 1, 4-dioxanyl,

Provided that when m, p and q are all 0, Z is one of the above heterocyclic groups,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl and (1-4C) alkoxy.

Another specific value of Z in this embodiment is a group selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, and (1-4C) alkoxy- (2-4C) alkoxy, more specifically Z is hydroxy or (1-4C) alkoxy.

In this embodiment each R²Specific values of (A) may be the same or different and are selected from the group consisting of fluorine, chlorine or bromine and (2-4C) alkynyl;

the specific 4-anilino group in formula I in this embodiment is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino, and 3-ethynylanilino. More specifically still, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt, or a pharmaceutically-acceptable ester thereof, wherein:

R¹is selected from (1)-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a):

Wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents optionally bearing 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino and (2-4C) alkanoyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 oxo substituent;

b is 1, 2 or 3;

each R²May be the same or different and is selected from the group consisting of fluoro, chloro, bromo and (2-4C) alkynyl;

Q¹is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different, is selected from halogen (specifically fluorine), hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹is CO;

X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein each R^12aMay be the same or different and is selected from the group consisting of (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino-, (1-4C) alkyl (in particular R)^12aIs (1-4C) alkyl),

Wherein R is^12bSelected from hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino, di- [ (1-4C) alkyl]-amino, hydroxy- (1-4C) alkyl, (1-3C) alkoxy- (1-4C) alkyl, amino- (1-4C) alkyl, (1-4C) alkylamino- (1-4C) alkyl and di- [ (1-4C) alkyl]-amino- (1-4C) alkyl (specifically R)^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-an amino group);

z is selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy, or

Z-X²Selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X²By ring carbon atoms with X¹The connection is carried out in a connecting way,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl; with the following conditions:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R¹In the case of (1-3C) alkoxy, a is 0.

Specific values of Z in this embodiment are those selected from the group consisting of hydroxy and (1-4C) alkoxy (e.g., Z is hydroxy, methoxy or ethoxy).

In this embodiment, the specific 4-anilino group in formula I is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino, and 3-ethynylanilino. Still more specifically, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt, or a pharmaceutically-acceptable ester thereof, wherein:

R¹selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a) or (b),

wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents optionally bearing 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino and (2-4C) alkanoyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 oxo substituent (specifically R)¹Selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-3C) alkoxy- (2-4C) alkoxy, more particularly R¹Is (1-4C) alkoxy;

b is 1, 2 or 3 (especially b is 1, more especially b is 2);

each R²May be the same or different and is selected from the group consisting of fluoro, chloro, bromo and (2-4C) alkynyl;

Q¹is piperidin-4-yl;

a is 0 or 1 (preferably 0);

Each W, which may be the same or different, is selected from halogen (specifically fluorine), hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹is CO;

X²is of the formula- (CR)¹²R¹³)_q-(CR^12aaR^13aa) -a group of (a) or (b),

q is 1, 2 or 3 (specifically 1 or 2, more specifically 1),

each R¹²、R¹³And R^13aaWhich may be the same or different, are selected from hydrogen and (1-6C) alkyl,

R^12aaselected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]An amino group;

z is selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy, or

Z-X²Selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X²By ring carbon atoms with X¹The connection is carried out in a connecting way,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl; with the following conditions:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R¹In the case of (1-3C) alkoxy, a is 0.

Specific values of Z in this embodiment are those selected from the group consisting of hydroxy and (1-4C) alkoxy (e.g., Z is hydroxy, methoxy or ethoxy).

In this embodiment, the specific 4-anilino group in formula I is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino, and 3-ethynylanilino. More specifically, the 4-anilino group in formula I in this embodiment is selected from the group consisting of 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, and 3-bromoanilino. Still more specifically, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Preferably, the anilino group is 3-chloro-2-fluoroanilino.

Another particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt, or a pharmaceutically-acceptable ester thereof, wherein:

R¹selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a):

wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents of the heterocyclyl group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl]Amino (specifically R)¹Selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-3C) alkoxy- (2-4C) alkoxy, more particularly R¹Is (1-4C) alkoxy, e.g. methoxy, ethoxy, isopropoxy, and even more particularly R¹Is methoxy);

the 4-anilino group in formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino;

b is 1 or 2;

each R²May be the same or different and is selected from the group consisting of fluoro, chloro, bromo and ethynyl;

Q¹Is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different, is selected from halogen (specifically fluorine), hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹is CO;

X²selected from the group consisting of formula- (CHR)^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein each R^12aWhich may be the same or different, are (1-4C) alkyl (particularly (1-3C) alkane)A radical),

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino (in particular R)^12bSelected from (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino, more particularly di- [ (1-3C) alkyl]-an amino group);

z is selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy, or

Z-X²Selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl through a ring carbon atom with X¹The connection is carried out in a connecting way,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl.

Specific values of Z in this embodiment are those selected from the group consisting of hydroxy and (1-4C) alkoxy (e.g., Z is hydroxy, methoxy or ethoxy).

In this embodiment, the specific 4-anilino group in formula I is selected from the group consisting of 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino, and 3-ethynylanilino. Still more specifically, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt, or a pharmaceutically-acceptable ester thereof, wherein:

R¹selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a):

wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Upper substitutionAny heterocyclyl group in (a) optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl]Amino (specifically R)¹Selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-3C) alkoxy- (2-4C) alkoxy, more particularly R¹Is (1-4C) alkoxy, e.g. methoxy, ethoxy, isopropoxy, and even more particularly R¹Is methoxy);

the 4-anilino group in formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino;

z is hydroxy or (1-4C) alkoxy (specifically Z is hydroxy, methoxy or ethoxy, more specifically Z is hydroxy or methoxy, especially Z is hydroxy);

Q¹Is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different, is selected from hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹is CO;

X²selected from the group consisting of formula- (CHR)^12a) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein R is^12aIs (1-4C) alkyl (specifically (1-3C) alkyl, more specifically methyl),

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino (in particular R)^12bSelected from (1-3C) alkylamino and di- [ (1-3C) alkyl]-amino, more particularly di- [ (1-3C) alkyl]-amino, even more particularly R^12bIs methylamino, especially dimethylamino).

The specific 4-anilino group in formula I in this embodiment is selected from the group consisting of 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino, and 3-ethynylanilino. Still more specifically, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino.

Another particular embodiment of the invention is a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt, or a pharmaceutically-acceptable ester thereof, wherein:

R¹is (1-4C) alkoxy (e.g., methoxy, ethoxy, isopropoxy, specifically methoxy);

the 4-anilino group in formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino;

Q¹Is piperidin-4-yl;

a is 0 or 1 (preferably 0);

each W, which may be the same or different, is selected from hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹is CO;

Z-X²selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl (particularly Z-X)²Is tetrahydrofuranyl or pyrrolidinyl), wherein Z-X²By ring carbon atoms with X¹The connection is carried out in a connecting way,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, methyl, methoxy and acetyl.

The specific 4-anilino group in formula I in this embodiment is selected from the group consisting of 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino, and 3-ethynylanilino, and more specifically the anilino group is selected from the group consisting of 3-bromo-2-fluoroanilino and 3-chloro-2-fluoroanilino.

Another embodiment of the compound of formula I is a quinazoline derivative of the formula Ia:

wherein:

R¹selected from the group consisting of hydrogen, (1-6C) alkoxy, cyclopropyl- (1-4C) alkoxy, cyclobutyl- (1-4C) alkoxy, cyclopentyl- (1-4C) alkoxy, cyclohexyl- (1-6C) alkoxy, tetrahydrofuranyl- (1-4C) alkoxy and tetrahydropyranyl- (1-4C) alkoxy,

Wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen substituents, or substituents selected from hydroxy and (1-4C) alkoxy;

b₁is 0, 1 or 2;

each R²Which may be the same or different, is selected from the group consisting of halogen (in particular fluorine, chlorine or bromine), cyano, hydroxy, trifluoromethyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl and (1-4C) alkoxy (in particular R)²Selected from fluoro, chloro, bromo or ethynyl, more particularly R²Selected from fluorine, chlorine and bromine);

R^2ais halogen (in particular fluorine, chlorine or bromine, more particularly fluorine or chlorine, even more particularly chlorine or bromine, especially R^2aIs chlorine);

a is 0, 1 or 2;

each W, which may be the same or different, is selected from halogen (specifically fluorine), hydroxy, (1-4C) alkyl and (1-4C) alkoxy;

X²is of the formula- (CR)¹²R¹³)_p-(Q⁵)_m-(CR¹⁴R¹⁵)_q-a group of (a) or (b),

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3 or 4,

each R¹²、R¹³、R¹⁴And R¹⁵May be the same or different and is selected from the group consisting of hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and di- [ (1-6C) alkyl]Amino group, Q⁵Selected from (3-7C) cycloalkylene and (3-7C) cycloalkenylene,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl ]An amino group;

z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a):

wherein X⁹Is a direct bond or is selected from O, N (R)¹⁶)、SO₂And SO₂N(R¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl or heterocyclyl- (1-4C) alkyl,

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein adjacent carbon atoms in any (2-6C) alkylene chain in the Z substituent are optionally separated by an intervening chain selected from: o, S, SO₂、N(R¹⁷) CO, -C ═ C-and-C.ident.C-, where R is¹⁷Is hydrogen or (1-6C) alkyl,

wherein any CH in any Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogens or (1-6C) in the radical) An alkyl substituent, or a substituent selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more (e.g. 1, 2 or 3) substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl ]Amino- (1-4C) alkyl; with the following conditions:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R¹In the case of (1-3C) alkoxy, a is 0.

Another embodiment of the present invention is the quinazoles of formula Ia, as defined aboveQuinoline derivatives, wherein X²Is selected from (3-6C) cycloalkylene (e.g. cyclopropylidene), -CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³) -a group of (a) or (b),

wherein each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl, provided that R¹²And R¹³Not all of them are hydrogen,

wherein X²In (3-6C) cycloalkylene group₂Radicals being optionally in each of said CH₂Or a group bearing one or more (1-4C) alkyl substituents, or substituents selected from hydroxy, (1-4C) alkoxy, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl.

Another embodiment of the invention are quinazoline derivatives of the formula 1a, as defined above, wherein X²Is a group selected from: cyclopropylidene, -CH₂-、-CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³)-，

Wherein each R¹²And R¹³Which may be the same or different, are selected from hydrogen and (1-4C) alkyl.

Another embodiment of the invention are quinazoline derivatives of the formula 1a, as defined above, wherein Z is selected from hydroxy, amino, (1-6C) alkylamino, hydroxy- (2-6C) alkylamino, (1-4C) alkoxy- (2-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- [ hydroxy- (2-6C) alkyl group]-N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino, di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino group,(1-6C) alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl and 1, 4-dioxanyl; or

Group Z-X²Selected from the group consisting of tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl, the Z-X²The heterocyclic group represented is attached to the carbonyl group in formula Ia through a ring carbon atom,

wherein Z-X²Any of the heterocyclyl groups in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl.

More specifically, in formula 1a, Z is selected from the group consisting of hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N- (2-hydroxyethyl) amino, N- (2-methoxyethyl) amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N- (2-hydroxyethyl) -N-methylamino, N- (2-hydroxyethyl) -N-ethylamino, N-di- (2-hydroxyethyl) amino, N- (2-methoxyethyl) -N-methylamino, N- (2-methoxyethyl) -N-ethylamino, pyrrolidin-1-yl, p-hydroxy-ethyl, N-methyl-amino, N- (2-methoxyethyl) -N-ethylamino, p-hydroxy-ethyl-amino, p-methyl-amino, p-, Piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or

Group Z-X²Selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl and (1-4C) alkoxy. More specifically, Z is selected from the group consisting of hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, and (1-4C) alkoxy- (2-4C) alkoxy, and even more specifically Z is selected from the group consisting of hydroxy and (1-4C) alkoxy (e.g., Z is hydroxy or methoxy). Preferably, Z is hydroxy.

Another embodiment of the invention is a quinazoline derivative of the formula 1a, as defined above, wherein:

R^2aIs bromine or chlorine (specifically chlorine);

b is 0 or 1, R²In the ortho (2-), is halogen (in particular R)²Is fluorine); or

b is 0 or 1, R²In para (4-), is halogen (in particular R)²Is fluorine), wherein R¹、W、a、X²And Z has any of the meanings defined above for the quinazoline derivative of the formula 1 a.

Another specific embodiment of the invention are quinazoline derivatives of the formula 1a as defined above wherein the anilino group at the 4-position on the quinazoline ring is selected from the group consisting of 3-bromo-2-fluoroanilino, 3-bromoanilino, 3-chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. Specifically, the anilino group is selected from 3-chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. More specifically, the anilino group is 3-chloro-4-fluoroanilino. Preferably, the anilino group is 3-chloro-2-fluoroanilino. Wherein R in this embodiment¹、W、a、X²And Z has any of the meanings defined above for the quinazoline derivative of the formula 1 a.

Another embodiment of the compound of formula I is a quinazoline derivative of the formula Ib:

wherein:

R¹selected from the group consisting of hydrogen, (1-6C) alkoxy, cyclopropyl- (1-4C) alkoxy, cyclobutyl- (1-4C) alkoxy, cyclopentyl- (1-4C) alkoxy, cyclohexyl- (1-6C) alkoxy, tetrahydrofuranyl- (1-4C) alkoxy and tetrahydropyranyl- (1-4C) alkoxy,

Wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen substituents, or substituents selected from hydroxy and (1-4C) alkoxy;

R^2bis bromine or chlorine (specifically chlorine);

a is 0, 1 or 2 (specifically a is 0);

each W, which may be the same or different, is selected from hydroxy, halo (specifically fluoro), (1-4C) alkyl and (1-4C) alkoxy;

X²is selected from the formula-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³) Group of (A) to (B)

Wherein each R¹²And R¹³Which may be the same or different, are selected from hydrogen and (1-4C) alkyl (in particular X)²Is CH₂More specifically X²Is (CHR)^12a) -, wherein R^12aIs (1-4C) alkyl);

z is selected from hydroxy, amino, (1-6C) alkylamino, hydroxy- (2-6C) alkylamino, (1-4C) alkoxy- (2-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- [ hydroxy- (2-6C) alkyl group]- N- (1-6C) alkylamino,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- (1-6C) alkylamino, di- [ hydroxy- (2-6C) alkyl]-amino, di- [ (1-4C) alkoxy- (2-6C) alkyl]Amino group,N- [ (1-4C) alkoxy- (2-6C) alkyl]- N- [ hydroxy- (2-6C) alkyl group]-amino, (1-6C) alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl and 1, 4-dioxanyl; or

Group Z-X²Selected from the group consisting of tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl, the Z-X²The heterocyclic group represented is attached to the carbonyl group in formula Ib through a ring carbon atom,

wherein Z-X²Any of the heterocyclyl groups in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl.

In embodiments of formula Ib, Z is selected from the group consisting of hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N- (2-hydroxyethyl) amino, N- (2-methoxyethyl) amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N- (2-hydroxyethyl) -N-methylamino, N- (2-hydroxyethyl) -N-ethylamino, N-di- (2-hydroxyethyl) amino, N- (2-methoxyethyl) -N-methylamino, N- (2-methoxyethyl) -N-ethylamino, pyrrolidin-1-yl, and mixtures thereof, Piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or

Group Z-X²Selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl,

wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl and (1-4C) alkoxy.

In another embodiment of formula Ib, R¹Selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2, 2-difluoroethoxy and 2, 2, 2-trifluoroethoxy (specifically R)¹Selected from hydrogen and (1-3C) alkoxy, more particularly R¹Is (1-3C) alkoxy, e.g., methoxy).

In another embodiment of formula Ib, R¹Selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-3C) alkoxy- (2-4C) alkoxy; a is 0; z is selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy, more particularly Z is selected from hydroxy and (1-4C) alkoxy, particularly Z is hydroxy or methoxy (especially hydroxy); x²Have any of the meanings defined above for quinazolines of formula 1 b.

Another embodiment of the compound of formula I is a quinazoline derivative of the formula Ic:

Wherein:

R^1aselected from (1-3C) alkoxy, hydroxy- (2-3C) alkoxy and (1-3C) alkoxy- (2-3C) alkoxy (specifically R)^1aIs methoxy);

X^2aselected from the group consisting of formula- (CHR)^12a) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein R is^12aIs (1-4C) alkyl (specifically (1-3C) alkyl, more specifically methyl),

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-amino (in particular R)^12bSelected from (1-3C) alkylamino and di- [ (1-3C) alkyl]-amino, more particularly di- [ (1-3C) alkyl]-amino, even more particularly R^12bIs methylamino, especially dimethylamino);

Z¹selected from hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy and (1-4C) alkoxy- (2-4C) alkoxy (in particular Z)¹Is hydroxy or (1-4C) alkoxy, e.g. hydroxy or methoxy), or a group Z¹X^2aSelected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl, wherein Z is¹-X^2aAttached to the carbonyl group through a ring carbon atom,

wherein Z¹Any of the heterocyclyl groups in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C) alkyl, (1-4C) alkoxy and (2-4C) alkanoyl.

In the present embodiment, Z is preferred¹Selected from hydroxy and (1-4C) alkoxy (in particular Z) ¹Is hydroxy or methoxy, even more particularly Z¹Is a hydroxyl group).

In the present embodiment, X is preferred^2aIs of the formula- (CHR)^12a) -a group of (a) or (b),

wherein R is^12aIs (1-4C) alkyl (specifically (1-3C) alkyl, more specifically methyl).

Another embodiment of the compound of formula I is a quinazoline derivative of the formula Id:

wherein:

R^1bis (1-4C) alkoxy,

wherein R is^1bAny CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen substituents on the radical, or R¹In which any CH not bound to an oxygen atom₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-3C) alkoxy;

X^2bis selected from the formula-CH₂-、-CH₂CH₂-、-(CHR¹²)-、-(CHR¹²CH₂) -and- (CH)₂CHR¹²) -a group of (a) or (b),

wherein R is¹²Selected from (1-3C) alkyl, hydroxy- (1-3C) alkyl and (1-3C) alkoxy- (1-3C) alkyl;

Z²selected from the group consisting of hydroxy, (1-3C) alkoxy, hydroxy- (2-3C) alkoxy, (1-3C) alkoxy- (2-3C) alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl and 1, 4-dioxanyl;

wherein Z²-X^2bAny of the heterocyclyl groups in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C) alkyl, (1-3C) alkoxy and (2-3C) alkanoyl.

In embodiments of formula Id, R^1bSelected from the group consisting of methoxy, ethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2, 2-difluoroethoxy and 2, 2, 2-trifluoroethoxy (specifically R)^1bIs (1-3C) alkoxy, such as methoxy).

In another embodiment of formula Id, X^2bIs selected from the formula-CH₂-、-CH₂CH₂-and- (CHR)¹²) A group of (a) wherein R¹²Selected from (1-3C) alkyl, hydroxy- (1-3C) alkyl and (1-3C) alkoxy- (1-3C) alkyl (e.g. R)¹²Is methyl).

In another embodiment of formula Id, X^2bIs selected from the formula-CH₂-and- (CHR)¹²) A group of (a) wherein R¹²Is (1-3C) alkyl (e.g., methyl). For example X^2bIs selected from-CH₂-and-CH (CH)₃) -, in particular X^2bis-CH (CH)₃)-。

In another embodiment of formula Id, Z²Selected from hydroxy and (1-3C) alkoxy (especially hydroxy).

In another embodiment of formula Id, the group Z²-X^2b-is selected from hydroxymethyl, methoxymethyl, (S) -1-hydroxyethyl, (R) -1-hydroxyethyl, (S) -1-methoxyethyl, (R) -1-methoxyethyl. In particular the group Z²-X^2b-is 1-hydroxyethyl, more particularly (S) -1-hydroxyethyl or (R) -1-hydroxyethyl.

In another embodiment of formula Id, R^1bIs (1-3C) alkoxy, such as methoxy; group Z ²-X^2b-is selected from hydroxymethyl, methoxymethyl, (S) -1-hydroxyethyl, (R) -1-hydroxyethyl, (S) -1-methoxyethyl, (R) -1-methoxyethyl. Specifically, Z in the present embodiment²-X^2bIs 1-hydroxyethyl, more particularly (S) -1-hydroxyethyl or (R) -1-hydroxyethyl.

Specific compounds of the invention are, for example, quinazoline derivatives of the formula I selected from:

1) n- (3-chloro-2-fluorophenyl) -7- ({1- [ (dimethylamino) acetyl ] piperidin-4-yl } oxy) -6-methoxyquinazolin-4-amine;

2) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2-methoxyethoxy) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

3) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (methoxyacetyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

4)2- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-oxoethanol;

5) n- (3-chloro-2-fluorophenyl) -7- { [1- (ethoxyacetyl) piperidin-4-yl ] oxy } -6-methoxyquinazolin-4-amine;

6) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (3-methoxypropionyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

7)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-oxopropan-1-ol;

8) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

9) (2S, 3S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-methyl-1-oxopentan-2-ol;

10)4- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-methyl-4-oxobutan-2-ol;

11) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (tetrahydrofuran-2-ylcarbonyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

12)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2, 2-dimethyl-3-oxopropan-1-ol;

13) (3R, 5S) -1-acetyl-5- { [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] carbonyl } pyrrolidin-3-ol;

14) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (4-methylpiperazin-1-yl) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine; or a pharmaceutically acceptable salt or ester thereof.

Further specific compounds of the invention are, for example, quinazoline derivatives of the formula I selected from:

1) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (methoxyacetyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

2)2- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-oxoethanol;

3) n- (3-chloro-2-fluorophenyl) -7- { [1- (ethoxyacetyl) piperidin-4-yl ] oxy } -6-methoxyquinazolin-4-amine;

4) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

5)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2, 2-dimethyl-3-oxopropan-1-ol;

6) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-ol;

7) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (1-methyl-L-prolyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

8) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -tetrahydrofuran-2-ylcarbonyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

9) (2R) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

10) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

11) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

12) (2R) -3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2- (dimethylamino) -3-oxopropan-1-ol;

13) (2S) -1- [4- ({4- [ (3-chloro-4-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

14) (2S) -1- [4- ({4- [ 3-bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

15) (2S) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

16) (2R) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

17) (2R) -1- [4- ({4- [ 3-bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol; or a pharmaceutically acceptable salt or ester thereof.

In a particular embodiment, the invention provides a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as described herein.

Quinazoline derivatives of formula I, or pharmaceutically-acceptable salts or pharmaceutically-acceptable esters thereof, may be prepared according to any of the available methods known for the preparation of chemically-related compounds. Suitable processes include, for example, those described in WO 94/27965, WO 95/03283, WO 96/33977, WO96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO 01/66099, US 5,252,586, EP 520722, EP 566226, EP 602851 and EP 635507. When used in the preparation of quinazoline derivatives of the formula I, which constitute a further aspect of the invention, are illustrated by the following representative process variants in which R, unless otherwise indicated, is ¹、R²、X¹、X²、Q¹W, a, b and Z have any of the meanings defined above. The necessary starting materials can be obtained using standard methods of organic chemistry. The preparation of this starting material is described in connection with the following representative process variations and accompanying examples. Alternatively, the desired starting materials may be obtained by processes analogous to those described, which are within the ordinary skill in the art of organic chemistry.

Method (a):

for X in¹Preparation of a compound of formula I that is CO, conveniently reacting a quinazoline of formula II:

wherein R is in addition to protecting any functional groups if desired¹、R²W, a, b and Q¹Have any of the meanings defined above; coupling with an acid of formula III:

Z-X²-COOH

III

wherein Z and X are, in addition to any functional groups which may be protected if desired²Have any of the meanings defined above;

or

Process (b) conveniently reacting a quinazoline of the formula II, or a salt thereof (as defined in process (a) above), with a compound of the formula IV:

Z-X²-X¹-L¹

IV

wherein L is in addition to protecting any functional groups if desired¹As a replaceable group, Z, X¹And X²Have any of the meanings defined above;

or

The process (c) is a process in which Z is bonded to X via nitrogen²Linking a quinazoline derivative of the formula I, conveniently in the presence of a suitable base, with a compound of the formula V:

Wherein L is in addition to protecting any functional groups if desired²Being a replaceable group, R¹、R²、W、X¹、X²A, b and Q¹Have any of the meanings defined above; with a compound of formula ZH, wherein Z is as defined above except for protecting any functional groups if desired; or method (d)

For the preparation of quinazoline derivatives bearing mono-or di- (1-6C) alkylamino groups, the corresponding quinazoline derivatives of the formula I containing an N-H group are reductively aminated using formaldehyde or (2-6C) alkanaldehyde (e.g. acetaldehyde or propionaldehyde); or

Method (e)

To prepare wherein R¹A quinazoline derivative of the formula I wherein R is a hydroxy group, cleaving¹Quinazoline derivatives of the formula I which are (1-6C) alkoxy; or

Method (f)

To prepare wherein R¹A quinazoline derivative of the formula I linked to the quinazoline ring via an oxygen atom by reacting a compound of the formula VI:

wherein R is in addition to protecting any functional groups if desired²、W、X¹、X²Z, a, b and Q¹Have any of the meanings defined above; and formula R^1’Coupling of compounds of OH, where the radical R is in addition to any functional groups protected if desired^1’O is as above for R¹One of the groups defined as being linked to oxygen (e.g. R)^1’Is (1-6C) alkoxy or Q²-O-)；

Thereafter, if desired (in any order):

(i) converting a quinazoline derivative of the formula I to another quinazoline derivative of the formula I;

(ii) Removing any protecting groups present by conventional means;

(iii) forming a pharmaceutically acceptable salt or ester.

The specific conditions of the above reaction are as follows:

conditions of Process (a)

The coupling reaction is conveniently carried out in the presence of a suitable coupling agent, for example a carbodiimide or a suitable peptide coupling agent, for example an uronium coupling agent, for example O- (7-azabenzotriazol-1-yl) -N, N '-tetramethyluronium Hexafluorophosphate (HATU) or O- (1H-benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate (TBTU); or a carbodiimide such as dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine.

The coupling reaction is conveniently carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases, such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylamine, triethylamine,N-methylmorpholine or diazabicyclo [5.4.0]Undec-7-ene, or, for example, an alkali metal or alkaline earth metal carbonate, such as sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate.

The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1, 4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N， N-dimethylformamide,N， N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, 0 to 120 ℃, conveniently at or near room temperature.

The term "reactive derivative" of an acid of formula III refers to a carboxylic acid derivative that reacts with a quinazoline of formula II to produce the corresponding amide. Suitable reactive derivatives of carboxylic acids of formula III are, for example, acid halides, such as acid chlorides formed by the reaction of an acid with an inorganic acid chloride (e.g., thionyl chloride); mixed anhydrides, such as the anhydride formed by the reaction of an acid with a chloroformate, such as isobutyl chloroformate; active esters, e.g. by reaction of acids with phenols (e.g. pentafluorophenol orN-hydroxybenzotriazole) reaction; or acyl azides, such as the azide formed by the reaction of an acid with an azide (e.g., diphenylphosphoryl azide); acyl nitriles, for example, formed by the reaction of an acid with a nitrile such as diethyl phosphoryl nitrile. The reaction of such reactive derivatives of carboxylic acids with amines, for example compounds of formula II, is well known in the art and may be carried out, for example, in the presence of a base, for example a base as described above, in a suitable solvent, for example a solvent as described above. The reaction can be conveniently carried outAt the temperatures mentioned above.

Preparation of the starting Material for Process (a)

The quinazolines of formula II can be obtained by conventional methods, for example as described in scheme 1:

reaction scheme 1

Wherein R is in addition to protecting any functional groups if desired¹、R²、Q¹W, a and b are as defined above, followed by removal of any protecting groups present by conventional means, Pg being a suitable hydroxy protecting group, Pg¹Is a suitable amino protecting group, L³Are alternative groups.

Conditions in reaction scheme 1

Step (i): suitable hydroxy protecting groups represented by Pg are well known in the art and include those described herein below, for example, lower alkanoyl groups such as acetyl or benzyl.

Suitable substitutable groups L³Is, for example, halogen (in particular chlorine), alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkylsulfonyloxy or arylsulfonyloxy, such as chlorine, bromine, methoxy, phenoxy, pentafluorophenoxy, methylthio, methylsulfonyl, methylsulfonyloxy or toluene-4-sulfonyloxy. Specific replaceable groups L³Is chlorine.

The reaction is conveniently carried out in the presence of an acid. Suitable acids include, for example, hydrogen chloride gas (conveniently dissolved in a suitable solvent such as diethyl ether or dioxane) or hydrochloric acid.

Or, wherein L³Quinazoline derivatives of formula IIa which are halogen (e.g. chlorine) may be reacted with aniline in the absence of acid or base. In this reaction, a halogen leaving group L³Replacement of (A) results in the in situ formation of acid HL³The reaction is autocatalytic.

Alternatively, the reaction of a quinazoline of the formula IIa with an aniline may be carried out in the presence of a suitable base. Suitable bases are, for example, organic amine bases such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylamine, triethylamine,N-methylmorpholine or diazabicyclo [5.4.0]Undec-7-ene, or an alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate, or an alkali metal hydride such as sodium hydride, an alkali metal fluoride such as cesium fluoride, or a disilylaminated alkali metal such as sodium hexamethyldisilylamide.

The above reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1, 4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as tolueneN， N-dimethylformamide,N， N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide or acetonitrile. The above reaction is conveniently carried out at a temperature in the range, for example, from 0 to 250 c, conveniently at from 40 to 80 c, or preferably at or near the reflux temperature of the solvent (when used).

Aniline and compounds of formula IIa are commercially available or can be prepared using conventional methods.

Step (ii):

deprotection is carried out using known methods. For example, when Pg is a benzyl group, it may be removed by treating the compound of formula lib with a suitable acid, such as trifluoroacetic acid. Alternatively, the benzyl protecting group may be removed by metal catalysed hydrogenation, for example by hydrogenation in the presence of a palladium on carbon catalyst. Similarly, when Pg is a lower alkanoyl group such as acetyl, it can be removed by hydrolysis under basic conditions, for example using ammonia, conveniently as a solution of ammonia in methanol.

Step (iiia):

suitable amino protecting groups Pg₂Are well known, for example the tert-Butoxycarbonyl (BOC) group.

L⁴Being suitable alternative groups, e.g. L²The above-mentioned group in (1), for example, a halogen (specifically, chlorine or bromine) or an alkylsulfonyloxy group (specifically, a methanesulfonyloxy group) or an arylsulfonyloxy group (specifically, a toluene-4-sulfonyloxy group or a 4-nitrophenylsulfonyloxy group).

The reaction of the compound of formula IIc with the compound of formula IId is conveniently carried out in the presence of a suitable base. Suitable bases include the bases described above in step (i), for example cesium fluoride or potassium carbonate. The reaction is conveniently carried out in the presence of a suitable inert solvent, e.g. a dipolar aprotic solvent such asN， N-dimethylformamide,N， N-dimethylacetamide,N-methylpyrrolidin-2-one, dimethylsulfoxide or acetonitrile. The above reaction is conveniently carried out at a temperature in the range, for example, from 0 to 250 c, conveniently at from 40 to 80 c, or preferably at or near the reflux temperature of the solvent (when used).

Step (iiib):

an alternative to step (iiia) is to couple the compound of formula IIc with an alcohol of formula IIe using a Mitsunobu coupling reaction. Suitable Mitsunobu conditions are well known and include, for example, reaction in the presence of a suitable tertiary phosphine and a dialkyl azodicarboxylate in an organic solvent such as THF or a suitable dichloromethane at a temperature in the range 0 ℃ to 100 ℃, for example 0 ℃ to 60 ℃, but suitably at or near room temperature. Suitable tertiary phosphines include, for example, tri-n-butyl phosphine, or especially triphenylphosphine. Suitable dialkyl azodicarboxylates include, for example, diethyl azodicarboxylate (DEAD) or suitable di-tert-butyl azodicarboxylate (DTAD). Details of the Mitsunobu reaction are contained in tet.letters, 31, 699, (1990); the Mitsunobu Reaction, D.L. Hughes, Organic Reactions, 1992, Vol.42, 335. quadrature. 656 and Progress in The Mitsunobu Reaction, D.L. Hughes, Organic Preparations and Progress International, 1996, Vol.28, 127. quadrature. 164.

The compounds of formula IId and IIe are commercially available or can be prepared using conventional methods.

Step (iv):

removal of the amino protecting group Pg Using known methods₁. For example when Pg₁In the case of the BOC group, the reaction is carried out by treatment with a suitable acid, such as trifluoroacetic acid or hydrochloric acid.

In an alternative to the pathway shown in scheme 1, the aniline in step (i) can be reacted with an unprotected variant of the compound of formula IIa (i.e., Pg is hydrogen) to directly produce the compound of formula IIc.

The compound of formula II can also be prepared according to reaction scheme 2:

reaction scheme 2

Wherein R is in addition to protecting any functional groups if desired¹、R²、Q¹、W、a、b、L³And Pg¹Any protecting groups present are subsequently removed by conventional means, as defined above.

Conditions in reaction scheme 2

Step (i):

coupling was performed under Mitsunobu conditions as described in step (iiib) of scheme 1.

Step (ii):

the reaction is conveniently carried out in the presence of an acid. Suitable acids include, for example, hydrogen chloride gas (conveniently dissolved in a suitable solvent such as diethyl ether or dioxane) or hydrochloric acid. The reaction is conveniently carried out in a suitable inert solvent, for example as described in step (i) of scheme 1. Conveniently, as a result of acidic conditions in the aniline coupling reactionPosition-removing protecting group Pg ¹E.g. when Pg¹When it is tert-butoxycarbonyl. Alternatively, the protecting group may be removed after the reaction using conventional methods.

Quinazolines of formula IIg are commercially available or can be prepared using conventional methods.

Wherein R is¹Quinazoline derivatives of formula II that are heterocyclyl- (2-6C) alkoxy, the nitrogen-linked (2-6C) alkoxy group of a heterocyclyl can be prepared according to reaction scheme 3:

reaction scheme 3

Wherein R is in addition to protecting any functional groups if desired¹、R²、Q¹、W、X²、L¹、L²A, b and Pg¹As defined above, X^3’Is (2-6C) -alkylene, Q²Is a heterocyclic group containing an NH ring group, and any protecting groups present are subsequently removed by conventional means.

Step (i): l is¹And L²Are alternative groups as defined in process (b), for example halogens such as chlorine. The reaction with the compound of formula IIj may be carried out under conditions analogous to those described in method (b) herein.

The compounds of formula IIj may be prepared using standard procedures, for example as described in WO 03/082831, to give compounds of formula IIj bearing 2, 3-dihaloanilines. Similar methods can be used to prepare compounds of formula IIj by coupling 4-chloro-6-hydroxy-7-methoxyquinazoline with the appropriate aniline.

Step (ii): similar to the conditions described in method (b) herein.

Step (iii): cleavage of the methoxy group is carried out under standard conditions for this reaction, for example by treatment of a compound of formula IIm with pyridinium hydrochloride at elevated temperature, for example 60-180 ℃, conveniently at about 170 ℃.

Step (iv): coupling was performed under Mitsunobu conditions as described in step (iiib) of scheme 1.

Step (v): deprotection to remove the amine protecting group Pg¹E.g. when Pg¹In the case of tert-butoxycarbonyl, the compound of formula (IIo) is prepared by treating with a suitable acid such as trifluoroacetic acid.

Reaction conditions of Process (b)

Suitable substitutable groups L¹Including, for example, halogens such as chlorine.

The reaction is conveniently carried out in the presence of a suitable base, for example, conveniently in the presence of a suitable base, for example, an organic amine base such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylamine, triethylamine,N-methylmorpholine or diazabicyclo [5.4.0]Undec-7-ene, or, for example, an alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or an alkali metal hydride such as sodium hydride, or a disilylamide alkali metal such as sodium hexamethyldisilylamide.

The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1, 4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such asN， N-dimethylformamide, N， N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide.

The reaction is suitably carried out at a temperature of from 0 ℃ to 30 ℃, conveniently at room temperature.

When Z is hydroxy, the hydroxy group is conveniently protected in the reaction with a compound of formula II. Suitable protecting groups are well known, for example alkanoyl groups such as acetyl. The protecting group may be removed by conventional means after reaction with a compound of formula II, for example base hydrolysis in the presence of a suitable base such as sodium hydroxide.

The compounds of formula IV are commercially available compounds or they are known in the literature or they can be prepared by standard methods known in the art.

Reaction conditions of Process (c):

L²suitable substitutable groups represented include, for example, halogen or sulfonyloxy groups, such as chloro, bromo, methylsulfonyloxy or toluene-4-sulfonyloxy. Specific radicals L²Is chlorine.

The reaction is conveniently carried out in the presence of a suitable base, for example one as described in method (b).

The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1, 4-dioxane, an ester such as ethyl acetate, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N， N-dimethylformamide,N， N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulfoxide.

The reaction is suitably carried out at a temperature of from 0 ℃ to 80 ℃, conveniently at room temperature.

Preparation of the starting Material for Process (c)

The compound of formula V used as starting material may be prepared, for example, by reacting a quinazoline of the formula II, or a salt thereof, as defined in process (a) above with a compound of the formula Va, conveniently in the presence of a suitable base:

L²-X²-X¹-L⁵

Va

wherein X¹And X²As defined above, L²And L⁵Is a suitable substitutable group, provided that L⁵Ratio L²And is more unstable.

L²And L⁵Suitable substitutable groups for representation include, for example, halogen such as chlorine.

The reaction is conveniently carried out in the presence of a suitable base in a suitable inert solvent or diluent, as hereinbefore defined for the reaction of a quinazoline of the formula V with a compound of the formula ZH.

The compounds of formula ZH and Va are commercially available compounds or they are known in the literature or they can be prepared by standard methods known in the art.

Conveniently, in embodiments of method (c), the quinazoline of formula I may be prepared directly from the quinazoline of formula II by reacting the quinazoline of formula II with the compound of formula Va, and then directly reacting the resulting product with the compound of formula ZH without isolating the compound of formula V. This reaction allows the preparation of a quinazoline of the formula I starting from a quinazoline of the formula II in a single reaction vessel.

Reaction conditions of Process (d)

Method (d) may be used to alkylate the NH group in a quinazoline derivative of formula I, for example when Z is amino or (1-6C) alkylamino, or when the group Z-X²With amino or (1-6C) alkylamino substituents. Suitable reductive amination conditions are well known in the art. For example, to produce a catalyst containingNA quinazoline derivative of the formula I having a methyl group, the corresponding compound containing an N-H group being reacted with formaldehyde in the presence of a suitable reducing agent. Suitable reducing agents are, for example, hydride reducing agents such as formic acid, alkali metal aluminum hydrides such as lithium aluminum hydride, or suitable alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently carried out in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the stronger reducing agents such as lithium aluminium hydride and for example dichloromethane or protic solvents such as methanol and ethanol for the weaker reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is suitably carried out under acidic conditions in the presence of a suitable acid such as hydrochloric acid or acetic acid,buffers may also be used to maintain the pH at the desired level during the reaction. When the reducing agent is formic acid, the reaction is conveniently carried out using an aqueous solution of formic acid. The reaction is carried out at a temperature in the range, for example-10 to 100 c, for example 0 to 50 c, conveniently at or near room temperature.

Quinazoline derivatives of formula I containing an NH group (e.g. when Z is amino or (1-6C) alkylamino) may be prepared using one of the methods described above. For example by coupling a compound of formula II with a suitable optionally protected amino acid using method (a), followed by removal of any protecting groups.

Reaction conditions of Process (e)

The cleavage reaction may be conveniently carried out by any known method for such conversion. A particularly suitable cleavage reaction is treatment of R in which R is treated with an alkali metal halide such as lithium iodide in the presence of 2, 4, 6-trimethylpyridine¹Quinazoline derivatives of the formula I which are (1-6C) alkoxy groups. We have found that the use of 2, 4, 6-trimethylpyridine provides for the selective cleavage of the (1-6C) alkoxy group at the C6 position on the quinazoline ring. The reaction may be carried out in the presence of a suitable inert solvent or diluent as defined above. However, the reaction can conveniently be carried out using only 2, 4, 6-trimethylpyridine without the need for further solvents/diluents. The reaction is suitably carried out at a temperature in the range, for example, 10-170 deg.C, preferably at an elevated temperature, for example 120-170 deg.C, for example about 130 deg.C.

Reaction conditions of Process (f)

The coupling reaction is conveniently carried out under Mitsunobu conditions as described in step (iiib) of scheme 1.

Preparation of the starting Material for Process (f)

The compounds of formula VI used as starting materials can be prepared, for example, by cleaving a quinazoline derivative of the formula I, wherein R is¹For example methoxy. Alternatively, the compounds of formula VI may be prepared using conventional methods. For example, when X¹For CO, the compound of formula VI can be prepared using the method described in scheme 4:

reaction scheme 4

Wherein R is in addition to protecting any functional groups if desired¹、R²、Q¹、W、X²A, b, Pg and Pg¹Any protecting groups present are subsequently removed by conventional means, as defined above.

Conditions in reaction scheme 4

Step (i): the methoxy group is cleaved under similar conditions as described in step (iii) of reaction scheme 3.

Step (ii) Pg is a suitable hydroxy protecting group as defined above, for example an alkanoyl group such as acetyl. The group Pg may be introduced under standard conditions, for example by reacting a compound of formula VIb with acetic anhydride.

Step (iii) coupling under Mitsunobu conditions as described in scheme 1, step (iiib).

Step (iv): deprotection to remove the protecting group Pg. For example by base hydrolysis in an alcohol, for example using ammonia in methanol, when Pg is acetyl.

Step (v): deprotection to remove the amine protecting group Pg ¹E.g. when Pg¹In the case of tert-butoxycarbonyl, the compound of formula (VId) is prepared by treating it with a suitable acid, such as trifluoroacetic acid.

Step (vi): using the process described for Process (a) with an acid Z-X²-COOH coupling.

The quinazoline derivative of the formula I may be obtained in the form of the free base using the methods described above, or it may be obtained in the form of a salt, an acid addition salt. When it is desired to obtain the free base from a salt of a compound of formula I, the salt may be treated with a suitable base, for example, an alkali or alkaline earth metal carbonate or hydroxide (e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide), or with ammonia, for example using a solution of ammonia in methanol (e.g., a solution of 7N ammonia in methanol).

In general, the protecting group used in the above-mentioned method may be selected from any group described in the literature or known to those skilled in the art as being suitable for protecting the functional group to be protected, and the protecting group may be introduced by a conventional method. The protecting group may be removed by any convenient method described in the literature or known to those skilled in the art to be suitable for removing the protecting group to be removed, such method being selected such that the method removes the protecting group with minimal impact on other groups in the molecule.

For convenience, specific examples of protecting groups are given below, wherein "lower" (as in lower alkyl) denotes groups preferably having 1 to 4 carbon atoms. It should be understood that these examples are not exhaustive. Likewise, the specific examples of methods for removing the protecting group given below are not exhaustive. Of course, it is understood that the use of protecting groups and the removal thereof not specifically mentioned are also included in the scope of the present invention.

The carboxyl protecting group may be the residue of an aliphatic or araliphatic ester-forming alcohol or of an ester-forming silanol, the alcohol and silanol preferably having from 1 to 20 carbon atoms. Examples of carboxyl protecting groups include straight and branched chain (1-12C) alkyl groups (e.g., isopropyl and tert-butyl); lower alkoxy-lower alkyl (e.g., methoxymethyl, ethoxymethyl, and isobutoxymethyl); lower acyloxy-lower alkyl (such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl (e.g., 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl (e.g., benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl, and 2-benzo [ c ] furanone); tri (lower alkyl) silyl (e.g., trimethylsilyl and t-butyldimethylsilyl); tri (lower alkyl) silyl-lower alkyl (e.g., trimethylsilylethyl); and (2-6C) alkenyl (e.g., allyl). Particularly suitable methods for removing the carboxyl protecting group include, for example, acid, base, metal or enzyme catalyzed cleavage.

Examples of hydroxy protecting groups include lower alkyl (e.g., t-butyl), lower alkenyl (e.g., allyl); lower alkanoyl (e.g., acetyl); lower alkoxycarbonyl (such as tert-butoxycarbonyl); lower alkenyloxycarbonyl (e.g., allyloxycarbonyl); aryl-lower alkoxycarbonyl (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl); tri (lower alkyl) silyl groups (e.g., trimethylsilyl and t-butyldimethylsilyl) and aryl-lower alkyl groups (e.g., benzyl).

Examples of amino protecting groups include formyl, aryl-lower alkyl (such as benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2, 4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furanylmethyl; lower alkoxycarbonyl (such as tert-butoxycarbonyl); lower alkenyloxycarbonyl (e.g., allyloxycarbonyl); aryl-lower alkoxycarbonyl (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl (e.g., pivaloyloxymethyl); trialkylsilyl groups (e.g., trimethylsilyl and t-butyldimethylsilyl); alkylene (e.g., methylene) and benzylidene and substituted benzylidene groups.

Suitable methods for removing the hydroxy and amino protecting groups include, for example, acid, base, metal or enzyme catalyzed hydrolysis of the group (e.g., hydrolysis of 2-nitrobenzyloxycarbonyl), hydrogenation of the group, for example benzyl, and photolysis of the group, for example 2-nitrobenzyloxycarbonyl. For example, a tert-butoxycarbonyl protecting group may be removed from an amino group by acid-catalyzed hydrolysis with trifluoroacetic acid.

The reader is referred to advanced organic Chemistry, 4 th edition, edited by J.March, published by John Wiley & Sons 1992, and to guidelines for protecting Groups, edited by Protective Groups in organic Synthesis, 2 nd edition, T.Green et al, published by John Wiley & Son.

It is to be understood that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions, or generated by conventional functional group modifications either before or after the above-described processes, which are included in the process aspects of the present invention. Such reactions and modifications include, for example, the introduction of substituents by aromatic substitution reactions, the reduction of substituents, the alkylation of substituents, and the oxidation of substituents. The reagents and reaction conditions for such a step are well known in the chemical art. Specific examples of aromatic substitution reactions include introduction of a nitro group with concentrated nitric acid, introduction of an acyl group with, for example, an acid halide and a Lewis acid (e.g., aluminum trichloride) under Friedel Crafts conditions; introducing an alkyl group under Friedel crafts conditions with an alkyl halide and a Lewis acid (e.g., aluminum trichloride); and introducing a halogen group.

When a pharmaceutically acceptable salt, e.g. an acid addition salt, of a quinazoline derivative of the formula I is required, it may be obtained, for example, by reacting the quinazoline derivative with a suitable acid using conventional methods.

When a pharmaceutically acceptable ester of a quinazoline derivative of the formula I is required, it may be obtained by reacting the quinazoline derivative with a suitable acid or alcohol, for example using conventional methods as described in the definition of pharmaceutically acceptable esters herein.

As noted above, certain compounds of the present invention may contain one or more chiral centers and thus may exist as stereoisomers (e.g., when Q is¹In the case of piperidin-3-yl). Stereoisomers may be prepared using conventional techniques such as chromatography or fractional crystallisation. Enantiomers can be separated by separation of the racemates, for example, by fractional crystallization, resolution or HPLC. Diastereomers may be separated by different physical properties of the diastereomers, for example, by fractional crystallization, HPLC, or flash chromatography. Alternatively, specific stereoisomers can be prepared by chiral synthesis from chiral starting materials, or by derivatization with a chiral agent, under conditions that do not cause racemization or epimerization. When a particular stereoisomer is isolated, it is suitably separated to its essential Free of other stereoisomers, for example containing less than 20%, especially less than 10%, more especially less than 5% by weight of other stereoisomers.

In the section above relating to the preparation of quinazoline derivatives of the formula I, the term "inert solvent" refers to a solvent which does not react with the starting materials, intermediates or products in a manner which adversely affects the yield of the desired product.

It will be appreciated by those skilled in the art that the various process steps mentioned above may be performed in a different order and/or that the various reactions may be performed at different stages of the overall route (i.e., chemical transformations may be performed on different intermediates as described above in connection with the particular reaction) in order to alternatively, and in some cases more conveniently, obtain the compounds of the invention.

Certain intermediates used in the above processes are novel and constitute further features of the invention. According to a further aspect of the invention there is provided a quinazoline derivative of the formula II, or a salt thereof, as defined above wherein a is 2 and each R is²Which may be identical or different, are halogen (in particular selected from fluorine and chlorine), where R is²The groups are located at ortho (2-) and meta (3-) positions on the aniline ring. A specific compound of formula II is a compound of formula II wherein the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino, more specifically the anilino group is 3-chloro-2-fluoroanilino. In one embodiment, in the compound of formula II or salt thereof, R ¹Is (1-4C) alkoxy; a is 0 or 1; w when present is at Q¹On a mid-ring carbon atom, selected from (1-4C) alkyl, hydroxy and (1-4C) alkoxy (preferably W is 0); q¹Is piperidin-4-yl, the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino, more particularly the anilino group is 3-chloro-2-fluoroanilino. The intermediate of formula II may be in the form of a salt of the intermediate. Such salts need not be pharmaceutically acceptable salts. For example, it may be useful to prepare intermediates in the form of non-pharmaceutically acceptable salts if, for example, such salts are used in the production of compounds of formula I. Preferably the salt of the compound of formula II is a pharmaceutically acceptable salt as defined above for the quinazoline derivative of formula I.

Biological assay

The inhibitory activity of compounds was evaluated in a non-cell based protein tyrosine kinase assay as well as in a cell based proliferation assay prior to their evaluation for in vivo activity by xenograft studies.

a) Protein tyrosine kinase phosphorylation assay

This assay measures the ability of test compounds to inhibit phosphorylation of tyrosine-containing polypeptide substrates by EGFR, erbB2, and erbB4 tyrosine kinases.

Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (search numbers X00588, X03363 and L07868, respectively) were cloned and expressed in a baculovirus/Sf 21 system. By dissolving with ice-cold buffer (20mM N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid (HEPES) pH 7.5, 150mM NaCl, 10% glycerol, 1% Triton X-100, 1.5mM MgCl ₂1mM ethylene glycol-bis (. beta. -aminoethylether) N ', N', N ', N' -tetraacetic acid (EGTA)) plus protease inhibitor, followed by clarification by centrifugation, and preparation of lysates from these cells.

Constitutive kinase activity of these recombinant proteins was determined by their ability to phosphorylate synthetic peptides (random interpolymers composed of glutamic acid, alanine and tyrosine in a ratio of 6: 3: 1). Specifically, Maxisorb was coated with synthetic peptide (0.2 μ g peptide in 200 μ l Phosphate Buffered Saline (PBS) solution and incubated overnight at 4 ℃)^Tm96-well enzyme label plate. Plates were washed at room temperature in 50 mh epes, pH 7.4, to remove any excess unbound synthetic peptide. By adding Adenosine Triphosphate (ATP) and 10mM MnCl in peptide-coated plates at 100mM HEPES, pH 7.4, Km concentration of each enzyme₂、0.1mM Na₃VO₄0.2mM DL-Dithiothreitol (DTT), 0.1% Triton X-100, with test compound in dimethyl sulfoxide (DMSO) (final concentration 2.5%), and incubated at room temperature to assess the activity of EGFR or erbB 2. The reaction was stopped by removing the liquid components of the assay, followed by washing the plate with PBS-T (phosphate buffered saline plus 0.5% Tween 20).

The immobilized phosphorylated peptide product of the reaction is detected by immunological methods. First, the plates were incubated with mouse-derived anti-phosphotyrosine primary antibody (4G10, from UpstateBiotechnology) at room temperature for 90 minutes. After thorough washing, the plates were treated with horseradish peroxidase (HRP) conjugated goat anti-mouse secondary antibody (NXA 931 from Amersham) for 60 minutes at room temperature. After further washing, 2' -azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt crystal (ABOTS) ^TMFrom Roche) as substrate the HRP activity in each well of the plate was determined colorimetrically.

Color development and corresponding enzyme activity values were quantified by measuring absorbance at 405nm on a Molecular Devices ThermoMax microplate reader. Using IC' s₅₀Values are expressed for kinase inhibition for a given compound. This can be determined by calculating the concentration of compound required to obtain 50% inhibition of phosphorylation in this assay. The extent of phosphorylation was calculated from the positive control value (vehicle plus ATP) and the negative control value (vehicle minus ATP).

b) EGFR-driven KB cell proliferation assay

This assay measures the ability of test compounds to inhibit proliferation of KB cells (human nasopharyngeal carcinoma cells, from American Type Culture Collection (ATCC)).

In Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 2mM glutamine and non-essential amino acids, 7.5% CO at 37 deg.C₂KB cells were cultured in the air incubator of (1). Cells were harvested from stock (stock) flasks using trypsin/ethylenediaminetetraacetic acid (EDTA). Cell density was measured using a hemocytometer, viability was calculated using trypan blue solution, and then 7.5% CO at 37 deg.C₂At a rate of 1.25X 10 per well³Cell density, cells were seeded in a 96-well plate in DMEM containing 2.5% charcoal-adsorbed serum, 1mM glutamine, and non-essential amino acids, and then allowed to stand for 4 hours.

After adsorption to the plates, the cells were treated with or without Epidermal Growth Factor (EGF) (final concentration 1ng/ml) and with or without a range of compounds in Dimethylsulfoxide (DMSO) (final concentration 0.1%) and then incubated for 4 days. After the incubation period, the cell number was determined by adding 50. mu.l of 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) (stock 5mg/ml) for 2 hours. The MTT solution was then decanted and the plate gently tapped to dissolve the cells in 100. mu.l DMSO added.

The absorbance of the lysed cells was read at 540nm using a Molecular Devices ThermoMax microplate reader. Using IC' s₅₀Values indicate inhibition of proliferation. This can be calculated by calculating the concentration of compound required to obtain 50% inhibition of proliferation in this assay. The extent of proliferation was calculated from the positive (vehicle plus EGF) and negative (vehicle minus EGF) control values.

c) Assay for clone 24 phospho-erbB 2 cells

This immunofluorescence end-point assay measures the ability of test compounds to inhibit phosphorylation of erbB2 in MCF7 (breast cancer) -derived cell lines obtained by transfecting MCF7 cells with the full-length erbB2 gene using standard methods to give cell lines that overexpress the full-length wild-type erbB2 protein (hereinafter referred to as 'clone 24' cells).

At 37 ℃ in 7.5% CO₂Clone 24 cells were cultured in growth medium (phenol red-free Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 2mM glutamine and 1.2mg/ml G418) in an air incubator. Cells were harvested from a T75 stock flask by washing once in PBS (phosphate buffered saline, pH 7.4, Gibco No.10010-015), and then harvested with 2ml trypsin (1.25 mg/ml)/ethylenediaminetetraacetic acid (EDTA) (0.8mg/ml) solution. Resuspending the cells in growth medium. Cell density was measured by hemocytometer, viability was calculated using trypan blue solution, and cells were re-diluted in growth medium at 1 × 10 per well⁴Cell density (in 100. mu.l) were seeded in clear-bottom 96-well plates (Packard, No. 6005182).

After 3 days, the growth medium was removed from each well and replaced with 100. mu.l of test medium (phenol red free DMEM with 2mM glutamine, 1.2mg/ml G418) with or without erbB inhibitor compound. The plate was returned to the incubator for 4 hours, then 20. mu.l of a 20% formaldehyde solution in PBS was added to each well, and the plate was left at room temperature for 30 minutes. The fixative was removed using a multi-channel pipette, and 100. mu.l PBS was added to each well, then removed using a multi-channel pipette, and 50. mu.l PBS was added to each well. Plates were then sealed and stored at 4 ℃ for up to 2 weeks.

Immunostaining was performed at room temperature. Add 200. mu.l PBS/Tween 20 (by adding 1 bag of PBS/Tween dry powder (Sigma, No. P3563) to 1L of redistilled H using a plate washer₂O) was washed once and then 200 μ l of blocking solution (5% Marvel dry skim milk (Nestle) in PBS/Tween 20) was added and incubated for 10 minutes. The blocking solution was removed with a plate washer and 200. mu.l of 0.5% Triton X-100/PBS was added to permeabilize the cells. After 10 minutes, the plate was washed with 200. mu.l PBS/Tween 20, followed by an additional 200. mu.l blocking solution and incubation for 15 minutes. After removing the blocking solution with a plate washer, 30. mu.l of rabbit polyclonal anti-ErbB phosphate 2 IgG antibody (epitope P-Tyr 1248, Santa Cruz, No. SC-12352-R) diluted 1: 250 in the blocking solution was added to each well, followed by incubation for 2 hours. This primary antibody solution was then removed with a plate washer and washed twice with 200. mu.l PBS/Tween 20 using a plate washer. Then 30. mu.l of Alexa-Fluor 488 goat anti-rabbit IgG secondary antibody (Molecular Probes, No. A-11008) diluted 1: 750 in blocking solution was added to each well. From now on, the plates were protected from light as much as possible by being closed with a black bottom tape at this stage. Each plate was incubated for 45 minutes, then the secondary antibody solution was removed from the wells, and washed twice with 200. mu.l PBS/Tween 20 using a plate washer. Then 100. mu.l PBS was added to each plate, incubated for 10 minutes, and removed with a plate washer. Then, 100. mu.l PBS was added to each plate, and then the plate was removed with a plate washer without further prolonged incubation. Then 50 μ l PBS was added to each well, the plates were resealed with a black bottom band and stored at 4 ℃ for up to 2 days before analysis.

Using an Acumen Explorer Instrument (Acumen bioscience)Ltd.) a plate reader that can rapidly quantify image characteristics by laser scanning, the fluorescence signal in each well is measured. The instrument is configured to measure the amount of fluorescent target that exceeds a predetermined threshold, thereby providing a means for measuring the phosphorylation state of erbB2 protein. The fluorescence agent amount response data obtained for each compound is entered into an appropriate software package (e.g., Origin) for curve fitting analysis. Using IC' s₅₀Values indicate inhibition of erbB2 phosphorylation. This can be determined by calculating the concentration of compound required to obtain 50% inhibition of the phosphorylation signal of erbB2 in this assay.

d) In vivo xenograft assay

This assay measures the ability of the test compound to inhibit the growth of LoVo tumors (colorectal adenocarcinoma, obtained from ATCC) in female Swiss additive mice (AlderleyPark, nu/nu genotype).

Female Swiss athymic (nu/nu genotype) mice were bred and fed into alderley park negative pressure isolation devices (PFI Systems Ltd.). The mice were housed in a hurdle set, cycled 12 hours light/dark, and provided an unlimited amount of sterilized diet and water. All steps were performed with mice at least 8 weeks old. By subcutaneous injection of 100. mu.l of 1X 10 in serum-free medium per animal ⁷Cells were freshly cultured and xenografts of LoVo tumor cells (colorectal adenocarcinoma, obtained from ATCC) were established in the hind ribs of donor mice. On day 5 post-implantation, mice were randomized into 7 groups and dosed once daily at 0.1ml/10g body weight prior to treatment with compound or vehicle controls. The volume of the tumor was determined by measuring the bilateral sides of the tumor twice a week with a vernier caliper, applying the formula (length x width) × √ (length x width) × (π/6), where length is the diameter of the tumor in the longitudinal direction and width is the corresponding vertical line. Growth inhibition from the start of the study was calculated by comparing the mean change in tumor volume for the control and treated groups, and statistical significance was assessed between the two groups using the Students t test.

Although the pharmacological properties of the compounds of formula I vary with structural changes, as desired, in general, the compounds of formula I may be demonstrated to be active in one or more of the above tests (a), (b), (c) and (d) at the following concentrations or dosages: -

Test (a): -IC₅₀In the range of, for example, 0.001 to 1. mu.M

Test (b): -IC₅₀In the range of, for example, 0.001 to 5. mu.M

Test (c): -IC₅₀In the range of, for example, 0.01 to 5. mu.M

Test (d): the activity is, for example, in the range from 1 to 200 mg/kg/day

At an effective dose of the test compound of the present invention, no physiologically unacceptable toxicity is observed in test (d). Thus, no troublesome toxic effects are expected when a compound of formula I as defined above or a pharmaceutically acceptable salt thereof is administered in the dosage ranges defined below.

By way of example, using test (a) (inhibition of EGFR tyrosine kinase protein phosphorylation) and test (b) (KB cell assay) above, representative compounds described in the examples herein obtain the IC shown in table a below₅₀As a result:

TABLE A

EXAMPLES Compounds	IC of test (a) (inhibition of phosphorylation of EGFR tyrosine kinase protein)50(nM)	IC of assay (b) (EGFR-driven KB cell proliferation assay)50(nM)
			2	76	112
3	41	55
			4[1]	30	37
4[3]	65	84
			4[4]	52	109

Another aspect of the invention provides a pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, aqueous or oily solutions or suspensions), for administration by inhalation (for example as a fine powder or a liquid aerosol), for administration by insufflation (for example as a fine powder) or for parenteral administration (for example as a sterile aqueous or oily solution, for intravenous, subcutaneous, intramuscular or for rectal administration).

The compositions of the present invention may be prepared by conventional methods using a variety of conventional pharmaceutical excipients well known in the art. Thus, compositions for oral administration may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, formulations for oral administration in humans will generally contain, for example, from 0.5mg to 0.5g of the active agent (more suitably from 0.5 to 100mg, e.g. from 1 to 30mg), in combination with a suitable convenient amount of excipient which may be from about 5% to 98% by weight of the total composition.

Of course, the size of the dose of the quinazoline derivative of the formula I, when used for therapeutic or prophylactic purposes, will vary with the nature and severity of the condition of the animal or patient, the age and sex and the route of administration, according to principles well known in the medical arts.

In the case of quinazoline derivatives of the formula I which are to be administered for therapeutic or prophylactic purposes, they are generally administered in a daily dose in the range, for example, from 0.1mg/kg to 75mg/kg body weight, and may be administered in divided doses if necessary. Generally, when the parenteral route is used, lower doses should be administered. Thus, for example, for intravenous administration, a dosage range of, for example, 0.1mg/kg to 30mg/kg body weight is generally employed. Similarly, for administration by inhalation, a dosage range of, for example, 0.05mg/kg to 25mg/kg body weight is generally used. However, oral administration, especially in the form of tablets, is preferred. Typically, unit dosage forms contain from about 0.5mg to 0.5g of a compound of the invention.

We have found that the compounds of the invention possess anti-proliferative properties, such as anti-cancer properties, which are believed to result from their erbB family receptor tyrosine kinase inhibitory activity, particularly the inhibition of EGF receptor (erbB1) tyrosine kinase. In addition, certain compounds of the invention have significantly better potency against EGF receptor tyrosine kinase than other tyrosine kinases, such as erbB2, VEGF or KDR receptor tyrosine kinases. Such compounds have sufficient potency towards EGF receptor tyrosine kinase that they may be used in amounts sufficient to inhibit EGF receptor tyrosine kinase whilst exhibiting little or significantly less activity towards other tyrosine kinases such as erbB 2. Such compounds are useful for the selective inhibition of EGF receptor tyrosine kinase and are useful for the effective treatment of, for example, EGF driven tumors.

Accordingly, it is desirable that the compounds of the present invention are useful in the treatment of diseases or medical conditions mediated alone or in part by erbB receptor tyrosine kinases, particularly EGF receptor tyrosine kinase, i.e. that the compounds are useful in the production of erbB receptor tyrosine kinase inhibitory effects in a warm-blooded animal in need of such treatment. Accordingly, the compounds of the present invention provide a method of treating malignant cells characterised by the inhibition of one or more erbB family receptor tyrosine kinases. In particular, the compounds of the invention are useful for producing anti-proliferative and/or pro-apoptotic and/or anti-invasive effects mediated alone or in part by inhibition of erbB receptor tyrosine kinases. In particular, the compounds of the invention are expected to be useful in the prevention or treatment of tumours which are sensitive to inhibition of one or more erbB receptor tyrosine kinases (e.g. EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases, especially EGF receptor tyrosine kinase) which are involved in the signal transduction steps which drive proliferation and survival of these tumour cells. The compounds of the present invention are therefore expected to be useful in the treatment of psoriasis, Benign Prostatic Hyperplasia (BPH), atherosclerosis and restenosis and/or cancer, in particular erbB receptor tyrosine kinase sensitive cancer, by providing an antiproliferative effect. Such benign or malignant tumors can affect any tissue, including non-solid tumors such as leukemia, multiple myeloma or lymphoma, but also solid tumors such as cancers of the bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurogenic, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterus and vulva.

According to this aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, for use as a medicament.

According to this aspect of the invention there is provided a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or a pharmaceutically-acceptable ester thereof, for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined above in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase, which kinases are involved in signal transduction steps which lead to the proliferation of tumour cells.

According to a further feature of this aspect of the invention there is provided a method of preventing or treating a tumour which is susceptible to inhibition of one or more erbB family receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase, involved in the signal transduction steps which lead to proliferation and/or survival of tumour cells, in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, for use in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase, which kinases are involved in signal transduction steps which lead to tumour cell proliferation, in a warm-blooded animal such as man.

According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, as defined hereinbefore in the manufacture of a medicament for use in providing an EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method of providing an EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as man, which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, for use in providing an EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as man.

According to a further feature of the invention, there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method of providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore.

According to a further feature of this aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as man.

By "selective EGFR kinase inhibition" is meant that the quinazoline derivatives of the formula I are more potent on EGF receptor tyrosine kinase than on other kinases. In particular, certain compounds of the invention are more potent against EGF receptor kinase than against other tyrosine kinases (e.g. other erbB receptor tyrosine kinases such as erbB 2). For example of the inventionThe selective EGFR kinase inhibitor is at least 5-fold, preferably at least 10-fold more potent than the EGF receptor tyrosine kinase than the erbB2 tyrosine kinase, as measured by relative IC in a suitable assay₅₀And (4) determining the value. For example, IC determined by comparing KB cells for a given test compound as described above₅₀Values (determination of EGFR tyrosine kinase inhibitory Activity) and IC determined for clone 24 phospho-erbB 2 cells₅₀Values (determination of erb-B2 tyrosine kinase inhibitory activity).

According to a further aspect of the invention there is provided the use of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurogenic, oesophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulval cancers) in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there is provided a method of treating cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neurogenic, oesophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulval cancers) in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, as defined hereinbefore.

According to a further aspect of the present invention there is provided a compound of formula I, or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof, for use in the treatment of cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, oesophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulval cancers) in a warm-blooded animal such as man.

As noted above, the size of the dose required for the treatment or prevention of a particular disease will necessarily vary depending upon the host treated, the route of administration, and the severity of the disease being treated, among other factors.

The anti-proliferative/tyrosine kinase inhibitory/anti-cancer treatments defined above may be used alone as monotherapy or in combination with conventional surgery, radiation or chemotherapy in addition to the compounds of the invention. Such chemotherapeutic methods may include one or more of the following classes of antineoplastic agents: -

(i) Antiproliferative/antineoplastic agents and combinations thereof employed in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea), antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin and chlortetracycline), antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as taxol and taxotere), and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor down-regulation modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, fluorochlorzole (ravozole) and exemestane) and 5 α -reductase inhibitors such as finasteride;

(iii) cancer cell invasive agents (e.g., metalloproteinase inhibitors such as marimastat and inhibitors of the urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, such inhibitors including growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ Herceptin ]^TM]And the anti-erbB 1 antibody cetuximab [ C225]) Farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example further inhibitors of the epidermal growth factor family (such as EGFR family tyrosine kinase inhibitors, for example N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), inhibitors such as the platelet-derived growth factor family and inhibitors such as the hepatocyte growth factor family;

(v) Anti-angiogenic agents, e.g. drugs inhibiting the action of vascular endothelial growth factor (e.g. anti-vascular endothelial growth factor antibody bevacizumab [ Avastin)^TM]Such as those disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) as well as compounds that act by other mechanisms (such as tricarboxyaminoquinolines, inhibitors of integrin α v β 3 function and angiostatin);

(vi) vascular damaging agents, such as combretastatin A4 and the compounds disclosed in International patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapeutics, e.g., those targeted to the above-listed targets, such as ISIS 2503, anti-ras antisense therapeutics;

(viii) gene therapy methods, including, for example, methods of replacing an aberrant gene (e.g., aberrant p53 or aberrant BRCA1 or BRCA2), GDEPT (gene-directed enzyme prodrug therapy) methods, such as methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods of increasing a patient's tolerance to chemotherapy or radiation therapy (e.g., gene therapy for resistance to multiple drugs);

(ix) immunotherapy approaches, including, for example, in vitro and in vivo approaches to increasing the immunogenicity of patient tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor), approaches to reduce T-cell anergy; methods using transfected immune cells such as cytokine-transfected dendritic cells; approaches using cytokine-transfected tumor cell lines and methods using anti-idiotypic antibodies;

(x) Cell cycle inhibitors, including, for example, CDK inhibitors (e.g., flavopiridol) and other cell cycle checkpoint inhibitors (e.g., checkpoint kinase); aurora kinase inhibitors and inhibitors of other kinases involved in mitosis and regulation of cytoplasmic movement (e.g., mitotic kinesins); and histone deacetylase inhibitors.

Such combination therapy may be performed by administering the individual components of the therapy simultaneously, sequentially or separately. Such combinations employ the compounds of the present invention in the dosage ranges previously described, as well as other pharmaceutically active agents in approved dosage ranges.

According to one aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the formula I as defined hereinbefore in association with a further anti-tumour agent, as defined hereinbefore, for use in combination therapy for cancer.

Although the compounds of formula I are useful primarily as therapeutic agents in warm-blooded animals including humans, they may also be used to inhibit the action of erbB receptor tyrosine protein kinases when required. Therefore, these compounds can be used as drug standards in the development of new biological tests and in the research of new pharmacological drugs.

The invention will now be further illustrated in the following non-limiting examples in which, unless otherwise stated:

(i) The temperature is given in degrees Celsius (. degree. C.); the operation is carried out at room temperature or ambient temperature, i.e. at a temperature in the range of 18-25 ℃;

(ii) drying the organic solution by anhydrous magnesium sulfate or sodium sulfate; the evaporation of the solvent is carried out under reduced pressure (600-;

(iii) chromatography refers to silica gel rapid chromatography; thin Layer Chromatography (TLC) was performed on silica gel plates;

(iv) generally, the course of the reaction is monitored by TLC and/or analytical LCMS, and the reaction times are given for illustration only;

(v) the final product has satisfactory proton Nuclear Magnetic Resonance (NMR) spectrum and/or mass spectrum data;

(vi) yields are given for illustration only and are not necessarily achievable by efforts to improve the process; repeat the preparation if more starting materials are needed;

(vii) when given, NMR data is in the form of delta values for the major characteristic protons, given in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard, except as otherwise noted, deuterium-dimethyl sulfoxide (DMSO-d) was used₆) As solvent, at the operating frequency of the NMR instrument used (300 or 400 MHz); the following abbreviations are used: s represents a single peak; d represents a double peak; t represents a triplet; q represents a quartet; m represents a multiple peak; br represents a broad peak;

(viii) Chemical symbols have their usual meaning; SI units and symbols are used;

(ix) the solvent ratio is given in volume: volume (v/v);

(x) Mass Spectrometry (MS) was performed in either the cationic or anionic mode using Waters or Micromass electrospray LC-MS; giving the m/z value; generally, only ions indicating a basis mass (parent mass) are reported(ii) a Unless otherwise stated, reference to a mass ion is (MH)⁺；

(xi) When the synthesis is described as similar to that described in the preceding examples, the amounts used are millimolar ratio equivalents of the amounts used in the preceding examples;

(xii) When the compound was purified by Mass-initiated preparative LCMS, the following conditions were used:

column: ThermoHypersil Keystone B-Basic 5. mu.21 mm. times.100 mm

Eluent: 7.5 min gradient, 20% -95% acetonitrile/water (buffer 2g/l (NH)₄)₂CO₃，pH 8.9)

Flow rate: 25 ml/min;

(xiii) Melting point (mp) was measured using a Buchi B-545 automatic melting point apparatus;

(xiv) Unless otherwise stated, compounds containing asymmetrically substituted carbon atoms are not resolved;

(xv) The following abbreviations are used:

HATU hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium;

DIPEA: diisopropylethylamine;

DMA: n, N-dimethylacetamide;

DMF: n, N-dimethylformamide;

DCM: dichloromethane;

DMSO, DMSO: dimethyl sulfoxide

EtOAc: ethyl acetate;

IPA: isopropyl alcohol;

TBTU: o- (1H-benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran.

Example 1

N- (3-chloro-2-fluorophenyl) -7- ({1- [ (dimethylamino) acetyl ] piperidin-4-yl } oxy) -6-methoxyquinazolin-4-amine

N, N-dimethylaminoacetyl chloride hydrochloride (100mg) was added in portions to a stirred solution of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (250mg, 0.57mmol) and diisopropylethylamine (300. mu.l) in dichloromethane (25ml) at 0 ℃. The reaction mixture was stirred for 2 hours to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution (25ml) and dried (MgSO)₄) Filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/methanol mixtures of increasing polarity (100/0 to 90/10), and dichloromethane/methanol saturated with ammonia (90/10). Fractions containing the desired product were combined and evaporated in vacuo to afford the title product as a white foam (0.125g, 45%);¹ h NMR spectrum: (DMSO d₆)1.50-1.65(m，1H)；1.65-1.80(m，1H)；1.95-2.15(m，2H)；2.25(s，6H)；3.10-3.50(m，4H)；3.75-4.05(m，2H)；3.95(s，3H)；4.90(m，1H)；7.30(m，1H)；7.35(s，1H)；7.40-7.60(m，2H)；7.85(s，1H)；8.40(s，1H)；9.65(s，1H)； Mass spectrometry：(M+H)⁺488。

The N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride used as the starting material was prepared as follows:

4.0M HCl in dioxane (4.0ml) was added to a stirred suspension of 7- (benzyloxy) -4-chloro-6-methoxyquinazoline (CAS registry No162364-72-9, prepared as described in WO 98/13354, example 1) (60g, 0.2mol) and 3-chloro-2-fluoroaniline (31.96g, 0.22mol) in acetonitrile (1200 ml). The reaction mixture was heated at 80 ℃ for 1 hour and then allowed to stand overnight. Acetonitrile (500ml) was added and the resulting precipitate was filtered, washed with acetonitrile (3X 500ml) and dried in vacuo to give 7- (benzyloxy) -N- (3-chloro-2-fluorophenyl) -6-methoxyquinazolin-4-amine hydrochloride as a pale brown solid (85.45g, 96%);¹ h NMR spectrum:(DMSO d₆)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 spectrometry：(M+H)⁺410。

A solution of 7- (benzyloxy) -N- (3-chloro-2-fluorophenyl) -6-methoxyquinazolin-4-amine hydrochloride (85.45g, 0.192mol) in trifluoroacetic acid (300ml) was heated at 80 ℃ for 1 h. The reaction mixture was evaporated to dryness and the residue redissolved in methanol (200 ml). The solution was added dropwise to a stirred saturated aqueous sodium bicarbonate solution (500 ml). The resulting precipitate was collected by filtration, washed with acetonitrile and dried in vacuo. The resulting solid was then purified by trituration with a hot (100 ℃) mixture of butanone (500ml) and MeOH (100ml), filtered and dried to give 4- [ 3-chloro-2-fluoroaniline ]-6-methoxyquinazolin-7-ol as a cream solid (45g, 73%);¹ h NMR spectrum:(DMSO d₆)：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 spectrometry：(M+H)⁺320。

4- [ 3-chloro-2-fluoroaniline base]-6-Methoxyquinazolin-7-ol (500mg, 1.565mmol) was dissolved in DMA (20 ml). Tert-butyl (4-methanesulfonyloxy) piperidine-1-carboxylate (436.6mg, 1.565mmol) and cesium fluoride (236.3mg, 1.565mmol) were added and the mixture was heated to 60 ℃ with stirring. After 18 hours, the same amount of tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride are added to the reaction mixture and heating is continued at 60 ℃ for a further 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate (50ml) and EtOAc (2 × 50 ml). Combine the organics over MgSO₄Drying and evaporating. The resulting product was then purified by column chromatography eluting with increasingly polar dichloromethane/EtOAc mixtures (100/0 to 0/100). The fractions containing the desired product were combined and evaporated in vacuo to give 4- ({4- [ 3-chloro-2-fluoroaniline)]-6-methoxyquinazolin-7-yl } oxy) Colorless foam of tert-butyl piperidine-1-carboxylate (757mg, 96%);¹ H NMR spectrum:(DMSO-d₆)：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 spectrometry：(M+H)⁺503。

Trifluoroacetic acid (50ml) was added to 4- ({4- [ 3-chloro-2-fluoroaniline)]A solution of tert-butyl (6-methoxyquinazolin-7-yl) piperidine-1-carboxylate (750mg, 1.49mmol) in dichloromethane (1ml) and triethylsilane (1ml) was stirred for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was redissolved in EtOAc (5 mL). The solution was then treated with 1M HCl/diethyl ether (1ml) and then more diethyl ether (50ml) to give a white precipitate. The resulting solid was collected by centrifugation and dried in vacuo to give N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride as a white solid (750 mg); ¹ H NMR spectrum:(DMSO-d₆)：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 spectrometry：(M+H)⁺403。

Example 2

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2-methoxyethoxy) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (300mg), diisopropylethylamine (0.45ml) and 2- (2-methoxyethoxy) acetyl chloride (0.105g) were stirred in dichloromethane (9ml) for 2.5 hours. Dichloromethane (20ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30ml) and water (30 ml). Subjecting the obtained product to flash column chromatographyPurification, eluting with methanol (3%) and dichloromethane (97%), yielded a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain the title product as a white solid (0.110 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.73(m，2H)，2.02(m，2H)，3.29(s，3H)，3.42(m，2H)，3.51(t，J＝7Hz，2H)，3.60(t，J＝9Hz，2H)，3.78(m，2H)，3.96(s，3H)，4.17(s，2H)，4.87(m，1H)，7.27(m，1H)，7.33(s，1H)，7.42(m，1H)，7.58(m，1H)，7.85(s，1H)，8.39(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺519; melting point 110-.

Example 3

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (methoxyacetyl) piperidin-4-yl ] oxy } quinazolin-4-amine

HATU (0.24g) was added to a solution of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (250mg), diisopropylethylamine (0.37ml) and methoxyacetic acid (0.054g) in dichloromethane (9ml), and the mixture was stirred at room temperature for 2.5 hours. Dichloromethane (20ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and dichloromethane (97%) to give a foam. It was reprecipitated by stirring in diethyl ether (20ml) to obtain the title product as a white solid (0.200 g); ¹ H NMR spectrum:(DMSO d₆ 373K)1.73(m，2H)，2.02(m，2H)，3.37(s，3H)，3.41(m，2H)，3.77(m，2H)，3.98(s，3H)，4.09(s，2H)，4.85(m，1H)，7.26(m，1H)，7.30(s，1H)，7.39(m，1H)，7.59(m，1H)，7.81(s，1H)，8.38(s，1H)，9.34(br s，1H)； mass spectrometry：(M+H)⁺475。

Example 4

Using an analogous method to that described in example 3, N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride was coupled with the appropriate carboxylic acid to give the compounds shown in table I:

TABLE 1

Numbering and notes	R
		[1]	Hydroxyacetyl radical
[2]	Ethoxy acetyl group
		[3]	3-methoxy propionyl group

Note that:

in Table 1Refers to the point in Table 1 where the carbonyl group is attached to the nitrogen in the piperidin-4-yl group.

[1]2- [4- ({4- [ 3-chloro-2-fluoroaniline base)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-2-oxoethanol (0.170 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.78(m，2H)，2.02(m，2H)，3.42(m，2H)，3.75(m，2H)，3.97(s，3H)，4.11(s，2H)，4.84(m，1H)，7.25(m，1H)，7.31(s，1H)，7.40(m，1H)，7.50-7.67(m，2H)，7.82(s，1H)，8.38(s，1H)，9.31(br s，1H)； mass spectrometry：(M+H)⁺461。

[2]N- (3-chloro-2-fluorophenyl) -7- { [1- (ethoxyacetyl) piperidin-4-yl group]White solid of oxy } -6-methoxyquinazolin-4-amine (0.185 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.18(t，J＝8Hz，3H)，1.74(m，2H)，2.03(m，2H)，3.41(m，2H)，3.52(q，J＝8Hz，2H)，3.79(m，2H)，3.98(s，3H)，4.12(s，2H)，4.84(m，1H)，7.23(m，1H)，7.32(s，1H)，7.42(m，1H)，7.58(m，1H)，7.81(s，1H)，8.38(s，1H)，9.30(br s，1H)； mass spectrometry：(M+H)⁺489; melting point 160-.

[3]N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (3-methoxypropionyl) piperidin-4-yl]Oxy } quinazolin-4-amine (0.155 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.73(m，2H)，2.01(m，2H)，2.62(t，J＝9Hz，2H)，3.28(s，3H)，3.41(m，2H)，3.60(t，J＝9Hz，2H)，3.79(m，2H)，3.97(s，3H)，4.82(m，1H)，7.24(m，1H)，7.30(s，1H)，7.40(m，1H)，7.58(m，1H)，7.81(s，1H)，8.38(s，1H)，9.30(br s，1H)； mass spectrometry：(M+H)⁺489; melting point 184-.

[4]3- [4- ({4- [ 3-chloro-2-fluoroaniline base)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-3-oxoprop-1-ol (0.061 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.72(m，2H)，2.01(m，2H)，2.62(t，J＝8Hz，2H)，3.40(m，2H)，3.71(m，2H)，3.80(m，2H)，3.96(s，3H)，4.13(t，J＝5Hz，1H)，4.83(m，1H)，7.28(m，1H)，7.31(s，1H)，7.42(m，1H)，7.59(m，1H)，7.83(s，1H)，8.39(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺475; melting point 128-.

[5](2S) -2-Hydroxypropionic acid and N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yl) dihydrochloride Following the coupling reaction between oxy) quinazolin-4-amine, the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia in methanol (98.6/1.4) to give a foam. It was reprecipitated by stirring in diethyl ether (20ml) to obtain (2S) -1- [4- ({4- [ 3-chloro-2-fluoroaniline-based)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]Amorphous white solid of (0.092g) (melting point 107-. Recrystallizing acetonitrile to obtain a crystalline solid (melting point 189-191 ℃);¹ h NMR spectrum:(DMSO d₆)1.19(d，3H)，1.48-1.75(m，2H)，1.94-2.13(m，2H)，3.21-3.53(m，2H)，3.93(s，3H)，3.78-4.06(m，2H)，4.40-4.52(m，1H)，4.83-4.99(m，2H)，7.28(dd，1H)，7.33(s，1H)，7.42-7.55(m，2H)，7.81(s，1H)，8.36(s，1H)，9.62(s，1H)；mass spectrometry：(M+H)⁺475。

[6]After the coupling reaction, the product was purified by flash column chromatography eluting with dichloromethane/7N ammonia in methanol (98/2) to give a foam. By stirring in diethyl ether (20ml), it was reprecipitated to obtain (2S, 3S) -1- [4- ({4- [ 3-chloro-2-fluoroaniline-based)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-white solid of 3-methyl-1-oxopent-2-ol (0.244 g);¹ H NMR spectrum:(DMSO d₆)0.78(d，J＝7Hz，3H)，0.91(t，J＝7Hz，3H)，1.21(m，1H)，1.44(m，1H)，1.61(m，3H)，2.05(m，2H)，3.40(m，2H)，3.79(m，1H)，3.95(s，3H)，4.00(m，1H)，4.28(m，1H)，4.43(m，1H)，4.93(m，1H)，7.29(m，1H)，7.36(s，1H)，7.48(m，1H)，7.53(m，1H)，7.83(s，1H)，8.39(s，1H)，9.63(br s，1H)； mass spectrometry：(M+H)⁺517; melting point 114-.

[7]After the coupling reaction, the product was purified by flash column chromatography eluting with methanol (4%) and dichloromethane (96%) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain 4- [4- ({4- [ 3-chloro-2-fluoroaniline)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ]-white solid of 2-methyl-4-oxobutan-2-ol (0.232 g);¹ h NMR spectrum:(DMSOd₆)1.20(s，6H)，1.54-1.77(m，2H)，2.04(m，2H)，2.49(s，2H)，3.30(m，1H)，3.45(m，1H)，3.86(m，1H)，3.96(s，3H)，4.00(m，1H)，4.88(s，1H)，4.91(1H，m)，7.28(m，1H)，7.35(s，1H)，7.47(m，1H)，7.54(m，1H)，7.83(s，1H)，8.40(s，1H)，9.63(br s，1H)；mass spectrometry：(M+H)⁺503; melting point 196-.

[8]After the coupling reaction, the product was purified by flash column chromatography eluting with dichloromethane/7N ammonia in methanol (98/2) to give a foam. By stirring diethyl ether (20ml) in the same, it was reprecipitated to obtain N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (tetrahydrofuran-2-ylcarbonyl) piperidin-4-yl]White solid of oxy } quinazolin-4-amine (0.260 g);¹ h NMR spectrum:(DMSOd₆ 373K)1.73(m，2H)，1.99(m，2H)，2.05(m，3H)，2.14(m，1H)，3.48(m，2H)，3.83(m，4H)，3.99(s，3H)，4.69(t，J＝7Hz，1H)，4.89(1H，m)，7.29(m，1H)，7.37(s，1H)，7.43(m，1H)，7.60(m，1H)，7.83(s，1H)，8.39(s，1H)，9.33(br s，1H)； mass spectrometry：(M+H)⁺501; melting point 199-.

[9]After the coupling reaction, the product was purified by flash column chromatography eluting with methanol (4%) and dichloromethane (96%) to give a foam. By stirring in diethyl ether (20ml), it was reprecipitated to obtain 3- [4- ({4- [ 3-chloro-2-fluoroaniline)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-2, 2-dimethyl-3-oxopropan-1-ol as a white solid (0.244g).¹ H NMR spectrum:(DMSO d₆)1.10(s，6H)，1.64(m，2H)，2.03(m，2H)，3.39(m，2H)，3.45(m，2H)，3.95(s，3H)，3.98(m，2H)，4.54(t，J＝6Hz，1H)，4.91(1H，m)，7.29(m，1H)，7.35(s，1H)，7.48(m，1H)，7.53(m，1H)，7.83(s，1H)，8.39(s，1H)，9.64(br s，1H)； mass spectrometry：(M+H)⁺503; melting point 111-.

[10](3R, 5S) -1-acetyl-5- { [4- ({4- [ 3-chloro-2-fluoroanilino)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]Carbonyl } pyrrolidin-3-ol (0.160 g);¹ h NMR spectrum:(DMSOd₆ 373K)1.65-1.87(m，3H)，1.93(s，3H)，2.04(m，3H)，3.44-3.64(m，4H)，3.81(m，2H)，3.98(s，3H)，4.28-4.39(m，1H)，4.71(m，1H)，4.89(m，2H)，7.23(m，1H)，7.32(s，1H)，7.40(m，1H)，7.59(m，1H)，7.81(s，1H)，8.39(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺558; melting point 183-.

[11]After the coupling reaction, the product was purified by flash column chromatography eluting with methanol (3%) and dichloromethane (97%) to give a foam. By stirring in diethyl ether (20ml), it was reprecipitated to obtain (2S) -1- [4- ({4- [ 3-chloro-2-fluoroaniline) ]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-1-oxobutan-2-ol (0.108g) as a white solid;¹ h NMR spectrum:(DMSO d₆373K)0.91(t，J＝9Hz，3H)，1.52(m，1H)，1.70(m，3H)，2.05(m，2H)，3.40(m，2H)，3.84(m，2H)，3.94(s，3H)，4.28(m，1H)，4.40(m，1H)，4.88(m，1H)，7.26(m，1H)，7.32(s，1H)，7.42(m，1H)，7.60(m，1H)，7.80(s，1H)，8.38(s，1H)，9.30(br s，1H)； mass spectrometry：(M+H)⁺489; melting point 152-.

[12]After the coupling reaction, the product was purified by flash column chromatography eluting with dichloromethane/7N ammonia in methanol (98/2) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -tetrahydrofuran-2-ylcarbonyl)]Piperidin-4-yl } oxy) quinazolin-4-amine as a white solid (0.142 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.73(m，2H)，1.99(m，2H)，2.05(m，3H)，2.14(m，1H)，3.48(m，2H)，3.83(m，4H)，3.99(s，3H)，4.69(t，J＝7Hz，1H)，4.89(1H，m)，7.29(m，1H)，7.37(s，1H)，7.43(m，1H)，7.60(m，1H)，7.83(s，1H)，8.39(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺501; melting point 198-.

[13]After the coupling reaction, the product was purified by flash column chromatography eluting with dichloromethane/7N ammonia in methanol (98/2) to give a foam. By reaction in diethyl ether(20ml) was stirred, and this was reprecipitated to obtain N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -tetrahydrofuran-2-ylcarbonyl)]Piperidin-4-yl } oxy) quinazolin-4-amine as a white solid (0.212 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.73(m，2H)，1.99(m，2H)，2.05(m，3H)，2.14(m，1H)，3.48(m，2H)，3.83(m，4H)，3.99(s，3H)，4.69(t，J＝7Hz，1H)，4.89(1H，m)，7.29(m，1H)，7.37(s，1H)，7.43(m，1H)，7.60(m，1H)，7.83(s，1H)，8.39(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺501; melting point 193-194 ℃.

[14]After the coupling reaction, the product was purified by flash column chromatography eluting with methanol (2.5%) and dichloromethane (97.5%) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain (2S) -1- [4- ({4- [ 3-chloro-2-fluoroaniline) ]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-3, 3-dimethyl-1-oxobutan-2-ol (0.026g) as a white solid;¹ h NMR spectrum:(DMSO d₆ 373K)0.94(s，9H)，1.72(m，2H)，2.03(m，2H)，3.49(m，2H)，3.90(m，2H)，3.96(s，3H)，4.17(m，1H)，4.24(m，1H)，4.86(m，1H)，7.25(m，1H)，7.31(s，1H)，7.40(m，1H)，7.59(m，1H)，7.82(s，1H)，8.38(s，1H)，9.29(br s，1H)； mass spectrometry：(M+H)⁺517; melting point 205-.

[15]7- ({1- [ (1-acetylpiperidin-4-yl) carbonyl]Piperidin-4-yl } oxy) -N- (3-chloro-2-fluorophenyl) -6-methoxyquinazolin-4-amine;¹ h NMR spectrum:(DMSO+CD₃COOD)：1.33-1.46(m，1H)；1.50-1.62(m，1H)：1.62-1.74(m，3H)；1.75-1.85(m，1H)；2.00-2.18(m，2H)；2.02(s，3H)；2.62-2.71(m，1H)；2.92-3.00(m，1H)；3.13(dd，1H)；3.30-3.43(m，1H)；3.47-3.57(m，1H)；3.80-3.98(m，3H)；4.02(s，3H)；4.39(d，1H)；4.93(bs，1H)；7.41(dd，1H)；7.49(s，1H)；7.58(dd，1H)；7.68(dd，1H)；8.11(s，1H)；8.92(s，1H)； mass spectrometry：(M+H)⁺556。

[16]N- (3-chloro-2-fluorophenyl)) -6-methoxy-7- { [1- (tetrahydrofuran-3-ylcarbonyl) piperidin-4-yl]Oxy } quinazolin-4-amine;¹ h NMR spectrum:(DMSO+CD₃COOD)：11.64-1.74(m，1H)；1.74-1.84(m，1H)；2.01-2.17(m，4H)；3.33-3.55(m，3H)；3.66-3.80(m，3H)；3.80-3.99(m，3H)；4.03(s，3H)；3.93(bs，1H)；7.41(dd，1H)；7.48(s，1H)；7.58(dd，1H)；7.67(dd，1H)；8.12-(s，1H)；8.92(s，1H)； mass spectrometry：(M+H)⁺501。

[17]After the coupling reaction, the product was purified by flash column chromatography eluting with methanol (5%) and dichloromethane (95%) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain 1- { [4- ({4- [ 3-chloro-2-fluoroanilino)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]Carbonyl } cyclopropanol (0.125g) as a white solid;¹ h NMR spectrum:(DMSO d₆ 373K)0.80(m，2H)，0.95(m，2H)，1.72(m，2H)，2.02(m，2H)，3.54(m，2H)，3.96(s，3H)，4.00(m，2H)，4.87(m，1H)，5.90(s，1H)，7.25(m，1H)，7.31(s，1H)，7.40(m，1H)，7.58(m，1H)，7.80(s，1H)，8.38(s，1H)，9.30(br s，1H)； mass spectrometry：(M+H)⁺487, and (3) a method of preparing; melting point 177-.

Example 5

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [ (3S) -1- (methoxyacetyl) piperidin-3-yl ] oxy } quinazolin-4-amine

HATU (0.24g) was added to N- (3-chloro-2-fluorophenyl) -6-methoxy-7- [ (3S) -piperidin-3-yloxy) dihydrochloride]A solution (9ml) of quinazolin-4-amine (250mg), diisopropylethylamine (0.37ml) and methoxyacetic acid (0.054g) in dichloromethane was stirred at room temperature for 2.5 hours. Dichloromethane (20ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and dichloromethane (97%) And obtaining the foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain the title product as a white solid (0.202 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.60(m，1H)，1.88(m，2H)，2.10(m，1H)，3.32(s，3H)，3.51(m，2H)，3.62(m，1H)，3.87(m，1H)，3.98(s，3H)，4.02(d，J＝14Hz，1H)，4.12(d，J＝14Hz，1H)，4.66(m，1H)，7.26(m，1H)，7.33(s，1H)，7.43(m，1H)，7.62(m，1H)，7.83(s，1H)，8.40(s，1H)，9.34(br s，1H)； mass spectrometry：(M+H)⁺475。

The N- (3-chloro-2-fluorophenyl) -6-methoxy-7- [ (3S) -piperidin-3-yloxy ] quinazolin-4-amine dihydrochloride used as the starting material was prepared as follows:

diethyl azodicarboxylate (3.73g) was added dropwise to a mixture of tert-butyl (3R) -3-hydroxypiperidine-1-carboxylate (4.29g), 4-chloro-6-methoxyquinazolin-7-ol (3.00g) and triphenylphosphine (5.61g) in dichloromethane (75 ml). The solution was then heated to 40 ℃ and stirred for 3 hours. The cooled mixture was filtered and purified by flash column chromatography eluting with isohexane/acetone/triethylamine (80/20/1) to give (3S) -3- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy)]Tert-butyl piperidine-1-carboxylate (3.29g) as a colorless oil which was used as received;mass spectrometry：(M+H)⁺394。

4.0M HCl in dioxane (6.0ml) was added to a stirred solution of (3S) -3- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy group]Piperidine-1-carboxylic acid tert-butyl ester (3.21g) and 3-chloro-2-fluoroaniline (0.98mL) in acetonitrile (50 mL). The reaction mixture was heated at 80 ℃ and left at this temperature overnight. The solvent was evaporated and the residue was purified by flash column chromatography, eluting with a mixture of increasing polarity dichloromethane/7N ammonia in methanol (97/3-95/5) to give N- (3-chloro-2-fluorophenyl) -6-methoxy-7- [ (3S) -piperidin-3-yloxy) -dihydrochloride ]Solid of quinazolin-4-amine (3.20 g);¹ h NMR spectrum:(DMSO d₆)1.56(m，2H)，1.72(m，1H)，2.12(m，1H)，2.48-2.59(m，2H)，2.82(m，1H)，3.20(m，1H)，3.95(s，3H)，4.49(m，1H)，7.26(s，1H)，7.28(m，1H)，7.47(m，1H)，7.53(m，1H)，7.81(s，1H)，8.38(s，1H)，9.63(s，1H)； mass spectrometry：(M+H)⁺403。

Example 6

2- [ (3S) -3- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-oxoethanol

Using a method analogous to that described in example 5, N- (3-chloro-2-fluorophenyl) -6-methoxy-7- [ (3S) -piperidin-3-yloxy) -dihydrochloride]Quinazolin-4-amine (250mg) was coupled with glycolic acid (0.045 g). The resulting product was purified by flash column chromatography eluting with methanol (3%) and dichloromethane (97%) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain the title product as a white solid (0.105 g);¹ h NMR spectrum:(DMSO d₆ 373K)1.59(m，1H)，1.87(m，2H)，2.09(m，1H)，3.40-3.60(m，4H)，3.86(m，1H)，3.98(s，3H)，4.04-4.18(m，2H)，4.66(m，1H)，7.24(m，1H)，7.31(s，1H)，7.40(m，1H)，7.60(m，1H)，7.80(s，1H)，8.38(s，1H)，9.30(br s，1H)； mass spectrometry：(M+H)⁺461。

Example 7

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({ (3S) -1- [ (4-methylpiperazin-1-yl) acetyl ] piperidin-3-yl } oxy) quinazolin-4-amine

Chloroacetyl chloride (47. mu.l) was added to N- (3-chloro-2-fluorophenyl) -6-methoxy-7- [ (3S) -piperidin-3-yloxy) dihydrochloride]A solution of quinazolin-4-amine (250mg) and diisopropylethylamine (373. mu.l) in dichloromethane (10ml) was stirred at ambient temperature for 1 hour. 1-Methylpiperazine (228mg) was added, the solution was stirred for 1 hour, and then hydrogen was usedAqueous sodium oxide (2M, 10ml) and water (10 ml). The organics were then purified by flash column chromatography eluting with methylene chloride/7N ammonia in methanol (97/3) to give a foam. This was reprecipitated by stirring in diethyl ether (20ml) to obtain the title product as a white solid (0.135 g); ¹ H NMR spectrum:(DMSOd₆)1.42-1.67(m，1H)，1.70-1.95(m，2H)，1.98-2.48(m，9H)，2.18(s，3H)，2.82-3.05(m，1H)，3.20-4.02(m，8H)，4.68(m，1H，)，7.30(m，1H)，7.34(s，1H)，7.44-7.60(m，2H)，7.82(m，1H)，8.38(s，1H)，9.64(m，1H)； mass spectrometry：(M+H)⁺543; melting point 120-.

Example 8

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (4-methylpiperazin-1-yl) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine

Using a method similar to that described in example 7, N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (250mg) was reacted with chloroacetyl chloride (47 μ l) and then with 1-methylpiperazine (228mg), which was purified to obtain the title product as a white solid (0.110 g);¹ h NMR spectrum:(DMSO d₆)1.57(m，1H)，1.72(m，1H)，1.96-2.12(m，2H)，2.15(s，3H)，2.27-2.48(m，8H)，3.08-3.52(m，4H)，3.86-4.04(m，2H)，3.95(s，3H)，4.90(m，1H，)，7.30(m，1H)，7.37(s，1H)，7.47-7.58(m，2H)，7.83(s，1H)，8.38(s，1H)，9.63(s，1H)； mass spectrometry：(M+H)⁺543。

Example 9

(2R) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

A suspension (40ml) of the hydrochloride salt of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine (4.87g, 11.1mmol, prepared using a similar method to that described in example 1) was stirred and cooled in an ice/water bath. Triethylamine (4.7mls, 33.7mmol), N-diisopropylethylamine (1.9ml, 11mmol) and D- (-) -lactic acid (1.5g, 16.7mmol) were added. HATU (5.27g, 13.87mmol) was then added in portions, maintaining the internal temperature below 12 ℃. The reaction mixture was stirred at room temperature overnight in saturated aqueous sodium bicarbonate (NaHCO) ₃) And ethyl acetate (EtOAc). The combined organic layers were washed with saturated aqueous ammonium chloride (x2), 50% brine (x2) and brine (x1), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). The fractions containing the desired product were evaporated to a gel, which was triturated with diethyl ether/isohexane (1: 1). The solid was then crystallized from acetonitrile to give the title product as a white powder (2.93g, 55.6%);¹ h NMR spectrum:(DMSO d₆)1.20(d，3H)，1.50-1.80(m，2H)，1.93-2.13(m，2H)，3.15-3.53(m，2H)，3.94(s，3H)，3.72-4.08(m，2H)，4.35-4.55(m，1H)，4.80-5.00(m，2H)，7.27(dd，1H)；7.34(s，1H)；7.40-7.60(m，2H)；7.80(s，1H)；8.38(s，1H)；9.63(s，1H)；mass spectrometry：(M+H)⁺475; melting point: 189-189.5 ℃.

Example 10

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -2- (methylamino) propanoyl ] piperidin-4-yl } oxy) quinazolin-4-amine

(method (a))

{ (1R) -2- [4- ({4- [ (3-chloro-2-fluoroaniline)Base of]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-tert-butyl 1-methyl-2-oxoethyl } methylcarbamate (2.22g, 3.77mmol) was dissolved in acetonitrile (20ml), treated with 4M HCl in dioxane (3.8ml, 15.2mmol) at 80 ℃ for 5 min the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (92/8). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1: 1) to give the title product as a white powder (1.55g, 84.1%); ¹ H NMR spectrum:(DMSO d₆+CD₃CO₂D)1.35(d，3H)，1.61-1.81(m，2H)，1.98-2.15(m，2H)，2.48(s，3H)，3.26-3.51(m，2H)，3.65-3.79(m，1H)，3.92(s，3H)，3.84-4.08(m，1H)，4.32-4.42(m，1H)，4.85-4.99(m，1H)，7.20-7.29(m，1H)，7.36(s，1H)，7.42-7.54(m，2H)，7.81(s，1H)，8.35(s，1H)； quality of food Spectrum：(M+H)⁺488。

The starting material, { (1R) -2- [4- ({4- [ (3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-methyl-2-oxoethyl } methyl carbamic acid tert-butyl ester, was prepared as follows:

the hydrochloride salt of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine (2.0g, 4.55mmol) was coupled with N-tert-butoxycarbonyl-N-methyl-D-alanine as described in example 9. The product was purified by column chromatography, eluting with methylene chloride/7N ammonia in methanol (98/2), to give { (1R) -2- [4- ({4- [ (3-chloro-2-fluoroaniline)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-foam of tert-butyl 1-methyl-2-oxoethyl } methylcarbamate (2.34g, 87.6%);¹ h NMR spectrum:(CDCl₃)1.29(d，3H)，(1.48)(s，9H)，1.75-1.89(m，1H)，1.89-2.04(m，2H)，2.07-2.22(m，1H)，2.75(s，3H)，3.26-3.42(m，1H)，3.50-3.85(m，2H)，4.02(s，3H)，3.91-4.28(m，1H)，4.65-4.93(m，1H)，5.10-5.21(m，1H)，7.05(s，1H)，7.13-7.21(m，2H)，7.28-7.33(m，2H)，8.44-8.54(m，1H)，8.69(s，1H)； mass spectrometry：(M+H)⁺588。

Example 11

N- (3-chloro-2-fluorophenyl) -7- ({1- [ (2R) -2- (dimethylamino) propionyl ] piperidin-4-yl } oxy) -6-methoxyquinazolin-4-amine

(method (d))

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -2- (methylamino) propanoyl]A mixture of piperidin-4-yl } oxy) quinazolin-4-amine (0.5g, 1.03mmol) (example 10), paraformaldehyde (0.3g, 10.0mmol) and anhydrous magnesium sulfate (0.25g, 2.08mmol) in methanol (5ml) was treated with 4M hydrogen chloride in dioxane (257. mu.l, 1.03 mmol). Sodium cyanoborohydride (0.26g, 4.12mmol) was added and the mixture was heated to 40 ℃ for 3 hours. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1: 1) to give the title product as a white powder (0.415g, 80.7%); ¹ H NMR spectrum:(DMSO d₆+CD₃CO₂D)1.18-1.25(m，3H)，1.52-1.80(m，2H)，1.95-2.15(m，2H)，2.48(s，6H)，3.18-3.54(m，2H)，3.73-3.91(m，1.5H)，3.92(s，3H)，4.00-4.14(m，1.5H)，4.83-4.95(m，1H)，7.21-7.29(m，1H)，7.35(s，1H)，7.41-7.55(m，2H)，7.80(s，1H)，8.35(s，1H)； mass spectrometry：(M+H)⁺502。

Example 12

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine

(method (a))

Solid TBTU (285mg, 0.75mmol) was added to a stirred solution of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine (200mg, 0.50mmol), DIPEA (0.261ml, 1.50mmol) and (S) - (-) -2-methoxypropionic acid (57mg, 0.55mmol) in dichloromethane (3 ml). The resulting solution was stirred at room temperature overnight, diluted with dichloromethane (20ml), washed with 2N sodium hydroxide (2X 5ml), water (5ml) and dried (MgSO 4)₄) Filtered and evaporated. The resulting foam was purified by flash chromatography on silica eluting with increasingly polar methanol/dichloromethane mixtures (0/100-3/97) to afford the title compound as a white solid (100%);¹ h NMR spectrum:1.34(d，3H)，1.64-1.72(m，2H)，2.04-2.07(m，2H)，3.20(s，3H)，3.25-3.47(m，2H)，3.86-3.97(m，2H)，4.03(s，3H)，4.21-4.23(m，1H)，4.88-4.91(m，1H)，7.28(dd，1H)，7.33(s，1H)，7.47(dd，1H)，7.51(dd，1H)，7.92(s，1H)，8.38(s，1H)，9.67(s，1H)； mass spectrometry：(M+H)⁺489。

The starting material N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine was obtained from the corresponding dihydrochloride salt (example 1) by treatment of basic aqueous solution at pH 11.5 and extraction of the aqueous layer with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give a white foam of free amine;¹ h NMR spectrum:(CDCl₃)1.78-1.85(m，2H+1NH)，2.18(m，2H)，2.80(m，2H)，3.22(m，2H)，4.03(s，3H)，4.61(m，1H)，7.03(s，1H)，7.15(m，2H)，7.29(s，1H)，7.31(m，1H)，8.50(m，1H)，8.69(s，1NH)； mass spectrometry：(M+H)⁺403。

Example 13

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine

(method (a))

The method described in example 12 was repeated using (R) - (+) -2-methoxypropionic acid (57mg, 0.55mmol) to obtain the title compound as a white solid (82%);¹ h NMR spectrum:1.24(d，3H)，1.57-1.67(m，2H)，2.04-2.09(m，2H)，3.22(s，3H)，3.22-3.47(m，2H)，3.87-3.97(m，2H)，3.97(s，3H)，4.22-4.27(m，1H)，4.92-4.95(m，1H)，7.27-7.30(dd，1H)，7.35(s，1H)，7.47(dd，1H)，7.60(dd，1H)，7.82(s，1H)，8.37(s，1H)，9.67(s，1H)； mass spectrometry：(M+H)⁺489。

Example 14

(2R) -2-amino-3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-oxopropan-1-ol

(method (a))

TBTU (709mg, 1.87mmol) was added to a stirred solution (3ml) of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine (500mg, 1.24mmol), DIPEA (0.648ml, 3.72mmol) and N- (tert-butoxycarbonyl) -D-serine (280mg, 1.36mmol) in dichloromethane. The resulting solution was stirred at room temperature overnight, diluted with dichloromethane (20ml), washed with 2N NaOH (2X 5ml), water (5ml) and dried (MgSO 4)₄) And evaporated. The resulting foam was dissolved in dichloromethane (5ml) and treated with trifluoroacetic acid (5 ml). The resulting solution was allowed to stand at room temperature for 1 hour, concentrated and purified by mass-triggered (mass-tirgged) preparative LCMS to afford the title compound (42.5%);¹ h NMR spectrum:1.58-1.72(m，2H)，2.01-2.08(m，2H)，3.24-3.44(m，2H)，3.80-4.03(m，4H)，3.95(s，3H)，4.77(m，1H)，4.91-4.94(m，1H)，7.27(dd，1H)，7.35(s，1H)，7.47(dd，1H)，7.51(dd，1H)，7.82(s，1H)，8.38(s，1H)，9.67(s，1H)； mass spectrometry：(M+H)⁺490。

Example 15

(2S) -2-amino-3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-oxopropan-1-ol

The procedure described in example 14 was repeated, but using N- (tert-butoxycarbonyl) -L-serine (280mg, 1.36mmol), to give the title product (32%);¹ h NMR spectrum:1.58-1.73(m，2H)，2.01-2.08(m，2H)，3.24-3.44(m，2H)，3.80-4.00(m，4H)，3.97(s，3H)，4.74(m，1H)，4.93-4.96(m，1H)，7.28(dd，1H)，7.35(s，1H)，7.47(dd，1H)，7.51(dd，1H)，7.82(s，1H)，8.37(s，1H)，9.67(s，1H)； mass spectrum:(M+H)⁺490。

example 16

(2S) -3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2- (dimethylamino) -3-oxopropan-1-ol

(method (d))

Solid NaCNBH is added at 0-5 DEG C₃(38.3mg, 0.614mmol) was added stirred (2S) -2-amino-3- [4- ({4- [ 3-chloro-2-fluoroanilino)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-a solution of 3-oxoprop-1-ol (150mg, 0.307mmol, example 15), sodium acetate trihydrate (251mg, 3.07mmol), 37% formaldehyde (aq.) (2.5ml) and acetic acid (184mg, 3.07 mmol). The resulting solution was warmed to room temperature and stirred for 1 hour. The mixture was evaporated and the resulting yellow residue was purified by flash chromatography on silica gel eluting with a mixture of increasing polarity dichloromethane/7N ammonia in methanol (100/0-85/15). Fractions containing the desired product were combined and evaporated to afford the title compound as a white solid (26%); ¹ H NMR spectrum:1.52-1.69(m，2H)，1.94-2.07(m，2H)，2.28-2.30(2×s，6H)，3.15-3.22(m，2H)，3.53-3.76(m，4H)，3.94(s，3H)，4.02(m，1H)，4.49(m，1H)，4.92-4.94(m，1H)，7.27(dd，1H)，7.34(s，1H)，7.47(dd，1H)，7.51(dd，1H)，7.81(s，1H)，8.38(s，1H)，9.65(s，1H)； mass spectrum:(M+H)⁺518。

example 17

(2R) -3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2- (dimethylamino) -3-oxopropan-1-ol

(method (d))

Using (2R) -2-amino-3- [4- ({4- [ 3-chloro-2-fluoroaniline)]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-3-oxoprop-1-ol (150mg, 0.307mmol, example 14) the procedure described in example 16 was repeated to obtain the title compound (32%);¹ h NMR spectrum:1.58-1.69(m，2H)，1.93-2.06(m，2H)，2.26-2.28(2xs，6H)，3.17-3.20(m，2H)，3.53-3.74(m，4H)，3.94(s，3H)，4.04(m，1H)，4.47(m，1H)，4.91(m，1H)，7.26(dd，1H)，7.35(s，1H)，7.47(dd，1H)，7.51(dd，1H)，7.81(s，1H)，8.37(s，1H)，9.66(s，1H)； mass spectrum:(M+H)⁺518。

example 18

(2S) -1- (4- { [4- [ 3-chloro-2-fluoroanilino ] -6- (2-pyrrolidin-1-ylethoxy) quinazolin-7-yl ] oxy } piperidin-1-yl) -1-oxopropan-2-ol

(method (b))

(S) - (-) -2-acetyloxypropionyl chloride (0.131g, 0.87mmol) was added to a stirred solution of N- (3-chloro-2-fluorophenyl) -7- (piperidin-4-yloxy) -6- (2-pyrrolidin-1-ylethoxy) quinazolin-4-amine trihydrochloride (220mg, 0.395mmol) and triethylamine (0.110ml, 0.79mmol) in methylene chloride (10ml) at-10 ℃. The resulting solution was warmed to room temperature and stirred for 30 minutes. The resulting yellow solution was extracted with dichloromethane (10ml)Diluted, washed with water (3X 5ml) and dried (MgSO)₄) And evaporated. The resulting foam was dissolved in THF (1ml) and pyrrolidine (1ml) was added. The mixture was heated at 70 ℃ for 3 hours, evaporated and the residue purified by flash chromatography on silica gel eluting with dichloromethane/7N ammonia in methanol (95/5). Fractions containing the desired product were combined and evaporated to give the title product as a white solid (0.099g, 45.6%); ¹ H NMR spectrum:(DMSO-d₆)：δ1.20(d，3H)，1.52-1.82(m，6H)，1.86-2.08(m，4H)，3.24-3.50(m，4H)，3.74-3.86(m，2H)，4.28(m，2H)，4.45(m，1H)，4.89-4.95(m，3H)，7.27(dd，1H)，7.36(s，1H)，7.48(dd，1H)，7.53(dd，1H)，7.87(s，1H)，8.38(s，1H)，9.65(s，1H)； mass spectrometry：(M+H)⁺558。

The trihydrochloride N- (3-chloro-2-fluorophenyl) -7- (piperidin-4-yloxy) -6- (2-pyrrolidin-1-ylethoxy) quinazolin-4-amine (1) used as starting material was prepared as follows:

1, 2-dichloroethane (5ml) was added to a stirred suspension (10ml) of 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline 6(2.0g, 6.27mmol, prepared as described in reference example 2 of WO 03/082831) and potassium carbonate (1.39g, 10.0mmol) in DMF, and the resulting suspension was heated at 60 ℃ for 48 hours. The reaction mixture was diluted with dichloromethane (50ml), washed with water (3X 20ml) and dried (MgSO)₄) Evaporated to dryness to give 5(2.39g, 100%) of a brown oil, which was used without further purification;mass spectrometry：(M+H)⁺382。

Pyrrolidine (4.44g, 5.13ml, 62.5mmol) was added to a stirred solution of 5(2.38g, 6.25mmol) in DMF (30ml) and the resulting pale brown solution was heated at 90 ℃ for 2 h. The reaction mixture was evaporated to dryness on a rotary evaporator under high vacuum to give 4(2.6g, 100%) of a brown foam;mass spectrometry：(M+H)⁺417。

At 170 ℃ inIntermediate 4(2.60g, 6.3mmol) was added to neat liquid pyridinium hydrochloride (3.6g, 31.3mmol) over 5 minutes. The reaction mixture was stirred at 170 ℃ for 1 hour. The reaction mixture was cooled to room temperature, the resulting solid was suspended in water (30ml), and the resulting black precipitate was removed by filtration. The pH of the filtrate was increased to 7 with concentrated ammonia and the resulting solution was evaporated to dryness. The resulting light brown solid was purified by flash chromatography on silica gel eluting with a mixture of increasing polarity dichloromethane/7N ammonia in methanol (100/0-85/15). The fractions containing the desired product were combined and evaporated to dryness to give a pale green foam of 3 (1.62g, 64%). Mass spectrometry：(M+H)⁺403。

Di-tert-butyl azodicarboxylate (0.571g, 2.48mmol) was added to a stirred solution of 3(500mg, 1.24mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (374mg, 1.86mmol) and triphenylphosphine (660mg, 2.48mmol) in THF (10ml) at 0 deg.C over 5 min. The resulting yellow solution was allowed to warm to room temperature and then heated at 70 ℃ for 1 hour. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with a mixture of increasing polarity dichloromethane/7N ammonia in methanol (100/0-95/5). Fractions containing the desired product were combined and evaporated to give 2 as a pale green oil (0.52g, 72%);mass spectrometry：(M+H)⁺586。

TFA (1ml) was added to a stirred solution of 2(220mg, 0.395mmol) in dichloromethane (1ml) at 0 ℃ over 5 min. The resulting yellow solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was evaporated to dryness and the residue redissolved in dichloromethane (10 ml). Ether (10ml) and a solution of 4.0MHCl in dioxane (2ml) were added. The resulting thick white precipitate was collected by filtration, washed with diethyl ether (3 × 2ml), dried to constant weight to give N- (3-chloro-2-fluorophenyl) -7- (piperidin-4-yloxy) -6- (2-pyrrolidin-1-ylethoxy) quinazolin-4-amine trihydrochloride as a white solid (0.48g, 100%) which was used without further purification; Mass spectrometry：(M+H)⁺486。

Example 19

(2S) -1- (4- { [4- [ 3-chloro-2-fluoroanilino ] -6- (2-methoxyethoxy) quinazolin-7-yl ] oxy } piperidin-1-yl) -1-oxopropan-2-ol

(method (a))

TBTU (200mg, 0.525mmol) was added to a stirred solution of N- (3-chloro-2-fluorophenyl) -6- (2-methoxyethoxy) -7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (180mg, 0.404mmol), L- (+) -lactic acid (37mg, 0.44mmol) and DIPEA (0.091ml, 0.525mmol) in dichloromethane (10 ml). The resulting solution was stirred at room temperature for 2 hours and then diluted with dichloromethane (10 ml). The solution was washed with 2N NaOH (2X 5ml) and dried (MgSO₄) Filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/7N ammonia in methanol (95/5) to give the title product as a white solid (89mg, 42.6%);¹ h NMR spectrum:(DMSO-d₆)：δ1.21(d，3H)，1.64-1.72(m，2H)，1.86-2.07(m，2H)，3.37-3.46(m，2H)，3.77-3.92(m，5H)，4.27(m，2H)，4.46(m，1H)，4.90-4.92(m，3H)，7.29(dd，1H)，7.36(s，1H)，7.48(dd，1H)，7.52(dd，1H)，7.86(s，1H)，8.38(s，1H)，9.63(s，1H)； mass spectrometry：(M+H)⁺519。

The starting N- (3-chloro-2-fluorophenyl) -6- (2-methoxyethoxy) -7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride (intermediate 7 in the following reaction scheme) was prepared as follows:

solid 4- (3-chloro-2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline 6(1.00g, 3.13mmol) was added to neat liquid pyridinium hydrochloride (3.62g, 31.3mmol) over 10 minutes at 170 ℃. The reaction mixture was stirred at 170 ℃ for 2 hours and then cooled to room temperature. The mixture was then suspended in water (30ml) and the resulting precipitate collected by filtration, washed with acetonitrile (5ml), diethyl ether (5ml) and dried in vacuo at 50 ℃ to Constant weight, 10 as a light brown solid (0.71g, 77%);mass spectrometry：(M+H)⁺306。

An aqueous solution (3ml) of acetic anhydride (117mg, 1.15mmol) and NaOH (46mg, 1.15mmol) was added to a stirred suspension (3ml) of 10(350mg, 1.15mmol) in THF at-10 ℃. The resulting biphasic mixture was stirred at room temperature for 2 hours. The organic phase was retained and dried (MgSO)₄) And (5) drying by distillation. The resulting light brown foam was triturated with acetonitrile (3ml), cooled to 0 ℃, the resulting precipitate collected by filtration and dried in a vacuum oven at 40 ℃ to constant weight to give 9 as a light brown solid (232mg, 68%);mass spectrometry：(M+H)⁺348。

Di-tert-butyl azodicarboxylate (364mg, 1.58mmol) as a solid was added to a stirred solution of 9(250mg, 0.72mmol), triphenylphosphine (420mg, 1.58mmol) and 4-hydroxy-1-tert-butoxycarbonylpiperidine (289mg, 1.44mmol) in THF (10ml) at room temperature over 5 minutes. The resulting yellow solution was stirred at room temperature for 2 hours and concentrated to give a yellow foam. Dissolving the foam in 7N NH₃MeOH (5ml), and left for 1 hour. The solution was concentrated and purified by flash chromatography on silica gel (eluting with a mixture of DCM-MeOH 95/5) to give 8(138mg, 39%) as a light brown foam;mass spectrometry：(M+H)⁺489。

Di-tert-butyl azodicarboxylate (166mg, 0.72mmol) as a solid was added to a stirred solution (2ml) of 8(115mg, 0.24mmol), triphenylphosphine (0.191g, 0.72mmol) and 2-methoxyethanol (55mg, 0.72mmol) in THF at room temperature over 5 min. The resulting yellow solution was stirred at room temperature for 2 hours and then concentrated to a yellow foam. This was dissolved in DCM (1ml), treated with trifluoroacetic acid (1ml) and left to stand for 1 hour. The solution was concentrated and purified by mass triggered preparative LCMS to afford N- (3-chloro-2-fluorophenyl) -6- (2-methoxyethoxy) -7- (piperidin-4-yloxy) quinazolin-4-amine dihydrochloride as a white solid (80mg, 77%); mass spectrum: (M + H) ⁺447.13。

Example 20

4- [ 3-chloro-2-fluoroanilino ] -7- ({1- [ (2S) -2-hydroxypropionyl ] piperidin-4-yl } oxy) quinazolin-6-ol

Solid lithium iodide (2.11g, 15.8mmol) was added to stirred neat 2, 4, 6-trimethylpyridine (5ml) at 130 ℃. The resulting yellow solution was heated at 130 ℃ for 1 hour. Solid (2S) -1- [4- ({4- [ (3-chloro-2-fluoroanilino) was added over 10 minutes]-6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl]-1-oxoprop-2-ol (1.5g, 3.17mmol, example 4[5]). The resulting solution was stirred at 130 ℃ for 16 hours to obtain a dark brown solid precipitate. The liquid was decanted and the solid was purified by mass triggered preparative LCMS to afford the title product as a brown solid (1.30g, 87%);¹ h NMR spectrum:(DMSO-d₆)：δ1.21(d，3H)，1.61-1.77(m，2H)，1.95-2.08(m，2H)，3.41-3.51(m，2H)，3.86-3.92(m，2H)，4.47(m，1H)，4.91(m，1H)，7.26(m，1H)，7.32(s，1H)，7.45(m，1H)，7.53(m，1H)，7.70(s，1H)，8.33(s，1H)，9.45(s，2H)； mass spectrometry：(M+H)⁺461。

Example 21

(2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-isopropoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (f))

Solid di-tert-butyl azodicarboxylate (225mg, 0.98mmol) was added to a stirred solution of 2-propanol (0.074ml, 0.98mmol) and triphenylphosphine (260mg, 0.98mmol) in THF (1ml) at 0 ℃ over 5 min. The resulting yellow solution is warmed to room temperature and 4- [ 3-chloro-2-fluoroaniline is added]-7- ({1- [ (2S) -2-hydroxypropionyl group]Piperidin-4-yl } oxy) quinazolin-6-ol (250mg, 0.33mmol, example 20). The mixture was heated at 80 ℃ for 3 hours, cooled and evaporated. The residue was purified by mass triggered preparative LCMS To obtain a white solid of the title compound (75mg, 45.7%);¹ h NMR spectrum:(CDCl₃)：δ1.37(d，3H)，1.43(d，6H)，1.61-1.72(m，2H)，1.95-2.07(m，2H)，3.38-3.50(m，2H)，3.78-3.88(m，2H)，4.49(m，1H)，4.66(m，1H)，4.82(m，1H)，7.15(m，3H)，7.31(s，1H)，8.52(s，1H)，8.69(s，1H)； mass spectrometry：(M+H)⁺503。

Example 22

(2S) -1- [4- ({4- [ (3-chloro-4-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

HATU (190mg, 0.5mmol) was added to a stirred solution of N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride (200mg, 0.456mmol), L- (+) -lactic acid (45mg, 0.5mmol) and N-methylmorpholine (0.15ml, 1.39mmol) in DMF (10ml) at room temperature. After 2 hours the mixture was evaporated to dryness and the residue was purified by column chromatography on silica eluting with increasing polarity dichloromethane/methanol mixture (99/1-90/10). The fractions containing the desired product were evaporated to gel. It was triturated with diethyl ether (10ml) and the resulting solid collected by filtration and dried under high vacuum to give the title product as a white powder (54.2mg, 25%);¹ h NMR spectrum：(DMSO d₆)1.1-1.3(m，3H)，1.5-1.8(m，2H)，1.9-2.15(m，2H)，3.0-3.60(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.43(m，1H)，4.95(m，2H)，7.32(s，1H)，7.47(dd，1H)，7.7-7.8(m，1H)，7.83(s，1H)，8.0-8.1(m，1H)，8.58(s，1H)，9.87(bs，1H)；Mass spectrometry：(M+H)⁺475。

The starting N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride was prepared as follows:

at 5Di-tert-butyl azodicarboxylate (1.64g, 7.14mmol) in dichloromethane (20ml) was added slowly to a stirred suspension (50ml) of 4-chloro-6-methoxyquinazolin-7-ol (1.0g, 4.76mmol, prepared as described in WO2004041829, example 1 (preparation of starting material)), 4-hydroxy-1-tert-butoxycarbonylpiperidine (1.44g, 7.14mmol) and triphenylphosphine (1.87g, 7.14mmol) in dichloromethane (50ml) under nitrogen. The reaction mixture was allowed to warm to room temperature for 18 hours. The reaction mixture was then filtered and purified by flash chromatography on silica eluting with an increasing polarity isohexane/ethyl acetate/triethylamine mixture (75/24/1 then 0/99/1). The fractions containing the desired product were combined and evaporated in vacuo to give 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy ]White solid of tert-butyl piperidine-1-carboxylate (1.75g, 93.4%);¹ H NMR: wave spectrum：(DMSO d₆)1.40(s，9H)，1.5-1.7(m，2H)，1.9-2.1(m，2H)，3.1-3.3(m，2H)，3.60-3.80(m，2H)，3.95(s，3H)，4.92(m，1H)，7.38(s，1H)，7.58(s，1H)，8.83(s，1H)； Mass spectrometry：(M+H)⁺394。

4.0M HCl (1ml) in dioxane was added to 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy]A suspension (10ml) of tert-butyl piperidine-1-carboxylate (331mg, 0.84mmol) and 3-chloro-4-fluoroaniline (134.5mg) in acetonitrile. The reaction mixture was stirred and heated at 70 ℃ for 4 hours. The resulting precipitate was filtered while hot, washed with acetonitrile and dried under vacuum to give N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride (566 mg);mass spectrometry：(M+H)⁺403。

Example 23

(2R) -1- [4- ({4- [ 3-chloro-4-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using as described in example 22Coupling D-lactic acid with N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride under the same conditions to obtain the title product;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.5-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.50(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(pent，1H)，4.8-5.8(m，2H)，7.32(s，1H)，7.45(dd，1H)，7.7-7.85(m，2H)，8.1(dd，1H)，8.5(s，1H)，9.55(s，1H)； Mass spectrometry：(M+H)⁺475; melting Point 143.6 ℃.

Example 24

(2S) -1- [4- ({4- [ 3-Bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using an analogous method to that described in example 22, N- (3-bromophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride was coupled with L- (+) -lactic acid to give the title product as a white powder; ¹ H NMR spectrum：(DMSO d₆)1.2(d，3H)，1.5-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.60(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(m，1H)，4.8-5.0(m，2H)，7.2-7.4(m，3H)，7.8-7.9(m，2H)，8.13(s，1H)，8.5(s，1H)，9.5(s，1H)； Mass spectrometry：(M+H)⁺501，503。

The starting material, N- (3-bromophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, was prepared as follows.

Using a similar procedure to that described in example 21 (preparation of starting Material) for the preparation of N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy) was reacted]Coupling piperidine-1-carboxylic acid tert-butyl ester with 3-bromoaniline to obtain N- (3-bromophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine;¹ H NMR wave spectrum：(DMSO d₆)：1.8-2.1(m，2H)，2.1-2.3(m，2H)，3.0-3.35(m，4H)，4.05(s，3H)，4.88(m，1H)，7.38-7.52(m，2H)，7.6(s，1H)，7.8(d，1H)，8.05(s，1H)，8.5(s，1H)，8.87(s，1H)，9.2(bs，2H)，11.7(s，1H)； Mass spectrometry：(M+H)⁺431。

Example 25

(2R) -1- [4- ({4- [ 3-Bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Coupling of N- (3-bromophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride and D-lactic acid using an analogous method to that described in example 22 gave the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.5-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.43(m，1H)，4.8-5.0(m，2H)，7.2-7.4(m，3H)，7.8-7.9(m，2H)，8.15(s，1H)，8.5(s，1H)，9.5(s，1H)； Mass spectrometry：(M+H)⁺501，503。

Example 26

(2S) -1- [4- ({4- [ 5-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using a similar method to that described in example 22, N- (5-chloro-2-fluorophenyl) -6-methoxy-7- (piperidine-4-)Coupling of acyloxy) quinazolin-4-amine with L- (+) -lactic acid to obtain a white powder of the title product; ¹ H NMR spectrum：(DMSO d₆)1.2(d，3H)，1.5-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.60(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(m，1H)，4.8-5.0(m，2H)，7.3-7.45(m，3H)，7.7(d，1H)，7.85(s，1H)，8.5(s，1H)，9.95(s，1H)； Mass spectrometry：(M+H)⁺475。

The starting material, N- (5-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, was prepared as follows.

Using a similar procedure to that described in example 22 (preparation of starting Material) for the preparation of N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy) was reacted]Coupling piperidine-1-carboxylic acid tert-butyl ester with 2-fluoro-5-chloroaniline to obtain hydrochloric acid N- (5-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine;¹ h NMR spectrum：(DMSO d₆)1.8-2.1(m，2H)，2.1-2.35(m，2H)，3.0-3.35(m，4H)，4.05(s，3H)，4.8-5.0(m，1H)，7.4-7.55(m，2H)，7.55-7.75(m，2H)，8.45(s，1H)，8.82(s，1H)，9.22(bs，2H)，11.94(s，1H)；Mass spectrometry：(M+H)⁺403。

Example 27

(2R) -1- [4- ({4- [ 5-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Coupling of N- (5-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride and D-lactic acid using an analogous method to that described in example 22 gave the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(pent，1H)，4.8-5.0(m，2H)，7.25-7.45(m，3H)，7.7(dd，1H)，7.8(s，1H)，8.4(s，1H)，9.55(s，1H)； Mass spectrometry：(M+H)⁺475。

Example 28

(2S) -1- [4- ({4- [ 3-ethynylanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using a method analogous to that described in example 22, N- (3-ethynylphenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride was coupled with L- (+) -lactic acid to give the title product as a white powder; ¹ H NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.18(s，1H)，4.45(pent，1H)，4.8-5.0(m，2H)，7.2(d，1H)，7.33(s，1H)，7.39(dd，1H)，7.83(s，1H)，7.89(d，1H)，7.97(s，1H)，8.5(s，1H)，9.48(s，1H)； Mass spectrometry：(M+H)⁺447。

The starting material, N- (3-ethynylphenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, was prepared as follows:

using a similar procedure to that described in example 22 (preparation of starting Material) for the preparation of N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy) was reacted]Coupling piperidine-1-carboxylic acid tert-butyl ester with 3-ethynylaniline to obtain N- (3-ethynylphenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride.¹ H NMR spectrum：(DMSO d₆)1.85-2.1(m，2H)，2.1-2.3(m，2H)，3.0-3.35(m，4H)，4.05(s，3H)，4.25(s，1H)，4.8-4.95(m，1H)，7.39(d，1H)，7.47(dd，1H)，7.6(s，1H)，7.8(d，1H)，7.89(s，1H)，8.5(s，1H)，8.83(s，1H)，9.22(bs，2H)，11.68(s，1H)； Mass spectrometry：(M+H)⁺375。

Example 29

(2R) -1- [4- ({4- [ (3-ethynylanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using a method analogous to that described in example 28, coupling N- (3-ethynylphenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride with D-lactic acid to obtain the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.18(s，1H)，4.45(pent，1H)，4.8-5.0(m，2H)，7.2(d，1H)，7.33(s，1H)，7.39(dd，1H)，7.83(s，1H)，7.89(d，1H)，7.97(s，1H)，8.48(s，1H)，9.47(s，1H)； Mass spectrometry：(M+H)⁺447。

Example 30

(2S) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using a method analogous to that described in example 22, coupling N- (3-bromo-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride with L- (+) -lactic acid to obtain the title product as a white powder; ¹ H NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(pent，1H)，4.8-5.0(m，2H)，7.21(dd，1H)，7.32(s，1H)，7.48-7.65(m，2H)，7.8(s，1H)，8.37(s，1H)，9.6(s，1H)；Mass spectrometry：(M+H)⁺521。

The starting material, N- (3-bromo-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, was prepared as follows:

using a similar procedure to that described in example 22 (preparation of starting Material) for the preparation of N- (3-chloro-4-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, 4- [ (4-chloro-6-methoxyquinazolin-7-yl) oxy) was reacted]Coupling piperidine-1-carboxylic acid tert-butyl ester with (3-bromo-2-fluorophenyl) carbamic acid tert-butyl ester to obtain N- (3-bromo-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride;¹ h NMR spectrum：(DMSO d₆)1.85-2.1(m，2H)，2.1-2.32(m，2H)，3.0-3.35(m，4H)，4.02(s，3H)，4.83-5.0(m，1H)，7.3(dd，1H)，7.5-7.65(m，2H)，7.75(dd，1H)，8.45(s，1H)，8.8(s，1H)，9.15(bs，2H)，11.86(s，1H)； Mass spectrometry：(M+H)⁺447.12。

The starting tert-butyl (3-bromo-2-fluorophenyl) carbamate was prepared as follows. Triethylamine (0.6ml) was added to a stirred solution of 3-bromo-2-fluorobenzoic acid (438mg, 2mmol) in tert-butanol (10 ml). Diphenylphosphoryl azide (1ml, 4.6mmol) was then added and the reaction mixture was heated at reflux overnight.

The solution was evaporated to dryness and azeotroped with toluene. The residue was purified by flash chromatography on silica eluting with ethyl acetate/isohexane (10/90). The fractions containing the desired product were combined and evaporated to give tert-butyl (3-bromo-2-fluorophenyl) carbamate as a white solid (330 mg);¹ H NMR wave spectrum：(CDCl₃)1.5(s，9H)，6.4(s，1H)，7.1-7.25(m，1H)，7.7(dd，1H)。

Example 31

(2R) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Coupling of N- (3-bromo-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride and D-lactic acid using an analogous method to that described in example 22 gave the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.95(s，3H)，4.45(pent，1H)，4.8-5.0(m，2H)，7.22(dd，1H)，7.32(s，1H)，7.48-7.65(m，2H)，7.8(s，1H)，8.37(s，1H)，9.62(s，1H)；b Mass spectrometry：(M+H)⁺521。

Example 32

(2S) -1- [4- ({4- [ (4-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (a))

Using a method analogous to that described in example 22, coupling N- (4-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride with L- (+) -lactic acid to obtain the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.93(s，3H)，4.44(pent，1H)，4.8-5.0(m，2H)，7.25-7.4(m，2H)，7.45-7.65(m，2H)，7.8(s，1H)，8.33(s，1H)，9.5(s，1H)； Mass spectrometry：(M+H)⁺475; melting point 149 ℃.

The starting material, N- (4-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride, was prepared as follows:

4- [ (4-chloro-2-fluorophenyl) amino group]-6-Methoxyquinazolin-7-ol (5g, 15.65mmol, prepared as described in WO 2001/077085) was dissolved in DMA (200 ml). Tert-butyl (4-methanesulfonyloxy) piperidine-1-carboxylate (6.55g, 23.5mmol) and cesium fluoride (7.09g, 46.95mmol) were added and the mixture was heated to 60 ℃ with stirring. The solvent was evaporated and the residue partitioned between water (200ml) and EtOAc (200 ml). The organics were washed with water (2X 100ml) and brine (100ml), MgSO ₄Drying and evaporating to obtain 4- ({4- [ 4-chloro-2-fluoroaniline base]-tert-butyl 6-methoxyquinazolin-7-yl } oxy) piperidine-1-carboxylate (7.23g, 91.9%);¹ h NMR spectrum:(DMSO-d₆)：1.4(d，9H)，1.5-1.7(m，2H)，1.8-2.1(m，2H)，3.1-3.3(m，2H)，3.65-3.85(m，2H)，3.91(s，3H)，4.75-4.9(m，1H)，7.3(s，1H)，7.32(dd，1H)，7.54(dd，1H)，7.57(dd，1H)，7.80(s，1H)，8.32(s，1H)，9.5(s，1H)； mass spectrometry：(M+H)⁺503。

A stirred solution of 4M hydrogen chloride in dioxane (100ml) was added 4- ({4- [ 4-chloro-2-fluoroanilino)]-6-Methoxyquinazolin-7-yl } oxy) piperidine-1-carboxylic acid tert-butyl ester (7.23g, 14.4mmol) in acetonitrile (100 ml). The reaction mixture was heated at 70 ℃ for 1 hour and then concentrated to  volumes. The resulting precipitate was collected by filtration, washed with acetonitrile and dried in vacuo to afford N- (4-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride as a white solid (4.42g, 76.3%);¹ h NMR spectrum:(DMSO-d₆)：1.90-2.10(m，2H)，2.10-2.32(m，2H)，3.00-3.35(m，4H)，4.02(s，3H)，4.90(m，1H)，7.36-7.50(m，1H)，7.50-7.70(m，3H)，8.48(s，1H)，8.80(s，1H)，9.30(bs，2H)，11.90(bs，1H)； mass spectrometry：(M+H)⁺403。

Example 33

(2R) -1- [4- ({4- [ 4-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method) a))

Coupling of N- (4-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride and D-lactic acid using an analogous method to that described in example 22 gave the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.2(d，3H)，1.45-1.8(m，2H)，1.9-2.15(m，2H)，3.1-3.55(m，2H+H₂O)，3.7-4.1(m，2H)，3.93(s，3H)，4.43(pent，1H)，4.80-4.98(m，2H)，7.25-7.4(m，2H)，7.45-7.65(m，2H)，7.8(s，1H)，8.35(s，1H)，9.5(s，1H)； Mass spectrometry：(M+H)⁺475; melting Point 118 ℃.

Example 34

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (1-methyl-L-prolyl) piperidin-4-yl ] oxy } quinazolin-4-amine

(method (a))

Coupling of N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine hydrochloride and N-methyl-L-proline using an analogous method to that described in example 2 gave the title product as a white powder;¹ h NMR spectrum：(DMSO d₆)1.4-1.9(m，5H)，1.9-2.20(m，7H)，2.9-3.05(m，1H)，3.05-3.25(m，2H)，3.25-3.65(m，1H+H₂O)，3.75-4.2(m，2H)，3.95(s，3H)，4.75-5.0(m，1H)，7.2-7.4(m，2H)，7.4-7.6(m，2H)，7.8(s，1H)，8.37(s，1H)，9.65(s，1H)； Mass spectrometry：(M+H)⁺514; melting point 193 ℃.

Example 35

(2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol

(method (b))

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine (500mg, 1.05mmol) and 4-dimethylaminopyridine (128mg, 1.05mmol) were stirred in acetonitrile (2.5ml) and diisopropylethylamine (0.366ml, 2.10mmol) was added. The mixture was cooled to 0 ℃ and a solution of (S) - (-) -2-acetyloxypropionyl chloride (0.166ml, 1.31mmol) in acetonitrile (0.5ml) was added dropwise. The reaction mixture was then stirred at this temperature for 0.5 h. Water (1.0ml) and potassium hydroxide (0.641ml of 49% w/w aqueous solution) were added and the mixture was stirred at room temperature overnight. The layers were separated and the organic layer was diluted with ethyl acetate (2.5 ml). Water and glacial acetic acid (0.210ml) were added. The mixture was stirred and the layers were separated. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title product (215mg, 43%) as a white solid; ¹ H NMR spectrum:(DMSOd₆)1.19(d，3H)，1.48-1.75(m，2H)，1.94-2.13(m，2H)，3.21-3.53(m，2H)，3.93(s，3H)，3.78-4.06(m，2H)，4.40-4.52(m，1H)，4.83-4.99(m，2H)，7.28(dd，1H)，7.33(s，1H)，7.42-7.55(m，2H)，7.81(s，1H)，8.36(s，1H)，9.62(s，1H)； mass spectrum:(M+H)⁺475。

example 36

N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (3-methoxypropionyl) piperidin-4-yl ] oxy } quinazolin-4-amine

(method (b))

Using a method analogous to that described in example 35, N- (3-chloro-2-fluorophenyl) -6-methoxy-7- (piperidin-4-yloxy) quinazolin-4-amine and 3-methylCoupling with oxypropionyl chloride, but after addition of water and potassium hydroxide at the end of the coupling reaction, the layers were separated directly and the product was extracted and isolated as described in example 35 to give the title product;¹ h NMR spectrum:(DMSOd₆)1.59(m，1H)；1.69(m，1H)；2.04(m，2H)；2.61(t，2H)；3.21(s，3H)；3.26(m，1H)；3.41(m，1H)；3.57(t，2H)；3.77(m，1H)；3.95(m，4H)；4.90(m，1H)；7.29(m，1H)；7.35(s，1H)；7.48(m，1H)；7.53(m，1H)；7.83(s，1H)；8.39(s，1H)；9.63(s，1H)。 mass spectrum:(M+H)⁺489。

example 37

Pharmaceutical composition

The following illustrates a representative pharmaceutical dosage form of the invention as defined herein (the active ingredient being referred to as "compound X") which may be prepared for therapeutic or prophylactic use in humans:

(a) tablet I mg/tablet

A

A

.

.

.

(b) Injection I (50mg/ml)

A

.

0.1M hydrochloric acid (pH adjusted to 7.6)

A

The water for injection is 100 percent

The above-mentioned composition can be prepared by a conventional method well known in the pharmaceutical field. For example, tablet I can be prepared by mixing the ingredients and compressing the mixture into a tablet.

Claims (35)

1. A quinazoline derivative of the formula I:

wherein:

R¹selected from hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, or selected from the group of formula Q²-X³-a group of (a) or (b),

wherein X³Is a direct bond or O, Q²Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, S, SO₂、N(R³)、CO、CH(OR³)、CON(R³)、N(R³)CO、SO₂N(R³)、N(R³)SO₂CH ═ CH and C ≡ C where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂Either with a substituent selected from: halogen, carboxyl, carbamoyl, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, or selected from the formula Q³-X⁴-a group of (a) or (b),

wherein X⁴Is a direct bond or is selected from CO and N (R)⁴) CO, wherein R⁴Is hydrogen or (1-6C) alkyl, Q³Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

Wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thio, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkanesA radical- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino, or selected from the formula-X⁵-Q⁴The group of (a):

wherein X⁵Is a direct bond or is selected from O, S, SO₂、N(R⁵)、CO、CH(OR⁵)、CON(R⁵)、N(R⁵)CO、SO₂N(R⁵)、N(R⁵)SO₂、C(R⁵)₂O、C(R⁵)₂S and C (R)⁵)₂N(R⁵) Wherein R is⁵Is hydrogen or (1-6C) alkyl, Q⁴Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-6C) alkyl, (3-7C) cycloalkenyl- (1-6C) alkyl, heterocyclyl or heterocyclyl- (1-6C) alkyl,

wherein R is¹Any of the above substituents optionally bears one or more substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]A carbamoyl group,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino, or selected from the formula-X⁶-R⁶The group of (a) or (b),

wherein X⁶Is a direct bond or is selected from O, N (R)⁷) And C (O), wherein R⁷Is hydrogen or (1-6C) alkyl, R⁶Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, carboxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl, (1-6C) alkoxycarbonylamino- (1-6C) alkyl, carbamoyl- (1-6C) alkyl,N- (1-6C) alkylcarbamoyl- (1-6C) alkyl,N， NDi- [ (1-6C) alkyl]Carbamoyl- (1-6C) alkyl, (2-6C) alkanoyl- (1-6C) alkyl or (1-6C) alkoxycarbonyl- (1-6C) alkyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bearing 1 or 2 oxo or thioxo substituents;

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

each R²Which may be the same or different, is selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxycarbonyl,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl,N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula-X⁷-R⁸The group of (a) or (b),

wherein X⁷Is a direct bond or is selected from O and N (R)⁹) Wherein R is⁹Is hydrogen or (1-6C) alkyl, R⁸Is halogen- (1-6C) alkyl, hydroxy-(1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl, di- [ (1-6C) alkyl]Amino- (1-6C) alkyl, (2-6C) alkanoylamino- (1-6C) alkyl or (1-6C) alkoxycarbonylamino- (1-6C) alkyl;

Q¹Is piperidinyl;

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

each W, which may be the same or different, is selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X⁸-R¹⁰The group of (a): wherein X⁸Is a direct bond or is selected from O, CO, SO₂And N (R)¹¹) Wherein R is¹¹Is hydrogen or (1-6C) alkyl, R¹⁰Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl,N- (1-6C) alkylamino- (1-6C) alkyl orN， NDi- [ (1-6C) alkyl]Amino- (1-6C) alkyl;

X¹selected from CO and SO₂；

X²Is a group of the formula:

-(CR¹²R¹³)_p-(Q⁵)_m-(CR¹⁴R¹⁵)_q-

wherein m is 0 or 1, p is 0, 1, 2, 3 or 4, q is 0, 1, 2, 3 or 4,

each R¹²、R¹³、R¹⁴And R¹⁵May be the same or different and is selected from the group consisting of hydrogen, (1-6C) alkyl, amino, (1-6C) alkylamino and di- [ (1-6C) alkyl]Amino group, Q⁵Selected from (3-7C) cycloalkylene and (3-7C) cycloalkenylene,

wherein X²Any CH in the radical₂Or CH₃Radicals at each of said CH₂Or CH₃Optionally with one or more halogens or (1-6C) alkyl substituents A substituent, or a substituent selected from the group consisting of hydroxy, cyano, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]A substituent of an amino group;

z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a) or (b),

wherein X⁹Is a direct bond or is selected from O, N (R)¹⁶)、SO₂And SO₂N(R¹⁶) Wherein R is¹⁶Is hydrogen or (1-6C) alkyl, Q⁶Is (3-7C) cycloalkyl, (3-7C) cycloalkyl- (1-4C) alkyl, (3-7C) cycloalkenyl- (1-4C) alkyl, heterocyclyl, or heterocyclyl- (1-4C) alkyl;

with the proviso that when X⁹When it is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

and with the proviso that when m, p and q are all 0, Z is a heterocyclic group,

wherein adjacent carbon atoms in any (2-6C) alkylene chain in the Z substituent are optionally separated by an intervening chain selected from: o, S, SO₂、N(R¹⁷) CO, -C ═ C-and-C ≡ C-, where R is¹⁷Is hydrogen or (1-6C) alkyl,

wherein any CH in any Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl ]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoylamino,N- (1-6C) alkyl- (2-6C) alkanoylamino,N- (1-6C) alkylsulfamoyl, N， NDi- [ (1-6C) alkyl]Sulfamoyl, (1-6C) alkylsulfonylamino andN- (1-6C) alkyl- (1-6C) alkylsulfonylamino,

wherein any heterocyclyl group in the Z substituents optionally bears one or more substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, (1-6C) alkoxy, (1-6C) alkylthio, (1-6C) alkylsulfinyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (2-6C) alkanoyl, (2-6C) alkanoyloxy and of the formula-X¹⁰-R¹⁸The group of (a):

wherein X¹⁰Is a direct bond or is selected from O, CO, SO₂And N (R)¹⁹) Wherein R is¹⁹Is hydrogen or (1-4C) alkyl, R¹⁸Is halogen- (1-4C) alkyl, hydroxy- (1-4C) alkyl, (1-4C) alkoxy- (1-4C) alkyl, cyano- (1-4C) alkyl, amino- (1-4C) alkyl,N- (1-4C) alkylamino- (1-4C) alkyl andN， Ndi- [ (1-4C) alkyl]Amino- (1-4C) alkyl;

The conditions are as follows:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R is¹When it is hydrogen or (1-3C) alkoxy, a is 0, and Z is selected from the group consisting of hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino, (1-6C) alkoxy, (1-6C) alkylsulfonyl, (1-6C) alkylsulfonylamino,N- (1-6C) alkyl- (1-6C) alkylsulfonylamino and of formula Q⁶-X⁹-a group of (a).

2. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to claim 1, wherein:

R¹selected from hydrogen, hydroxy, (1-6C) alkoxy, (2-6C) alkenyloxy, (2-6C) alkynyloxy or of formula Q²-X³-a group of (a) or (b),

wherein X³Is a direct bond or O, Q²Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

wherein R is¹Adjacent carbon atoms in any (2-6C) alkylene chain in a substituent are optionally separated by an intervening chain selected from: o, N (R)³)、CON(R³)、N(R³) CO, CH ═ CH and C ≡ C, where R is³Is hydrogen or (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂The ≡ CH-or HC ≡ C-group is optionally at the terminal CH₂Either with a substituent selected from: a carbamoyl group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl ]Amino- (1-6C) alkyl,

wherein R is¹Any CH in the substituents₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-6C) alkyl substituents on the group, or substituents selected from: hydroxy, amino, cyano, carbamoyl, (1-6C) alkoxy, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl andN， Ndi- [ (1-6C) alkyl]Carbamoyl or of formula-X⁵-Q⁴The group of (a) or (b),

wherein X⁵Is a direct bond or is selected from O, N (R)⁵)、CON(R⁵)、N(R⁵) CO and C (R)⁵)₂O，

Wherein R is⁵Is hydrogen or (1-6C) alkyl, Q⁴Is a heterocyclic group or a heterocyclic- (1-6C) alkyl group,

wherein R is¹Any of the above substituents optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl, (1-6C) alkylsulfonyl, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group,N- (1-6C) alkylcarbamoyl,N， NDi- [ (1-6C) alkyl]Carbamoyl, (2-6C) alkanoyl, or selected from the group consisting of formula-X⁶-R⁶In which X is⁶Is a direct bond or is selected from O and N (R)⁷) Wherein R is⁷Is hydrogen or (1-6C) alkyl, R ⁶Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl, (1-6C) alkoxy- (1-6C) alkyl, cyano- (1-6C) alkyl, amino- (1-6C) alkyl, (1-6C) alkylamino- (1-6C) alkyl and di- [ (1-6C) alkyl]Amino- (1-6C) alkyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bears 1 or 2 oxo substituents.

3. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to claim 1, wherein:

R¹selected from hydrogen, hydroxy, (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a):

wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents optionally bearing 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl]Amino and (2-4C) alkanoyl,

wherein R is¹Any heterocyclyl group in the above substituents optionally bears 1 oxo substituent.

4. A quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or a pharmaceutically-acceptable ester thereof, according to claim 1, wherein R ¹Is (1-3C) alkoxy.

5. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

b is 1, 2 or 3;

each R²Which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C) alkyl, (2-4C) alkenyl and (2-4C) alkynyl.

6. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

b is 1, 2 or 3, one R²In formula 1, the meta position (3-) on the anilino group is halogen.

7. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 4, wherein the anilino group at the 4-position on the quinazoline ring in the compound of the formula I is selected from the group consisting of 3-chloro-2-bromoanilino, 3-chloro-2-fluoroanilino, 3-ethynylanilino and 3-bromoanilino.

8. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

X²is of the formula- (CR)¹²R¹³)_q-(CR^12aaR^13aa) A group of (a) wherein

q is 1, 2 or 3,

each R¹²、R¹³And R^13aaWhich may be the same or different, are selected from hydrogen and (1-6C) alkyl,

R^12aaselected from amino, (1-6C) alkylamino and di- [ (1-6C) alkyl]An amino group, a carboxyl group,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH ₂Or CH₃The radicals bearing one or more halogen substituents,

wherein X²Any CH in which 2 carbon atoms are attached to the substituent₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃With radicals selected from hydroxy, amino, (1-6C) alkoxy, (1-6C) alkylamino and di- [ (1-6C) alkyl]Taking amino groupsAnd (4) generation of base.

9. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7, wherein:

X²is of the formula- (CR)¹²R¹³)_qA group of (a) wherein

q is 1, 2, 3 or 4,

each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen and (1-6C) alkyl, with the proviso that X²At least one R¹²Or R¹³The group is (1-6C) alkyl,

wherein X²Any CH in the radical₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The radicals bearing one or more halogen substituents,

wherein X²Any CH in which 2 carbon atoms are attached to the substituent₂Radical or any CH bound to a carbon atom₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-6C) alkoxy.

10. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7, wherein:

X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12a) -a group of (a) or (b),

wherein each R ^12aWhich may be the same or different, is a (1-4C) alkyl group.

11. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

z is selected from hydroxy, amino, (1-6C) alkylamino, di- [ (1-6C) alkyl]Amino group, (1-6C) Alkoxy, hydroxy- (2-6C) alkoxy, (1-4C) alkoxy- (2-6C) alkoxy and of the formula Q⁶-X⁹-a group of (a):

wherein X⁹Is a direct bond, Q⁶Is a heterocyclic group, and is a heterocyclic group,

with the proviso that when m, p and q are all 0, Z is through a ring carbon atom with X¹The attached heterocyclic group(s),

wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, and homopiperazinyl,

wherein any CH in the Z group₂Or CH₃Group, removing CH in cyclic ring₂Outside the radicals, optionally in each of said CH₂Or CH₃With one or more halogen or (1-4C) alkyl substituents, or substituents selected from hydroxy and (1-4C) alkoxy,

wherein any heterocyclyl group in the Z substituents optionally bears one or more substituents, which may be the same or different, selected from halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylsulfonyl, (1-4C) alkylamino, di- [ (1-4C) alkyl ] amino and (2-4C) alkanoyl.

12. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

z is hydroxy or (1-4C) alkoxy;

the sum of m + p + q is at least 1.

13. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7, wherein:

X²is selected from the formula-CH₂-、-CH₂CH₂-、-(CHR^12a)-、-(CHR^12aCH₂)-、-(C(R^12a)₂CH₂)-、-(CH₂C(R^12a)₂) -and- (CH)₂CHR^12a) -a group of (a) or (b),

wherein each R^12aMay be the same or different and is a (1-4C) alkyl group;

z is hydroxy or (1-4C) alkoxy.

14. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein:

Q¹is piperidin-4-yl;

a is 0 or 1;

w is selected from the group consisting of halogen, hydroxy, (1-3C) alkyl and (1-3C) alkoxy.

15. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, wherein X¹Is CO.

16. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to claim 1, wherein:

R¹selected from the group consisting of hydrogen, (1-6C) alkoxy, cyclopropyl- (1-4C) alkoxy, cyclobutyl- (1-4C) alkoxy, cyclopentyl- (1-4C) alkoxy, cyclohexyl- (1-6C) alkoxy, tetrahydrofuranyl- (1-4C) alkoxy and tetrahydropyranyl- (1-4C) alkoxy,

Wherein R is¹Any CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen substituents, or substituents selected from hydroxy and (1-4C) alkoxy;

b is 1, 2 or 3;

each R²May be the same or different and is selected from the group consisting of halogen, cyano, hydroxy, trifluoromethyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl and (1-4C) alkoxy;

Q¹is piperidin-4-yl;

a is 0, 1 or 2;

each W, which may be the same or different, is selected from halogen, trifluoromethyl, hydroxy,Oxo, (1-6C) alkyl, (1-6C) alkoxy and of formula-X⁸-R¹⁰The group of (a):

wherein X⁸Is a direct bond or O, R¹⁰Is halogen- (1-6C) alkyl, hydroxy- (1-6C) alkyl or (1-6C) alkoxy- (1-6C) alkyl;

X¹is CO;

X²is selected from (3-6C) cycloalkylene, -CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-(CR¹²R¹³)-、-(CR¹²R¹³CH₂) -and- (CH)₂CR¹²R¹³) -a group of (a) or (b),

wherein each R¹²And R¹³May be the same or different and is selected from the group consisting of hydrogen, (1-4C) alkyl, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl, provided that R¹²And R¹³Not all of them are hydrogen,

wherein X²Any CH in (3-6C) cycloalkylene group in (1)₂Radicals being optionally in each of said CH₂Or a group bearing one or more (1-4C) alkyl substituents, or substituents selected from hydroxy, (1-4C) alkoxy, hydroxy- (1-4C) alkyl and (1-3C) alkoxy- (1-4C) alkyl;

Z is selected from hydroxy and (1-4C) alkoxy;

with the following conditions:

when the 4-anilino group in formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R¹Is hydrogen or (1-3C) alkoxy, X¹In the case of CO, a is 0.

17. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to claim 1, wherein:

the 4-anilino group on the quinazoline ring in formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino;

R¹selected from (1-4C) alkoxy, hydroxy- (2-4C) alkoxy, (1-3C) alkoxy- (2-4C) alkoxy or of formula Q²-X³-a group of (a):

wherein X³Is O, Q²Is azetidin-1-yl- (2-4C) alkyl, pyrrolidin-1-yl- (2-4C) alkyl, piperidino- (2-4C) alkyl, piperazino- (2-4C) alkyl or morpholino- (2-4C) alkyl,

wherein R is¹Any of the above substituents of the heterocyclyl group optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogen, hydroxy, amino, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [ (1-4C) alkyl]An amino group;

z is hydroxy or (1-4C) alkoxy;

Q¹is piperidin-4-yl;

a is 0 or 1;

each W, which may be the same or different, is selected from hydroxy, (1-3C) alkyl and (1-3C) alkoxy;

X¹Is CO;

X²selected from the group consisting of formula- (CHR)^12a) -and- (CH)₂CHR^12b) -a group of (a) or (b),

wherein R is^12aIs (1-4C) alkyl,

wherein R is^12bSelected from amino, (1-4C) alkylamino and di- [ (1-4C) alkyl]-an amino group.

18. A quinazoline derivative of the formula I, according to claim 1, having the formula Id or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof:

wherein:

R^1bis (1-4C) alkoxy,

wherein R is^1bAny CH in the substituents₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃With one or more halogen substituents on the radical, or R¹In which any CH not bound to an oxygen atom₂Or CH₃Radicals being optionally in each of said CH₂Or CH₃The group carries a substituent selected from the group consisting of hydroxy and (1-3C) alkoxy;

X^2bis selected from the formula-CH₂-、-CH₂CH₂-、-(CHR¹²)-、-(CHR¹²CH₂) -and- (CH)₂CHR¹²) -a group of (a) or (b),

wherein R is¹²Selected from (1-3C) alkyl, hydroxy- (1-3C) alkyl and (1-3C) alkoxy- (1-3C) alkyl;

Z²selected from the group consisting of hydroxy, (1-3C) alkoxy, hydroxy- (2-3C) alkoxy, (1-3C) alkoxy- (2-3C) alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1, 3-dioxolanyl, tetrahydropyranyl and 1, 4-dioxanyl;

wherein Z²-X^2bAny of the heterocyclyl groups in (a) optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C) alkyl, (1-3C) alkoxy and (2-3C) alkanoyl.

19. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, wherein Z²Is hydroxy, R¹²Is (1-3C) alkyl.

20. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, wherein:

R^1bis (1-3C) alkoxy;

group Z²-X^2b-is selected from the group consisting of hydroxymethyl, methoxymethyl, (S) -1-hydroxyethyl, (R) -1-hydroxyethyl, (S) -1-methoxyethyl and (R) -1-methoxyethyl.

21. A quinazoline derivative of the formula I according to claim 1, selected from:

1) n- (3-chloro-2-fluorophenyl) -7- ({1- [ (dimethylamino) acetyl ] piperidin-4-yl } oxy) -6-methoxyquinazolin-4-amine;

2) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2-methoxyethoxy) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

3) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (methoxyacetyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

4)2- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-oxoethanol;

5) n- (3-chloro-2-fluorophenyl) -7- { [1- (ethoxyacetyl) piperidin-4-yl ] oxy } -6-methoxyquinazolin-4-amine;

6) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (3-methoxypropionyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

7)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-oxopropan-1-ol;

8) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

9) (2S, 3S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3-methyl-1-oxopentan-2-ol;

10)4- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-methyl-4-oxobutan-2-ol;

11) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (tetrahydrofuran-2-ylcarbonyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

12)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2, 2-dimethyl-3-oxopropan-1-ol;

13) (3R, 5S) -1-acetyl-5- { [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] carbonyl } pyrrolidin-3-ol;

14) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (4-methylpiperazin-1-yl) acetyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

or a pharmaceutically acceptable salt or ester thereof.

22. A quinazoline derivative of the formula I, which compound is selected from:

1) N- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (methoxyacetyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

2)2- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2-oxoethanol;

3) n- (3-chloro-2-fluorophenyl) -7- { [1- (ethoxyacetyl) piperidin-4-yl ] oxy } -6-methoxyquinazolin-4-amine;

4) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

5)3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2, 2-dimethyl-3-oxopropan-1-ol;

6) (2S) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-ol;

7) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- { [1- (1-methyl-L-prolyl) piperidin-4-yl ] oxy } quinazolin-4-amine;

8) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -tetrahydrofuran-2-ylcarbonyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

9) (2R) -1- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

10) n- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2S) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

11) N- (3-chloro-2-fluorophenyl) -6-methoxy-7- ({1- [ (2R) -2-methoxypropionyl ] piperidin-4-yl } oxy) quinazolin-4-amine;

12) (2R) -3- [4- ({4- [ 3-chloro-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -2- (dimethylamino) -3-oxopropan-1-ol;

13) (2S) -1- [4- ({4- [ (3-chloro-4-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

14) (2S) -1- [4- ({4- [ 3-bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

15) (2S) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

16) (2R) -1- [4- ({4- [ 3-bromo-2-fluoroanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

17) (2R) -1- [4- ({4- [ 3-bromoanilino ] -6-methoxyquinazolin-7-yl } oxy) piperidin-1-yl ] -1-oxopropan-2-ol;

or a pharmaceutically acceptable salt or ester thereof.

23. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt thereof, according to any one of the preceding claims.

24. A pharmaceutical composition which comprises a quinazoline derivative of the formula I, or a pharmaceutically-acceptable salt or ester thereof, according to any one of the preceding claims in association with a pharmaceutically-acceptable diluent or carrier.

25. A quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 23 for use as a medicament.

26. The use of a quinazoline derivative of the formula I, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

27. Use of a quinazoline derivative of the formula I, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the prevention or treatment of tumours which are sensitive to inhibition by EGFR tyrosine kinase which is involved in signal transduction steps which lead to tumour cell proliferation.

28. The use of a quinazoline derivative of the formula I, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as man.

29. The use of a quinazoline derivative of the formula I, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man.

30. A method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 23.

31. A method for the prevention or treatment of tumours which are sensitive to inhibition of EGFR tyrosine kinase which are involved in signal transduction steps which lead to the proliferation and/or survival of tumour cells, in a warm-blooded animal such as man, which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 23.

32. A method for providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 23.

33. A method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the formula I, or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 23.

34. A process for the preparation of a quinazoline derivative of the formula I as defined in claim 1 which comprises:

method (a):

to prepare wherein X¹Coupling a quinazoline of the formula II, or a salt thereof, with an acid of the formula III, or a reactive derivative thereof:

r in formula II, except for protecting any functional groups if desired¹、R²W, a, b and Q¹As defined in claim 1, wherein the first and second groups are,

Z-X²-COOH

III

z and X in formula III, except for protecting any functional groups if desired²As defined in claim 1;

or

Process (b) reacting a quinazoline of the formula II, or a salt thereof, as defined in process (a) with a compound of the formula IV:

Z-X²-X¹-L¹

IV

l in formula IV except for any functional groups which may be protected if desired¹As a replaceable group, Z, X¹And X²As defined in claim 1;

or

The process (c) is a process in which Z is bonded to X via nitrogen²Reacting a compound of formula V with a compound of formula ZH, linked to a quinazoline derivative of formula I:

V

l in formula V, except for protecting any functional groups if desired²Being a replaceable group, R¹、R²、W、X¹、X²A, b and Q¹As defined in claim 1; the compounds of formula ZH wherein Z is as defined above, except that any functional group is protected if desired; or

Method (d)

For the preparation of quinazoline derivatives bearing a mono (1-6C) alkylamino or di (1-6C) alkylamino group, the corresponding quinazoline derivatives of the formula I containing an N-H group are reductively aminated using formaldehyde or (2-6C) alkanals; or

Method (e)

To prepare wherein R¹A quinazoline derivative of the formula I wherein R is a hydroxy group, cleaving¹Quinazoline derivatives of the formula I which are (1-6C) alkoxy; or

Method (f)

To prepare wherein R¹A quinazoline derivative of the formula I linked to the quinazoline ring via an oxygen atom, reacting a compound of the formula VI with a compound of the formula R^1’Coupling of OH compound:

r in formula VI, except that any functional groups are protected if desired²、W、X¹、X²Z, a, b are as defined in claim 1; formula R, except that any functional groups are protected if desired^1’Radical R in OH^1’O is the pair of R in claim 1¹One of the groups defined as attached to oxygen;

thereafter, if desired (in any order):

(i) converting a quinazoline derivative of the formula I to another quinazoline derivative of the formula I;

(ii) removing any protecting groups present by conventional means;

(iii) to form a pharmaceutically acceptable salt or a pharmaceutically acceptable ester of the quinazoline derivative of the formula I.

35. A quinazoline derivative of the formula II:

30

wherein:

R¹、W、Q¹and a is as defined in claim 1;

R^2cand R^2dWhich may be the same or different, is halogen.