ZA200602188B - Quinazoline derivatives - Google Patents

Description

QUINAZOLINE DERIVATIVES

The invention concerns certain novel quinazoline derivatives, or pharmaceutically acceptable salts, or pharmaceutically acceptable esters thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also concerns processes for the manufacture of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man.

Many of the current treatment regimes for diseases resulting from the abnormal regulation of cellular proliferation such as psoriasis and cancer, utilise compounds that inhibit

DNA synthesis and cellular proliferation. To date, compounds used in such treatments are generally toxic to cells however their enhanced effects on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to these cytotoxic anti-tumour agents are currently being developed, for example selective inhibitors of cell signalling pathways.

These types of inhibitors are likely to have the potential to display an enhanced selectivity of action against tumour cells and so are likely to reduce the probability of the therapy possessing unwanted side effects.

Eukaryotic cells are continually responding to many diverse extracellular signals that enable communication between cells within an organism. These signals regulate a wide variety of physical responses in the cell including proliferation, differentiation, apoptosis and motility. The extracellular signals take the form of a diverse variety of soluble factors including growth factors as well as paracrine and endocrine factors. By binding to specific transmembrane receptors, these ligands integrate the extracellular signal to the intracellular signalling pathways, therefore transducing the signal across the plasma membrane and allowing the individual cell to respond to its extracellular signals. Many of these signal transduction processes utilise the reversible process of the phosphorylation of proteins that are involved in the promotion of these diverse cellular responses. The phosphorylation status of target proteins is regulated by specific kinases and phosphatases that are responsible for the regulation of about one third of all proteins encoded by the mammalian genome. As phosphorylation is such an important regulatory mechanism in the signal transduction process, it is therefore not surprising that aberrations in these intracellular pathways result in abnormal cell growth and differentiation and so promote cellular transformation (reviewed in

Cohen et al, Curr Opin Chem Biol, 1999, 3, 459-465).

Tt has been widely shown that a number of these tyrosine kinases are mutated to constitutively active forms and/or when over-expressed result in the transformation ofa variety of human cells. These mutated and over-expressed forms of the kinase are present ina large proportion of human tumours (reviewed in Kolibaba et al, Biochimica et Biophysica

S Acta, 1997, 133, F217-F248). As tyrosine kinases play fundamental roles in the proliferation and differentiation of a variety of tissues, much focus has centred on these enzymes in the development of novel anti-cancer therapies. This family of enzymes is divided into two groups - receptor and non-receptor tyrosine kinases e.g. EGF Receptors and the SRC family respectively. From the results of a large number of studies including the Human Genome

Project, about 90 tyrosine kinase have been identified in the human genome, of this 58 are of the receptor type and 32 are of the non-receptor type. These can be compartmentalised in to 20 receptor tyrosine kinase and 10 non-receptor tyrosine kinase sub-families (Robinson ef al,

Oncogene, 2000, 19, 5548-5557).

The receptor tyrosine kinases are of particular importance in the transmission of mitogenic signals that initiate cellular replication. These large glycoproteins, which span the plasma membrane of the cell possess an extracellular binding domain for their specific ligands (such as Epidermal Growth Factor (EGF) for the EGF Receptor). Binding of ligand results in the activation of the receptor’s kinase enzymatic activity that is encoded by the intracellular portion of the receptor. This activity phosphorylates key tyrosine amino acids in target proteins, resulting in the transduction of proliferative signals across the plasma membrane of thecell.

It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and etbB4, are frequently involved in driving the proliferation and survival of tumour cells (reviewed in Olayioye et al, EMBO J., 2000, 19, 3159). One mechanism in which this can be accomplished is by overexpression of the receptor at the protein level, generally as a result of gene amplification. This has been observed in many common human cancers (reviewed in Klapper et al., Adv. Cancer Res, 2000, 77, 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 38, 458; Guerin et al., Oncogene Res., 1988, 3,21;

Slamon et al., Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol, 1995, 19, 183), non-small cell lung cancers (NSCLC) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 33, 2379;

Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as other cancers of the lung

(Hendler et al., Cancer Cells, 1989, 7, 347; Ohsaki et a]., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow etal, Clin. Cancer Res., 2001, 7, 1957, Zhau et al., Mo] Carcinog, 3, 254), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res.,

S 1987, 1, 149; Kapitanovic et al., Gastroenterology, 2000, 112, 1103; Ross et al., Cancer

Invest., 2001, 19, 554), cancer of the prostate (Visakorpi et al., Histochem. 1., 1992, 24, 481;

Kumar et al., 2000, 32, 73; Scher et al., J. Natl, Cancer Inst., 2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035, Martin-Subero gt al., Cancer Genet Cytogenet., 2001, 127, 174), ovarian (Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga ef al., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al., Neoplasma, 2001, 48, 188). As more human tumour tissues are tested for expression of the erbB family of receptor tyrosine kinases it is expected that their widespread prevalence and importance will be further enhanced in the future.

As a consequence of the mis-regulation of one or more of these receptors, it is widely believed that many tumours become clinically more aggressive and 80 correlate with a poorer prognosis for the patient (Brabender et al, Clin. Cancer Res., 2001, 7, 1850; Ross gt al, Cancer

Investigation, 2001, 19, 554, Yu et al., Bioessays, 2000, 22.7, 673). In addition to these clinical findings, a wealth of preclinical information suggests that the erbB family of receptor tyrosine kinases are involved in cellular transformation. This includes the observations that many tumour cell lines overexpress one or more of the erbB receptors and that EGFR or erbB2 when transfected into non-tumour cells have the ability to transform these cells. This tumourigenic potential has been further verified as transgenic mice that overexpress erbB2 spontaneously develop tumours in the mammary gland. In addition to this, a number of pre-clinical studies have demonstrated that anti-proliferative effects can be induced by knocking out one or more erbB activities by small molecule inhibitors, dominant negatives or inhibitory antibodies (reviewed in Mendelsohn et al., Oncogene, 2000, 19, 6550). Thus it has been recognised that inhibitors of these receptor tyrosine kinases should be of value as a selective inhibitor of the proliferation of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933, Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi ez al, 2000, Oncogene, 19, 5690-5701; 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 use in the treatment of advanced non-small cell lung cancer. Furthermore, findings using inhibitory antibodies against EGFR and ertbB2

(c-225 and trastuzumab respectively) have proven to be beneficial in the clinic for the treatment of selected solid tumours (reviewed in Mendelsohn et al, 2000, Oncogene, 19, 6550-6565).

Amplification and/or activity of members of the erbB receptor tyrosine kinases have been detected and so have been implicated to play a role in a number of non-malignant proliferative disorders such as psoriasis (Ben-Bassat, Curr. Phan. Des., 2000, 6, 933; Elder et al., Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar et al., Int. Urol.

Nephrol. 2000, 32,73), atherosclerosis and restenosis (Bokemeyer et al., Kidney Int., 2000, 58, 549). 1t is therefore expected that inhibitors of erbB receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders of excessive cellular proliferation.

European patent application EP 566 226 discloses certain 4-anilinoquinazolines that are receptor tyrosine kinase inhibitors.

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

European patent application EP 837 063 discloses aryl substituted 4-aminoquinazoline derivatives carrying moiety containing an aryl or heteroaryl group at the 6-or 7- position on the quinazoline ring. The compounds are stated to be useful far treating hyperproliferative disorders.

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

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

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

WO01/21596 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 stated to have an inhibitory effect upon signal transduction mediated by tyrosine kinases.

7- position by a substituted pyrrolidinyl-alkoxy or piperidinyl-alkoxy group.

We have now found that surprisingly certain quinazoline derivatives substituted at the 7-position with a substituent containing certain optionally substituted alkanoyl or sulfonyl groups possess potent anti-tumour activity. The compounds of the present invention also possess good cellular potency, and favourable physical properties, particularly solubility, which may provide advantages in the formulation and delivery of the compound to patients.

Some of the compounds of the invention posses favourable DMPK properties, for example high bioavailability and/or high free-plasma levels and/or advantageous half life and/or advantageous volume of distribution and such properties are expected to provide improved in- vivo efficacy and may reduce inter-patient variability in exposure to the compound compared to other EGFR tyrosine kinase inhibitors such as gefitinib.

Furthermore, many of the compounds according to the present invention are inactive or only weakly active in 8 hERG assay.

Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the erbB family of receptor tyrosine kinases that are involved in the signal transduction steps which lead to the proliferation of tumour cells. In particular, it is believed that the compounds of the present invention provide an anti-tumour effect by way of inhibition of EGF receptor tyrosine kinase.

Generally the compounds of the present invention possess potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibition of EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other kinases, such as VEGF and KDR receptor tyrosine kinases. Furthermore, the compounds of the present invention possess substantially better potency against the EGFR tyrosine kinase over that of the erbB2 tyrosine kinase. Accordingly, it may be possibie to administer a compound according to the present invention at a dose that is sufficient to inhibit

EGFR tyrosine kinase whilst having no significant effect upon erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by EGFR tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases.

According to a first aspect of the invention there is provided a quinazoline derivative of the Formula I

Bm " HN

Ww), SN py JL

Q' +0 N zz x wherein:

R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula :

Q-X’- wherein X? is a direct bond or is O, and Q? is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of a group selected from O,

S, SO, SO, N(R), CO, CH(OR?), CON(R?), NR?)CO, SO.N®R?), N(R*)SO,, CH=CH and

C=C wherein R® is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R' substituent optionally bears at the terminal CH,= or HC= position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoy], amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula :

Q*-x*- wherein X*is a direct bond or is selected from CO and N(R*CO, wherein R* is hydrogen or (1-6C)alkyl, and Q’ is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH; or CH; group within a R! substituent, other than a CH, group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (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.N-di-[(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,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: -X5-Q* wherein X® is a direct bond or is selected from O, S, SO, S02, N(R), CO, CH(OR’),

CONQY), NR*)CO, SONR?), NR*)SO,, CR®)0, C®R®),S and CR®),N(R®), wherein R® is hydrogen or (1-6C)alkyl, and Q* is (3-7C)cycloalkyl, (3-7C)cycloalkyl- (1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, 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.N-di-[(1-6C)alkyl}carbamoyl, N-(1-6C)alkylsulfamoyl,

N.N-di-[(1-6C)alkyl]sulfamoy], (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,

N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl,

N.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: -X%-R® wherein X%is a direct bond or is selected from O, NR") and C(O), wherein R” is hydrogen or (1-6C)alkyl, and R® is halogeno-(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.N-di-{(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl,

and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo or thioxo substituents; bis1,2,3,40r5; each R?, which may be the same or different, i8 selected from halogeno, 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)atkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N.N-di-[(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.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulphonylamino, N-(1- 6C)alkyl-(1-6C)alkanesulphonylamino and a group of the formula: -X"-R® wherein X is a direct bond or is selected from O and N(R®), wherein R” is hydrogen or (1- 6C)alkyl, and R® is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6Calkyl, ~~ } cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1- ) 6C)alkylJamino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1- i 6C)alkoxycarbonylamino-(1-6C)alkyl;

Q'is a4, 5, 6 or 7 membered saturated or partially unsaturated monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or 2 additional : heteroatoms selected from O, S and N, and which ring is linked to the oxygen atom in {

Formula I by a ring carbon; h ais 0,1,2,3 0r4; each W, which may be the same or different, is selected from halogeno, 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 from a group of the formula: -XE-R10 wherein X® is a direct bond or is selected from O, CO, SO; and N(R"), wherein R" is hydrogen or (1-6C)alkyl, and R'? is halogeno-(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 or N.N-di-[(1-6C)alkyl}amino-(1-6C)alkyl;

X! is selected from CO and SO;

X2 is a group of the formula:

ACRR), (QM) (CRMR®)- whereinmisOor1,pis0,1,2,30r4andqisO0,1,2,3 or 4, cach of R'2, RY, R™ and R™, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl}amino, and Q’is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH; or CH; group within an X? group, optionally bears on each said

CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-{(1-6C)alkyl]amino;

Z is selected from hydrogen, hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyi]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:

Q*-X- wherein X° is a direct bond or is selected from O, NR'®), SO, and SON(R'®), wherein RS is hydrogen ar (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X® is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, $0,, NR"), CO, -C=C- and -C=C- wherein R" is hydrogen or (1-6C)alkyl, and wherein and wherein any CH; or CH; group within any Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alky! substituents 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,

N-(1-6C)alkylcarbamoyl, N.N-di-[(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.N-di-[(1-6C)alkyl}sulfamoyl, (1-6C)alkanesulfonylamino and

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, 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 from a group of the formula: -x10-R® wherein X'° is a direct bond or is selected from O, CO, SO; and NR"), wherein R'is hydrogen or (1-4C)alkyl, and R'® is halogeno-(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 and N.N-di-[(1-4C)alkylJamino-(1-4C)alkyl, and wherein any heterocyclyl group within a Z substituent optionally bears 1 or 2 oxo substituents, provided that said oxo substituent(s) is not on a ring carbon which is adjacent to a ring oxygen in the heterocyclyl group; provided that: @) when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro- 2-flucroanilino, R! is hydrogen ar (1-3C)alkoxy, and X' is CO, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}jamino, (1-6C)alkoxy, (1- 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q°-X’-; and (ii) when Q' is piperidiny}, Z is hydrogen; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.

According to another 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 wherein R', R%, W, X', X, a and b are as hereinbefore defined; and

Z is selected from hydrogen, hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:

Q*X- wherein X° is a direct bond or is selected from O, N(R'®), SO; and SO,NR'®), wherein R' is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X® is a direct bond, Q° is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO,

S04, NR"), CO, -C=C- and -C=C- wherein R"” is hydrogen or (1-6C)alkyl, and wherein and wherein any CH; or CH; group within any Z group, other than a CH group within a heterocyclyl ring, optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alkyl substituents 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)alkyljamino,

N-(1-6C)alkylcarbamoy], N.N-di-{(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.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkyithio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: — xi RY? wherein X'° is a direct bond or is selected from O, CO, SO; and N(R'®), wherein R" is hydrogen or (1-4C)alkyl, and R" is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4Calkyl,

N-(1-4C)alkylamino-(1-4C)alkyl and N.N-di-[(1-4C)alkyljamino-(1-4C)alkyl; provided that: @ when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro- 2-fluoroanilino, R! is hydrogen or (1-3C)alkoxy, and X! is CO, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1- 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q%-X°-; and (ii) when Q! is piperidinyl, Z is hydrogen.

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 both straight-chain and branched-chain 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 individual alkyl groups such as “propyl” are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only and references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-[(1-6Calkyljamino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

Jt is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. It is further to be understood that in the names of chiral compounds (R,S) denotes any scalemic or racemic mixture while (R) and (S) denote the enantiomers. In the absence of (R.S), (R) or (5) in the name it is to be understood that the name refers to any scalemic or racemic mixture, wherein a scalemic mixture contains

R and S enantiomers in any relative proportions and a racemic mixture contains R and § enantiomers in the ratio 50:50. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.

Suitable values for the generic radicals referred to above include those set out below.

A suitable value for any one of the ‘Q’ groups (for example Q% Q* or Q% when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a ‘Q’ or R group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for any one of the ‘Q’ groups (for example Q?, Q* or Q°) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a ‘Q’ group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It is to be understood that reference to (3-7C)cycloalkylene used herein for Q’ refers to a divalent (3-7C)cycloalkane linking group, which group may be linked via different carbon atoms in the (3-

7C)cycloalkylene ring, or which may be linked via a single carbon atom in the (3- 7C)cycloalkylene ring. Accordingly, reference to, for example, & “cyclopropylene” group includes cycloprop-1,2-ylene and a cyclopropylidene group of the formula: x

However references to an individual (3-7C)cycloalklene group such as cyclopropylidene are specific for that group only. A silmilar convention is adopted for the (3-7C)cycloalkenylene groups represented by Q’.

A suitable value for any one of the ‘Q’ groups (for example Q*, Q’, Q* or Q%) when it is heterocyclyl or for the heterocyclyl group within a ‘Q’ group is a non-aromatic saturated (i.e. ring systems with the maximum degree of saturation) or partially saturated (i.e. ring systems retaining some, but not the full, degree of unsaturation) 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, which, unless specified otherwise, may be carbon or nitrogen linked, for example oxiranyl, oxetanyl, azetidinyl, tetrahydrofurany, 1,3-dioxolanyl, tetrahydropyranyl, 1.4- dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, : 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, : tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl, particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyl, thiamarpholinyl 1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidiny! or piperazinyl, more particularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrothien -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. A nitrogen or sulphur atom within a heterocyclyl group may be oxidized to give the corresponding N or S oxide, for example 1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for Q' is a non-aromatic saturated or partially saturated 4 to 7 membered monocyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, provided at least one heteroatom is nitrogen, which ring is carbon linked to the oxygen atom in Formula 1. Suitable values include, for example, those heterocyclic groups mentioned above that contain at least one nitrogen atom, for example azetidinyl, pyrrolinyl, pyrrolidinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidiny), tetrahydropyrimidinyl, decahydroisoquinolinyl or decahydroquinolinyl.

Particular values for Q' is a carbon linked non-aromatic 4, 5, 6 or 7 membered monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or 2 further heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclyl group may be fully saturated or partially saturated. More particularly Q' is a carbon linked 4, 5 or 6 membered monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 further heteroatom selected from oxygen, nitrogen and sulfur, which heterocyclyl group may be partially saturated or preferably fully saturated. Still more particularly Q'is a carbon linked monocyclic fully saturated 4, 5 or 6 membered monocyclic heterocyclyl group containing 1 nitrogen heteroatom. Suitable values of such groups represented by Q! include the appropriate heterocyclyl groups listed above, more particularly azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl (all of which are linked to the oxygen atom in Formula I by a ring carbon), more particularly, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-y, and still more particularly azetidin-3-yl.

A suitable value for a ‘Q’ group when it is heterocyclyl-(1-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values for ‘Q’ groups when, for example, rather than a heterocyclyl-(1-6C)alkyl group, an (3-7C)cycloalkyl-(1-6C)alkyl or (3-7C)cycloalkenyl-(1-6C)alkyl is present.

Suitable values for any of the ‘R’ groups ®R to R'%), W, or for various groups within a

X!, X? or Z group include:- for halogeno fluoro, chloro, bromo and iodo; for (1-6C)alkyl: 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)alkylsulphinyl: methylsulphinyl and ethylsulphinyl; for (1-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl; for (1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(1-6C)alkyljamino: dimethylamino, diethylamino, N-ethyl-

N-methylamino and diisopropylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butox ycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-cthylcarbamoyl and

N-propylcarbamoyl; for N.N-di-[(1-6C)alkyl]carbamoyl: N.N-dimethylcarbamoyl, N-cthyl-

N-methylcarbamoyl and N.N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl, butyryl and isobuyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; for N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; for N-(1-6C)alkyisulphamoyl: N-methylsulphamoyl and N-ethylsulphamoyl; for N.N-di-[(1-6C)alkyl}sulphamoyl: ~~ N.N-dimethylsulphamoyl; for (1-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino; for N-(1-6C)alkyl-(1-6C)alkanesulphonylamino: N-methylmethanesulphonylamino and

N-methylethanesulphonylamino; for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; 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-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 halogeno-(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-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)alkylsulphinyl-(1-6C)alkyl: methylsulphinylmethyl, ethylsulphinylmethyl, 2-methyisulphinylethyl, 1-methyisulphinylethyl and

3-methylsulphinylpropyl;

for (1-6C)alkylsulphonyl-(1-6C)alkyl: methylsulphonylmethyl, ethylsulphonylmethyl, 2-methylsulphonylethyl, 1-methylsulphonylethyl and 3-methylsulphonylpropyl;

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

2-acetamidoethyl;

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

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

(2-6C)alkanoyloxy-(1-6C)alkyl: acetoxymethyl, 2-acetoxyethyl and 2- propionyloxyethyl; for carbamoyl-(1-6C)alkyl: cartbamoylmethyl, 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-di[(1-6C)alkyl}carbamoyl-(1-6C)alkyl: N.N-dimethylcarbamoylmethyl,

N.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; and for NN di-(1-6C)alkylsulfamoyl(1-6C)alkyl: N.N-dimethylsulfamoylmethyl,

N.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.

When, as defined hereinbefore Z in Formula I is a group of the formula Q%-X°-, and

X° is SO,N(R), the SO, group is attached to Q° and the nitrogen atom is attached to Xin

Formula I. The same convention is applied to other groups defined herein. For example when X? is a group of the formula Q*-(CR!*R"%)n, the Q° group is attached to the group Z in

Formula I and the (CR™R'),, group is attached to the X' group in Formula L

Claims (23)

1. A quinazoline derivative of the Formula I: je ; HN Ww), Dee: (Sr a! 0 N _ XN I wherein: R! is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula : Q*- x3 - wherein X> is a direct bond or is O, and Q? is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R* substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO,, NR), CO, CH(OR?), CONR?), NR*)CO, SO:NR?), NR*)SO,, CH=CH and C=C wherein R is hydrogen or (1-6C)alkyl, and wherein any CH,=CH- or HC=C- group within a R' substituent optionally bears at the terminal CH,= or HC= position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula : Q _ x* - wherein X*is a direct bond or is selected from CO and N(R*)CO, wherein R* is hydrogen or (1-6C)alkyl, and Q® is heterocyclyl or heterocyclyl-(1-6C)alkyl,

and wherein any CH, or CH; group within a R' substituent, other than a CH; group within a heterocyclyl ring, optionally bears on each said CHz or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyljamino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N.N-di-[(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,N-di-[{(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: -x-Q* wherein X® is a direct bond or is selected from O, S, SO, SO, N(R®), CO, CH(OR®), CONGR®), NR®)CO, SON’), NR*)SO2, CR®)0, CR*)S and CR’Y:NR’), wherein R’ is hydrogen ar (1-6C)alkyl, and Q* is (3-7C)cycloalkyl, (3-7C)cycloalkyl- (1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, 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.N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl,

N.N-di-[(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.N-di-[(1-6C)alkyl]sulfamoy], (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: -X5-RS wherein X%is a direct bond or is selected from O, N(R”) and C(O), wherein R’ is hydrogen or (1-6C)alkyl, and R® is halogeno-(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]lamino-(1-6C)alky], (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl,

EE. carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,

N.N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R! optionally bears 1 or 2 oxo or thioxo substituents; bisl,23,40rS; each R?, which may be the same or different, is selected from halogeno, 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,N-di-[(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.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulphonylamino, N-(1- 6C)alkyl-(1-6C)alkanesulphonylamino and a group of the formula: -X'-R® wherein X’ is a direct bond or is selected from O and N(R), wherein R® is hydrogen or (1- 6C)alkyl, and R® is halogeno-(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)alkyllamino«(1-6C)alkyl, (2-6C)alkanoylamino~(1-6C)alkyl or (1- 6C)alkoxycarbonylamino-(1-6C)alkyl; Q'is a4, 5, 6 or 7 membered saturated or partially unsaturated monocyclic heterocyclyl group containing 1 nitrogen heteroatom and optionally 1 or 2 additional heteroatoms selected from O, S and N, and which ring is linked to the oxygen atom in Formula I by a ring carbon; ais0,1,2,3 or 4; each W, which may be the same or different, is selected from halogeno, 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 from a group of the formula: -X*R!° wherein X* is a direct bond or is selected from O, CO, SO, and NR"), wherein R! is hydrogen or (1-6C)alkyl, and R' is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, I e———

(1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)atkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; X! is selected from CO and SO2; X? is a group of the formula: {CRR'),-(Q)-(CRMR®),- whereinmisOor1,pis0,1,2,3 or4 and qis 0,1,2,3 or4, each of R12, R%, R™* and RS, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q’is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene,

and wherein any CH; or CH; group within an X? group, optionally bears on each said CH, or CH; group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkylJamino;

Z is selected from hydrogen, hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino,

N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula:

Q*-X’- wherein X” is a direct bond or is selected from O, N(R'%), SO, and SON(R'), wherein R'® is hydrogen or (1-6C)alkyl, and Q° is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyi-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl,

provided that when X” is a direct bond, Q° is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO,

SO; NR), CO, -C=C- and -C=C- wherein R"” is hydrogen or (1-6C)alkyl,

and wherein and wherein any CH; or CH; group within any Z group, other than a CH; group within a heterocyclyl ring, optionally bears on each said CH; or CH; group one or more halogeno or (1-6C)alkyl substituents 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,

N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,

Le N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, 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 from a group of the formula: _ x10- R wherein X'° is a direct bond or is selected from O, CO, SO; and NR™®), wherein R" is hydrogen or (1-4C)alkyl, and R'® is halogeno-(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 and N.N-di-[(1-4C)alkyl]amino-(1-4C)alky], and wherein any heterocyclyl group within a Z substituent optionally bears 1 or 2 oxo substituents, provided that said oxo substituent(s) is not on a ring carbon which is adjacent to a ring oxygen in the heterocyclyl group; provided that: i) when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro- 2-fluoroanilino, R' is hydrogen or (1-3C)alkoxy, and X! is CO, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1- 6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q%-X°-; and (ii) when Q! is piperidinyl, Z is hydrogen; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.

2. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R', R%, W, X", X% a and b are as defined in claim 1; and Z is selected from hydrogen, hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: Q-X>- I ———

wherein X° is a direct bond or is selected from O, N(R'®), SO; and SONR'), wherein R'® is hydrogen or (1-6C)alkyl, and Q%is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1 -4C)alkyl, (3-7 C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl,

provided that when X? is a direct bond, Q° is heterocyclyl,

and provided that when m, p and q are all 0, then Z is heterocyclyl,

and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO,, NR), CO, -C=C- and -C=C- wherein RY is hydrogen or (1-6C)alkyl,

and wherein and wherein any CH; or CH; group within any Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH; or CH3 group one Or more halogeno or (1-6C)alkyl substituents 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)alkyljamino,

N-(1-6C)alkylcarbamoyl, N.N-di-[(1-6C)alkylJcarbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N.N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,

and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, 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 from a group of the formula: — x10- R! 8 wherein X'? is a direct bond or is selected from O, CO, SO; and NR'®), wherein R" is hydrogen or (1-4C)alkyl, and R*? is halogeno-(14C)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 and N.N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: (i) when the 4-anilino group in Formula Iis 4-bromo-2-fluoroanilino or 4-chloro- 2-fluoroanilino, R! is hydrogen or (1-3C)alkoxy, and X! is CO, then ais 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-

6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q°-X-; and (ii) when Q' is piperidiny}, Z is hydrogen.

3. A quinazoline derivative of the Formula 1, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 or claim 2 wherein: R! is selected from 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, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R' substituent are optionally separated by the insertion into the chain of an O atom, and wherein any CH; or CH; group within a R! substituent optionally bears on each said CH, or CH; group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (1-3C)alkoxy.

4. 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 R! is (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: bis 1,2 o0r3; and cach R?, which may be the same or different, is selected from fluoro, chloro, bromo, 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: bis 1or2 and onc R? is at the meta (3-) position on the anilino group in Formula 1 and is chloro or bromo.

7. A quinazoline derivative of the Formula], 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 Formula I is selected from 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: X2 is selected from a group of the formula —CH;-, -CH,CHa-, ~(CHR'®)-, - (CHR™CH;)-, CR "™),CHz)-, (CH,C(R'™)z)- and -(CH,CBR'*)-, wherein each R'?, which may be the same or different, is (1-4C)alkyl.

9. 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: Q! is azetidin-3-yl; aigsQorl; and W is (1-3C)alkyl.

10. 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, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2- 4C)alkoxy), and the sum of m +p+q is at least 1.

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 X' is CO.

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 the group Z-X>-X! is selected from hydroxy-(2-4C)alkanoyl and (1-4C)alkoxy-(2- 4C)alkanoyl.

13. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 of the Formula Ib: SN Yio z—x" Ib wherein: R™ is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2- 4C)alkoxy or from a group of the formula: Q@-x’- wherein X3 is O, and Q? is 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; X? ig selected from a group of the formula —CH;-, -CH;CH,-, (CHR '?)-, - (CHR'*CH,)- and -(CH,CHR"%)- wherein R'? is selected from (1-3C)alkyl, hydroxy-(1-3C)alky! and (1-3C)alkoxy- (1-3C)alkyl; and Z%is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy and (1-3C)alkoxy-(2- 3C)alkoxy.

14. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R' is (1-4C)alkoxy; bis1or2; each R?, which may be the same or different, is selected from fluoro, chloro, bromo and ethynyl; Q! is azetidin-3-yl; ais 0; W is (1-3C)alkyi; X'is CO;

x? is selected from a group of the formula (CHR '2)-, —(CHR'™CH,)- and - (CH,CHR'*)-, wherein R'* is (1-4C)alkyl; Z is selected from hydroxy and (1-4C)alkoxy, or 7X2 is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, which is linked to X! by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl.

15. A quinazoline derivative of the Formula I according to claim 1 selected from: 7-[(1-acetylpiperidin-4-yljoxy]-N-3-chloro-2-flucrophenyl)-6-methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1 -(methylsulfonyl)piperidin4- ylJoxy }quinazolin-4-amine; (25)-1-[3({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl joxy)azetidin-1-yl}-1- oxopropan-2-ol; (2R)-1-[3-({4-[3-chloro-2-fluoroanilino}-6-methox yquinazolin-7-yl }oxy)ezetidin-1-yl]-1- oxopropan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{ [(3R)-1 -(methoxyacetyl)pyrrolidin-3- ylloxy}quinazolin-4-amine; 2-[(3R)-3-({4-[3-chloro-2-fluaroanilin]-6-methox yquinazolin-7-yl }oxy)pyrrolidin-1-yl}-2- oxoethanol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({ 3R)- 1-[(2-methoxyethoxy)acetyl]pyrrolidin-3- yl }oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{ [(3R)-1-(3-methoxypropanoyl)pyrrolidin-3- ylJoxy }quinazolin-4-amine; 3-[(3R)-3-({4-[3-chloro-2-flucroanilino]-6-methoxyquinazolin-7-yl }oxy)pyrrolidin-1-yl]-3- oxopropan-1-ol; and 5-{[4~({4-[3-chloro-2-flucroanilino]-6-methoxyquinazolin-7 -yl}oxy)piperidin-1- yl]carbonyl}pyrrolidin-2-one; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof.

16. A quinazoline derivative of the Formula I according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition which comprises a quinazoline derivative of the S Formulal,ora pharmaceutically acceptable salt or, a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, in association with a pharmaceutically-acceptable diluent or carrier. :

18. A quinazoline derivative of the Formula L, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 16, for use as a medicament.

19. Use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 16 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human.

20. Use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 16 in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of EGFR tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation of tumour cells.

21. Use of a quinazoline derivative of the Formula L, ora pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 16 in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human.

22. Use of a quinazoline derivative of the Formula, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 16 in the manufacture of a medicament for use in the treatment of a cancer in a warm-blooded animal such as a human.

PCT/GB2004/003915

.

23. A process for the preparation of a quinazoline derivative of the Formula | as defeined in Claim 1 which comprises: Process (a): for the preparation of compounds of the Formula I wherein X' is CO, the coupling of a quinazoline of the formula II or a salt thereof:

JR . HN (W), Dee: > 5% HN II wherein R!, R%, W, a, b and Q! are as defined in claim 1, except that any functional group is protected if necessary, with an acid of the formula III, or a reactive derivative thereof: Z-X*-COOH In wherein Z, X' and X? are as defined in claim 1, except that any functional group is protected if necessary; or Process (b) the reaction of a quinazoline of the formula IT or a salt thereof, as defined in relation to Process (a), with a compound of the formula IV: z-x-x'-L! Iv wherein L' is a displaceable group and Z, X' and X? are as defined in claim 1, except that any functional group is protected if necessary; or Progess (c) for the preparation of those quinazoline derivatives of the Formula wherein Z is linked to X? by nitrogen, the reaction of a compound of the formula V: AMENDED SHEET joi HN R!

W). SN poy Q! 0] N HN 1 wherein R!, R%, W, a, b and Q' are as defined in claim 1, except that any functional - group is protected if necessary, with an acid of the formula III, or a reactive derivative thereof: Z-X’-COOH m wherein Z, X' and X? are as defined in claim 1, except that any functional group is protected if necessary; or Process (b) the reaction of a quinazoline of the formula II or a salt thereof, as defined in relation to Process (a), with a compound of the formula I'V: zx:x'-L Iv wherein L! is a displaceable group and Z, X' and X* are as defined in claim 1, except that any functional group is protected if necessary; or Process (¢) for the preparation of those quinazoline derivatives of the Formula I wherein Z is linked to X? by nitrogen, the reaction of a compound of the formula V:

HN We “Or N Catt a! 0 N L2—xe-x-N A wherein L.2 is a displaceable group and R', R%, W, X', X’, a,b and Q' are as defined in claim 1, except that any functional group is protected if necessary, with a compound of the formula ZH, wherein Z is as hereinbefore defined, except that any functional group is protected if necessary; or Process (d) for the preparation of those quinazoline derivatives which carry a mono- or di-(1-

6C)alkylamino group, the reductive amination of the corresponding quinazoline derivative of the Formula I which contains an N-H group using formaldehyde or a (2-6C)alkanolaldehyde; or Process (e)

for the production of those quinazoline derivatives of the Formula I wherein R'is hydroxy, the cleavage of a quinazoline derivative of the Formula I wherein Rlisa(l- 6C)alkoxy group; or Process (f)

for the production of those quinazoline derivatives of the Formula I wherein R' is linked to the quinazoline ring by an oxygen atom, by coupling a compound of the Formula

VI: